Single-nucleus analysis reveals microenvironment-specific neuron and glial cell enrichment in Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a complicated neurodegenerative disease. Neuron-glial cell interactions are an important but not fully understood process in the progression of AD. We used bioinformatic methods to analyze single-nucleus RNA sequencing (snRNA-seq) data to investigate the cellular and molecular biological processes of AD. METHOD: snRNA-seq data were downloaded from Gene Expression Omnibus (GEO) datasets and reprocessed to identify 240,804 single nuclei from healthy controls and patients with AD. The cellular composition of AD was further explored using Uniform Manifold Approximation and Projection (UMAP). Enrichment analysis for the functions of the DEGs was conducted and cell development trajectory analyses were used to reveal underlying cell fate decisions. iTALK was performed to identify ligand-receptor pairs among various cell types in the pathological ecological microenvironment of AD. RESULTS: Six cell types and multiple subclusters were identified based on the snRNA-seq data. A subcluster of neuron and glial cells co-expressing lncRNA-SNHG14, myocardin-related transcription factor A (MRTFA), and MRTFB was found to be more abundant in the AD group. This subcluster was enriched in mitogen-activated protein kinase (MAPK)-, immune-, and apoptosis-related pathways. Through molecular docking, we found that lncRNA-SNHG14 may bind MRTFA and MRTFB, resulting in an interaction between neurons and glial cells. CONCLUSIONS: The findings of this study describe a regulatory relationship between lncRNA-SNHG14, MRTFA, and MRTFB in the six main cell types of AD. This relationship may contribute to microenvironment remodeling in AD and provide a theoretical basis for a more in-depth analysis of AD.

Inhibitory activities and mechanisms of free and bound phenolics on α-glucosidase in fresh fruits of Phyllanthus emblica Linn. using spectroscopy and molecular docking.

Phyllanthus emblica Linn. (PE) fresh fruits contain high concentrations of polyphenolics, of which free and bound phenolics are rich in biological activities. In this study, the inhibitory activity and mechanism of PEFP and PEBP on α-glucosidase (α-GLU) were investigated using spectroscopic techniques, kinetic analysis, and molecular docking. The results showed that 13 PEFP and 12 PEBP were identified by UPLC-MS/MS analysis, and Bis-HHDP-hexose and castalagin (vesgalagin) were found for the first time in PE fresh fruits. Kinetic analysis of enzyme inhibition showed that a mixture of free and bound phenolics inhibited α-GLU, and the effect of the conformational relationship of PEFP and PEBP with α-GLU on hypoglycemia was further explored by fluorescence quenching, circular dichroism (CD) spectroscopy, and molecular docking analysis. The findings demonstrated the inhibitory activity and mechanism of free and bound phenolics on α-GLU and provided a theoretical basis for PE polyphenolics as α-GLU inhibitors for hypoglycemia.

Fabrication of zein-tamarind seed polysaccharide-curcumin nanocomplexes: their characterization and impact on alleviating colitis and gut microbiota dysbiosis in mice.

In this work, a zein-tamarind seed polysaccharide (TSP) co-delivery system was fabricated using an anti-solvent precipitation method. The formation mechanism, characterization, and effect on alleviating colitis and gut microbiota dysbiosis in mice of zein-TSP-curcumin (Z/T-Cur) nanocomplexes were investigated. Hydrogen bonding and the hydrophobic effect played a key role in the formation of Z/T-Cur nanocomplexes, and the interactions were spontaneous and driven by enthalpy. The encapsulation efficiency, loading capacity, and bioavailability increased from 60.8% (Zein-Cur) to 91.7% (Z/T-Cur1:1), from 6.1% (Zein-Cur) to 18.3% (Z/T-Cur1:1), and from 4.7% (Zein-Cur) to 20.0% (Z/T-Cur1:1), respectively. The Z/T-Cur significantly alleviated colitis symptoms in DSS-treated mice. Additionally, the prepared nanocomplexes rebalanced the gut microbiota composition of colitis mice by increasing the abundance of Akkermansia. Odoribacter and Monoglobus were rich in the Z-T-Cur treatment group, and Turicibacter and Bifidobacterium were rich in the zein-TSP treatment group. This study demonstrated that the TSP could be helpful in the targeted drug delivery system.

Single-cell and spatial transcriptomics reveals that PTPRG activates the m6A methyltransferase VIRMA to block mitophagy-mediated neuronal death in Alzheimer's disease.

Neuronal death is one of the key pathologies in Alzheimer's disease (AD). How neuronal death begins in AD is far from clear, so clarifying this process may help develop effective therapies. This study collected single-cell RNA sequencing data of 85 AD samples and 83 control samples, covering the prefrontal cortex, internal olfactory cortex, superior parietal lobe, superior frontal gyrus, caudal internal olfactory cortex, somatosensory cortex, hippocampus, superior frontal cortex and peripheral blood mononuclear cells. Additionally, spatial transcriptomic data of coronal sections from 6 AppNL-G-F AD mice and 6 control C57Bl/6 J mice were acquired. The main single-cell and spatial transcriptomics results were experimentally validated in wild type and 5 × FAD mice. We found that the microglia subpopulation Mic_PTPRG can communicate with specific types of neurons (especially excitatory ExNeu_PRKN_VIRMA and inhibitory InNeu_PRKN_VIRMA neuronal subpopulations) and cause them to express PTPRG during AD progression. Within neurons, PTPRG binds and upregulates the m6A methyltransferase VIRMA, thus inhibiting translation of PRKN mRNA to prevent the clearance of damaged mitochondria in neurons through suppressing mitophagy. As the disease progresses, the energy and nutrient metabolic pathