miR-7160 inhibits gastric cancer cell proliferation and metastasis by silencing SIX1.

Upregulation of homeoprotein SIX1 in gastric cancer (GC) is related to tumour proliferation and invasion. MicroRNA-7160 (miR-7160) is a homeoprotein SIX1-targeting miRNA that downregulates miR-7160, leading to cancer development. Total gastric cancer samples were collected from six patients, and relative expression levels of SIX1 mRNA and miRNAs were analysed by qRT-PCR. To evaluate the regulation of SIX1 by miR-7160, pGL3-SIX1-mut, pGL3-SIX1, and miR-7160 mimics transfected into cells using lipofectamine 2000. After transfection, proliferation and apoptosis in cultured cells were assessed using the nuclear TUNEL staining and CCK8 reagent, respectively. We demonstrated that the downregulation of miR-7160 in human gastric cancer cells is related to the upregulation of SIX1 mRNA. In gastric cancer cell lines, miR-7160 overexpression could downregulate the expression and inhibit cancer cell proliferation and growth in vitro. However, overexpression of miR-7160 did not increase gastric cancer cell apoptosis. In vitro downregulation of SIX1 decreased vimentin, N-cadherin, and other EMT-related gene expression and increased E-cadherin expression. In brief, miR-7160, by targeting SIX1, inhibits gastric cancer proliferation and cell growth in vitro, which provides an idea for introducing a new treatment option for gastric cancer.

TLR2/NF-кB signaling may control expansion and function of regulatory T cells in patients with severe fever with thrombocytopenia syndrome (SFTS).

Severe fever with thrombocytopenia syndrome (SFTS) is a recently identified infectious ailment triggered by a new strain of bunyavirus. It is distinguished by elevated fatality rates, ranging from 12 % to 30 %. The mechanism underlying the development of severe illness caused by SFTS bunyavirus (SFTSV) is not yet fully understood. To evaluate the role of the TLR2 receptor pathway in regulating Treg function in the progression of SFTS disease and possible mechanisms, sequential serum samples from 29 patients with SFTS (15 mild, 14 severe cases) were examined. Flow cytometry was employed to scrutinize the phenotypic and functional characteristics of TLR2 expression on circulating CD4 T cells, CD8 T cells, and Tregs. In all admitted patients, the evaluation of correlations between the frequencies of the aforementioned cells and SFTS index (SFTSI) was conducted. For SFTS, the levels of TLR2 on CD4 T cells and Tregs were significantly heightened when compared to those in healthy subjects. Additionally, the expression of TLR2 on Tregs exhibited a positive correlation with Ki-67 expression in Tregs and the severity of disease. Additionally, compared with those in uninfected controls, the expression levels of NF-κB in Tregs were significantly increased. Collectively, Tregs may be activated and proliferate through the stimulation of the TLR2/NF-кB pathway in reaction to SFTSV infection.

Brain organoid maturation and implantation integration based on electrical signals input.

INTRODUCTION: Brain organoids are believed to be able to regenerate impaired neural circuits and reinstate brain functionality. The neuronal activity of organoids is considered a crucial factor for restoring host function after implantation. However, the optimal stage of brain organoid post-transplantation has not yet been established. External electrical signal plays a crucial role in the physiology and development of a majority of human tissues. However, whether electrical input modulates the development of brain organoids, making them ideal transplant donors, is elusive. METHODS: Bioelectricity was input into cortical organoids by electrical stimulation (ES) with a multi-electrode array (MEA) to obtain a better-transplanted candidate with better viability and maturity, realizing structural-functional integration with the host brain. RESULTS: We found that electrical stimulation facilitated the differentiation and maturation of organoids, displaying well-defined cortical plates and robust functional electrophysiology, which was probably mediated via the pathway of calcium-calmodulin (CaM) dependent protein kinase II (CAMK II)-protein kinase A (PKA)-cyclic-AMP response binding protein (pCREB). The ES-pretreated D40 organoids displayed superior cell viability and higher cell maturity, and were selected to transplant into the damaged primary sensory cortex (S1) of host. The enhanced maturation was exhibited within grafts after transplantation, including synapses and complex functional activities. Moreover, structural-functional integration between grafts and host was observed, conducive to strengthening functional connectivity and restoring the function of the host injury. CONCLUSION: Our findings supported that electrical stimulation could promote the development of cortical organoids. ES-pretreated organoids were better transplanted donors for strengthening connectivity between grafts and host. Our work presented a new physical approach to regulating organoids, potentially providing a novel translational strategy for functional recovery after brain injury. In the future, the development of 3D flexible electrodes is anticipated to overcome the drawbacks of 2D planar MEA, promisingly achieving multimodal stimulation and long-term recordings of brain organoids.

The Expression and Clinical Significance of USF1 in Newly Diagnosed Acute Myeloid Leukemia.

BACKGROUND: This study aimed to assess the expression level of upstream stimulator 1 (USF1) in the bone marrow of newly diagnosed acute myeloid leukemia (AML) patients and investigate its clinical and prognostic significance. METHODS: Bone marrow samples from 60 newly diagnosed AML patients constituted the observation group, while 20 samples from healthy individuals formed the control group. Real-time quantitative PCR (qRT-PCR) was used to measure the USF1 expression in both groups and to analyze its correlation with clinicopathological features and prognosis in AML patients. Kaplan-Meier curves were utilized to assess the impact of USF1 on the overall survival (OS) in AML patients. The prognostic factors of AML were examined by using Cox regression analysis. RESULTS: A univariate analysis revealed a significantly higher USF1 expression in the AML patients compared to the control group (p < 0.001), with no difference in the clinicopathological features between the low-expression group and the control group. However, there was a significant difference between the high-expression group and the control group (p < 0.01). Moreover, the OS of the high USF1 expression group was notably shorter than of the low USF1 expression group (p < 0.0001). A multivariate analysis identified high USF1 expression and age ≥ 60 years as independent risk factors for a poor AML prognosis. CONCLUSIONS: High expression of USF1 is linked to a worse prognosis and shorter survival time in AML patients. USF1 may serve as an indicator of prognosis and survival in AML patients and could be a potential target for AML treatment.

Dysregulation of myelination-related genes in schizophrenia.

Schizophrenic individuals display disrupted myelination patterns, altered oligodendrocyte distribution, and abnormal oligodendrocyte morphology. Schizophrenia is linked with dysregulation of a variety of genes involved in oligodendrocyte function and myelin production. Single-nucleotide polymorphisms (SNPs) and rare mutations in myelination-related genes are observed in certain schizophrenic populations, representing potential genetic risk factors. Downregulation of myelination-related RNAs and proteins, particularly in frontal and limbic regions, is consistently associated with the disorder across multiple studies. These findings support the notion that disruptions in myelination may contribute to the cognitive and behavioral impairments experienced in schizophrenia, although further evidence of causation is needed.

An insight into structure-activity relationships in subclass IIb bacteriocins: Plantaricin EvF.

This study reports the structure-activity relationships of a unique subclass IIb bacteriocin, plantaricin EvF, which consists of two peptide chains and possesses potent antimicrobial activity. Because the plantaricin Ev peptide chain lacks an α-helix structure, plantaricin EvF is unable to exert its antimicrobial activity through helix-helix interactions like typical subclass IIb bacteriocins. We have shown by various structural evaluation methods that plantaricin Ev can be stabilized by hydrogen bonding at amino acid residues R3, V12, and R13 to the N-terminal region of plantaricin F. This binding gives plantaricin EvF a special spade-shaped structure that exerts antimicrobial activity. In addition, the root-mean-square deviations (RMSDs) of the amino acid residues Y6, F8, and R13 of plantaricin Ev pre- and post-binding were 1.512, 1.723, and 1.369, respectively, indicating that they underwent large structural changes. The alanine scanning experiments demonstrated the important role of the above key amino acids in maintaining the structural integrity of plantaricin EvF. This study not only reveals the unique structural features of plantaricin EvF, but also provides an insight into the structure-activity relationships of subclass IIb bacteriocins.

How the perfectionistic climate of a sports team predicts the athletic performance of elite athletes: a case study of the CUBAL women's basketball team.

Objective: In competitive sports, understanding how the perfectionistic climate within teams influences the performance of elite female athletes can provide valuable insights for enhancing coaching practice and athletic achievement. Based on the cognitive appraisal theory of stress, this study constructs a dual-path model using stressors and coping strategies as mediators, referred to as the Perfectionistic Climate on Athletic Performance model (PCPM). The study explores the predictive role of the perfectionistic climate within sports teams on the athletic performance of elite female basketball players. Methods: The empirical study the relationships among the variables in the model using a sample of 125 core players from the top-level women's basketball teams in the 24th CUBAL24 tournament in 2022. A Structural Equation Modeling (SEM) analysis was conducted using AMOS 20.0, primarily employing the bias-corrected Bootstrap method to test the dual-path model. Results: The findings reveal double-edged paths towards a perfectionistic climate on athletic performance. In the positive pathway, a perfectionistic climate can positively predict athletic performance through challenge-related sources of stress and positive coping strategies. In the negative pathway, a perfectionistic climate can negatively predict athletic performance through threat-related sources of stress and negative coping strategies. Conclusion: Coaches need to pay attention to athletes' cognitive evaluations of the perfectionistic climate as a source of pressure. By setting challenging goals, coaches can guide athletes to view the perfectionistic climate of the sports team as a source of challenging pressure, thus unleashing their potential. Coaches should actively guide athletes in coping with the pressure brought about by the perfectionistic climate, enhancing their ability to handle stress. This will enable athletes to better adapt to the team's perfectionistic climate and further improve individual and team athletic performance.

Synergistic delivery of hADSC-Exos and antioxidants has inhibitory effects on UVB-induced skin photoaging.

Ultraviolet B (UVB) light exposure accelerates skin photoaging. Human adipose-derived stem cell exosomes (hADSC-Exos) and some antioxidants may have anti-photoaging effects. However, it is unknown whether the combination of hADSC-Exos and antioxidants plays a synergistic role in anti-photoaging. In cellular and 3D skin models, we showed that vitamin E (VE) and hADSC-Exos were optimal anti-photoaging combinations. In vivo, VE and hADSC-Exos increased skin tightening and elasticity in UVB-induced photoaging mice Combined treatment with VE and hADSC-Exos inhibited SIRT1/NF-κB pathway. These findings contribute to the understanding of hADSC-Exos in conjunction with other antioxidants, thereby providing valuable insights for the future pharmaceutical and cosmetic industries.

A comprehensive review on potential role of selenium, selenoproteins and selenium nanoparticles in male fertility.

Selenium (Se), a component of selenoproteins and selenocompounds in the human body, is crucial for the development of male reproductive organs, DNA synthesis, thyroid hormone, metabolism, and defence against infections and oxidative damage. In the testis, it must exceed a desirable level since either a shortage or an overabundance causes aberrant growth. The antioxidant properties of selenium are essential for preserving human reproductive health. Selenoproteins, which have important structural and enzymatic properties, control the biological activities of Se primarily. These proteins specifically have a role in metabolism and a variety of cellular processes, such as the control of selenium transport, thyroid hormone metabolism, immunity, and redox balance. Selenium nanoparticles (SeNPs) are less hazardous than selenium-based inorganic and organic materials. Upon being functionalized with active targeting ligands, they are both biocompatible and capable of efficiently delivering combinations of payloads to particular cells. In this review, we discuss briefly the chemistry, structure and functions of selenium and milestones of selenium and selenoproteins. Next we discuss the various factors influences male infertility, biological functions of selenium and selenoproteins, and role of selenium and selenoproteins in spermatogenesis and male fertility. Furthermore, we discuss the molecular mechanism of selenium transport and protective effects of selenium on oxidative stress, apoptosis and inflammation. We also highlight critical contribution of selenium nanoparticles on male fertility and spermatogenesis. Finally ends with conclusion and future perspectives.

KMT2D mutations promoted tumor progression in diffuse large B-cell lymphoma through altering tumor-induced regulatory T cell trafficking via FBXW7-NOTCH-MYC/TGF-ß1 axis.

Histone methyltransferase KMT2D is one of the most frequently mutated genes in diffuse large B-cell lymphoma (DLBCL) and has been identified as an important pathogenic factor and prognostic marker. However, the biological relevance of KMT2D mutations on tumor microenvironment remains to be determined. KMT2D mutations were assessed by whole-genome/exome sequencing (WGS/WES) in 334 patients and by targeted sequencing in 427 patients with newly diagnosed DLBCL. Among all 761 DLBCL patients, somatic mutations in KMT2D were observed in 143 (18.79%) patients and significantly associated with advanced Ann Arbor stage and MYC expression ≥ 40%, as well as inferior progression-free survival and overall survival. In B-lymphoma cells, the mutation or knockdown of KMT2D inhibited methylation of lysine 4 on histone H3 (H3K4), downregulated FBXW7 expression, activated NOTCH signaling pathway and downstream MYC/TGF-ß1, resulting in alterations of tumor-induced regulatory T cell trafficking. In B-lymphoma murine models established with subcutaneous injection of SU-DHL-4 cells, xenografted tumors bearing KMT2D mutation presented lower H3K4 methylation, higher regulatory T cell recruitment, thereby provoking rapid tumor growth compared with wild-type KMT2D via FBXW7-NOTCH-MYC/TGF-ß1 axis.

Prenatal Diagnosed Agenesis of the Corpus Callosum: Identifying the Underlying Genetic Etiologies.

OBJECTIVE: To assess the genetic etiologies underlying agenesis of the corpus callosum (ACC) and its pregnancy outcomes in the era of next-generation sequencing. METHODS: A retrospective analysis was conducted on prospectively collected prenatal ACC cases in which amniocentesis was performed between January 2016 and December 2022. ACC was divided into non-isolated and isolated according to the presence or absence of ultrasound abnormalities. Chromosomal microarray analysis (CMA), karyotyping and exome sequencing (ES) were performed after genetic counseling. Pregnancy outcomes were assessed by pediatric neurosurgeons and were followed up by telephone through their parents. RESULTS: Sixty-eight fetuses with ACC were enrolled in this study. CMA detected eight cases with pathogenic copy number variants (CNVs) and all were non-isolated ACC, with a detection rate of 11.8% (8/68). Among the CMA abnormalities, the majority (6/8) were detectable by karyotyping. ES was performed in 26 cases with normal CMA, revealing pathogenic or likely pathogenic gene variations in 12 cases (46.2%, 12/26), involving L1CMA, SMARCB1, PPP2R1A, ARID1B, USP34, CDC42, NFIA and DCC genes. The detection rates of ES in isolated and non-isolated ACC were 40% (6/15) and 54.5% (6/11), respectively. After excluding cases where pregnancy was terminated (56 cases), there were 12 live births, ranging in age from 15 months to 7 years. Of these, 91.7% (11 out of 12) demonstrated normal neurodevelopmental outcomes. Specifically, all five cases with isolated ACC and negative ES results exhibited normal neurodevelopment. The remaining six cases with favorable outcomes were all isolated ACC, among which ES identified variants of DCC and USP34 gene in one each case. The other four cases were CMA-negative and declined ES. CONCLUSIONS: We highlight the efficacy of prenatal ES in determining the genetic etiology of ACC, whether isolated or not. Favorable neurodevelopmental outcomes were observed when ACC was isolated and with normal ES results.

LncRNA KCNQ1OT1 promotes NLRP3 inflammasome activation in Parkinson's disease by regulating pri-miR-186/mature miR-186/NLRP3 axis.

Increasing evidence indicated that neuroinflammation was involved in progression of Parkinson's disease (PD). Long noncoding RNAs (lncRNAs) played important roles in regulating inflammatory processes in multiple kinds of human diseases such as cancer diabetes, cardiomyopathy, and neurodegenerative disorders. The mechanisms by which lncRNAs regulated PD related inflammation and dopaminergic neuronal loss have not yet been fully elucidated. In current study, we intended to explore the function and potential mechanism of lncRNA KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1) in regulating inflammasome activation in PD. Functional assays confirmed that knockdown of KCNQ1OT1 suppress microglial NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and attenuated dopaminergic neuronal loss in PD model mice. As KCNQ1OT1 located in both cytoplasm and nucleus of microglia, we demonstrated that KCNQ1OT1 promoted microglial NLRP3 inflammasome activation by competitive binding with miR-186 in cytoplasm and inhibited pri-miR-186 mediated NLRP3 silencing through recruitment of DiGeorge syndrome critical region gene 8 (DGCR8) in nucleus, respectively. Our study found a novel lncRNA-pri-miRNA/mature miRNA-mRNA regulatory network in microglia mediated NLRP3 inflammasome activation and dopaminergic neuronal loss, provided further insights for the treatment of Parkinson's disease.

Transcriptomic analyses reveals a diverse venom composition in Agelena limbata (Araneae: Agelenaidae).

Spider venom is a natural source of diverse biomolecules, but due to technical limitations, only a small fraction has been studied. With the advancement of omics technologies, research on spider venom has broadened, greatly promoting systematic studies of spider venom. Agelena limbata is a common spider found in vegetation, known for constructing funnel-shaped webs, and feeding on insects such as Diptera and Homoptera. However, due to its small size and the difficulty in obtaining venom, the composition of Agelena limbata venom has never been studied. In this study, a transcriptomics approach was used to analyze the toxin components in the venom of Agelena limbata, resulting in the identification of 28 novel toxin-like sequences and 24 peptidases. Based on sequence similarity and differences in cysteine motifs, the 28-novel toxin-like sequences were classified into 10 superfamilies. According to the results annotated in the database, the 24 peptidases were divided into six distinct families, with the serine protease family being the most common. A phylogenetic tree was constructed using the toxin-like sequences of Agelena limbata along with Psechrus triangulus and Hippasa lycosina. An analysis of the structural domains and motifs of Agelena limbata was also conducted. The results indicated that Agelena limbata is more distantly related to the other two species of funnel-web spiders, and that the toxin superfamily IX has a unique function compared to the other superfamilies. This study reveals the components of the Agelena limbata venom, deepening our understanding of it, and through bioinformatics analysis, has identified unique functions of the toxin superfamilies, providing a scientific basis for the development of bioactive drugs in the future.

Revealing the optimal traditional processing methods and its protective effects against febrile seizures of Arisaema cum bile.

Arisaema cum bile (known as Dan Nanxing in Chinese, DNX) is a herbal medicine used for treating febrile seizure (FS), which commonly prepared by using Arisaematis Rhizoma and animal bile. This study was designed to explore the optimal processing time of DNX and its potential mechanism on the anti-FS effect. A total of 17 volatile organic compounds (VOCs) were the characteristic ones to distinguish different fermentation stages of DNX by using gas chromatography-ion mobility spectrometry (GC-IMS), such as 2-heptanone monomer, and heptanal monomer. DNX with fermentation for 3 months had an obvious pattern of VOCs with others, which could be regarded as the optimal fermentation time. The Enterococcus and Staphylococcus might be the core bacteria on the production of VOCs. Additionally, DNX (2.8 g/kg, p.o.) reversed hot water bath-induced FSs of rats, as indicated by increased seizure latency and decreased seizure duration time. It also prevented hippocampal neuronal loss, increased GABAAR, and decreased GRIA1 expression. At the genus level, relative abundance of Enterococcus and Akkermansia were enriched after DNX treatment. These findings suggested that fermentation for 3 months might be the optimal process time for DNX, and DNX possess an anti-FS effect through regulating neurotransmitter disorder and gut microbiota.

Acupuncture Modulation of Chronic Neuropathic Pain and Its Association With Brain Functional Properties.

Chronic neuropathic pain has been one of the prominent causes of disability, and acupuncture has shown promise in treatment. The present study aimed to characterize acupuncture modulation of chronic neuropathic pain and explore the related functional brain changes. Sixty chronic sciatica patients were divided into acupuncture- or sham acupuncture groups and received 10 sessions of treatment during 4 weeks. The visual analog scale for leg pain, oswestry disability index (ODI), and resting-state functional magnetic resonance images were assessed at baseline and after treatment. Then, fractional amplitudes of low-frequency fluctuations (fALFF) and support vector regression analyses were performed. Compared with sham acupuncture, acupuncture significantly improved symptoms, including visual analog scale for leg pain and ODI. In addition, acupuncture exhibited increased fALFF of the right superior parietal lobule (SPL) and right postcentral gyrus. Furthermore, the actual 4-week ODI values were positively correlated with the support vector regression-predicted values based on the right SPL fALFF and baseline clinical measurements. These results indicate that the spontaneous neural activity of the right SPL and right postcentral gyrus may be involved in the modulation of acupuncture in chronic neuropathic pain. In addition, the spontaneous neural activity of the right SPL might be used as the predictor of response to acupuncture therapy. PERSPECTIVE: This clinical neuroimaging study elucidated the neural basis of acupuncture in chronic sciatica. Neurological indicators and clinical measurements could be used as potential predictors of acupuncture response. This study combines neuroimaging and artificial intelligence techniques to highlight the potential of acupuncture for the treatment of chronic neuropathic pain. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry, ChiCTR2100044585, http://www.chictr.org.cn.

Dysbiosis promotes recurrence of adenomatous polyps in the distal colorectum.

BACKGROUND: Colorectal polyps, which are characterized by a high recurrence rate, represent preneoplastic conditions of the intestine. Due to unclear mechanisms of pathogenesis, first-line therapies for non-hereditary recurrent colorectal polyps are limited to endoscopic resection. Although recent studies suggest a mechanistic link between intestinal dysbiosis and polyps, the exact compositions and roles of bacteria in the mucosa around the lesions, rather than feces, remain unsettled. AIM: To clarify the composition and diversity of bacteria in the mucosa surrounding or 10 cm distal to recurrent intestinal polyps. METHODS: Mucosal samples were collected from four patients consistently with adenomatous polyps (Ade), seven consistently with non-Ade (Pol), ten with current Pol but previous Ade, and six healthy individuals, and bacterial patterns were evaluated by 16S rDNA sequencing. Linear discriminant analysis and Student's t-tests were used to identify the genus-level bacteria differences between groups with different colorectal polyp phenotypes. Pearson's correlation coefficients were used to evaluate the correlation between intestinal bacteria at the genus level and clinical indicators. RESULTS: The results confirmed a decreased level of probiotics and an enrichment of pathogenic bacteria in patients with all types of polyps compared to healthy individuals. These changes were not restricted to the mucosa within 0.5 cm adjacent to the polyps, but also existed in histologically normal tissue 10 cm distal from the lesions. Significant differences in bacterial diversity were observed in the mucosa from individuals with normal conditions, Pol, and Ade. Increased abundance of Gram-negative bacteria, including Klebsiella, Plesiomonas, and Cronobacter, was observed in Pol group and Ade group, suggesting that resistance to antibiotics may be one risk factor for bacterium-related harmful environment. Meanwhile, age and gender were linked to bacteria changes, indicating the potential involvement of sex hormones. CONCLUSION: These preliminary results support intestinal dysbiosis as an important risk factor for recurrent polyps, especially adenoma. Targeting specific pathogenic bacteria may attenuate the recurrence of polyps.

Molecular interactions of the chaperone CcmS and carboxysome shell protein CcmK1 that mediate ß-carboxysome assembly.

The carboxysome is a natural proteinaceous organelle for carbon fixation in cyanobacteria and chemoautotrophs. It comprises hundreds of protein homologs that self-assemble to form a polyhedral shell structure to sequester cargo enzymes, ribulose 1,5-bisphosphate carboxylase/oxygenase (Rubisco) and carbonic anhydrases. How these protein components assemble to construct a functional carboxysome is a central question in not only understanding carboxysome structure and function but also synthetic engineering of carboxysomes for biotechnological applications. Here, we determined the structure of the chaperone protein CcmS, which has recently been identified to be involved in ß-carboxysome assembly, and its interactions with ß-carboxysome proteins. The crystal structure at 1.99 Å resolution reveals CcmS from Nostoc sp. PCC 7120 forms a homodimer, and each CcmS monomer consists of five α-helices and four ß-sheets. Biochemical assays indicate that CcmS specifically interacts with the C-terminal extension of the carboxysome shell protein CcmK1, but not the shell protein homolog CcmK2 or the carboxysome scaffolding protein CcmM. Moreover, we solved the structure of a stable complex of CcmS and the C-terminus of CcmK1 at 1.67 Å resolution and unveiled how the CcmS dimer interacts with the C-terminus of CcmK1. These findings allowed us to propose a model to illustrate CcmS-mediated ß-carboxysome assembly by interacting with CcmK1 at the outer shell surface. Collectively, our study provides detailed insights into the accessory factors that drive and regulate carboxysome assembly, thereby improving our knowledge of carboxysome structure, function, and bioengineering.

Schisandra chinensis (Turcz.) Baill neutral polysaccharides alleviate Parkinson's disease via effectively activating MCL-1 expression regulation of autophagy signaling.

The purified neutral polysaccharide fraction, namely SBP-1, was isolated and characterized from Schisandra chinensis (Turcz.) Baill crude polysaccharides, which have anti-Parkinson's disease activity were investigated in vivo and in vitro. Experiments have shown that the main chain of SBP-1 was Glcp-(1→, →4)-Glcp-(1→ and →4,6)-Glcp-(1→. We also revealed the effect of SBP-1 on the PD mice model and the potential underlying molecular mechanism. The results showed that SBP-1 administration improved behavioral deficits, increased tyrosine hydroxylase-positive cells, attenuated loss of dopaminergic neurons in MPTP-exposed mice, and reduced cell death induced by MPP+. The MCL-1 was identified as the target of SBP-1 by the combination of docking-SPR-ITC, WB, and IF experiments. Subsequently, the study showed that SBP-1 could target MCL-1 to enhance autophagy with a change in the apoptotic response, which was further demonstrated by a change in LC3/P62, PI3K/AKT/mTOR, and possesses a change in the expression of BCL2/BAX/Caspase3. These results demonstrate that SBP-1 may protect neurons against MPP+ or MPTP-induced damage in vitro and in vivo through enhancing autophagy. In summary, these findings indicate that SBP-1 and S. chinensis show potential as effective candidates for further investigation in the prevention and treatment of PD or associated illnesses, specifically through autophagy apoptotic-based mechanisms.

Formation and Reduction of Toxic Compounds Derived from the Maillard Reaction During the Thermal Processing of Different Food Matrices.

Advanced glycation end products (AGEs), heterocyclic aromatic amines (HAAs), acrylamide (AA), 5-hydroxymethylfurfural (5-HMF), and polycyclic aromatic hydrocarbons (PAHs) are toxic substances that are produced in certain foods during thermal processing by using common high-temperature unit operations such as frying, baking, roasting, grill cooking, extrusion, among others. Understanding the formation pathways of these potential risk factors, which can cause cancer or contribute to the development of many chronic diseases in humans, is crucial for reducing their occurrence in thermally processed foods. During thermal processing, food rich in carbohydrates, proteins, and lipids undergoes a crucial Maillard reaction, leading to the production of highly active carbonyl compounds. These compounds then react with other substances to form harmful substances, which ultimately affect negatively the health of the human body. Although these toxic compounds differ in various forms of formation, they all partake in the common Maillard pathway. This review primarily summarizes the occurrence, formation pathways, and reduction measures of common toxic compounds during the thermal processing of food, based on independent studies for each specific contaminant in its corresponding food matrix. Finally, it provides several approaches for the simultaneous reduction of multiple toxic compounds.

Accurate identification of genes associated with brain disorders by integrating heterogeneous genomic data into a Bayesian framework.

BACKGROUND: Genome-wide association studies (GWAS) have revealed many brain disorder-associated SNPs residing in the noncoding genome, rendering it a challenge to decipher the underlying pathogenic mechanisms. METHODS: Here, we present an unsupervised Bayesian framework to identify disease-associated genes by integrating risk SNPs with long-range chromatin interactions (iGOAT), including SNP-SNP interactions extracted from ∼500,000 patients and controls from the UK Biobank, and enhancer-promoter interactions derived from multiple brain cell types at different developmental stages. FINDINGS: The application of iGOAT to three psychiatric disorders and three neurodegenerative/neurological diseases predicted sets of high-risk (HRGs) and low-risk (LRGs) genes for each disorder. The HRGs were enriched in drug targets, and exhibited higher expression during prenatal brain developmental stages than postnatal stages, indicating their potential to affect brain development at an early stage. The HRGs associated with Alzheimer's disease were found to share genetic architecture with schizophrenia, bipolar disorder and major depressive disorder according to gene co-expression module analysis and rare variants analysis. Comparisons of this method to the eQTL-based method, the TWAS-based method, and the gene-level GWAS method indicated that the genes identified by our method are more enriched in known brain disorder-related genes, and exhibited higher precision. Finally, the method predicted 205 risk genes not previously reported to be associated with any brain disorder, of which one top-risk gene, MLH1, was experimentally validated as being schizophrenia-associated. INTERPRETATION: iGOAT can successfully leverage epigenomic data, phenotype-genotype associations, and protein-protein interactions to advance our understanding of brain disorders, thereby facilitating the development of new therapeutic approaches. FUNDING: The work was funded by the National Key Research and Development Program of China (2024YFF1204902), the Natural Science Foundation of China (82371482), Guangzhou Science and Technology Research Plan (2023A03J0659) and Natural Science Foundation of Guangdong (2024A1515011363).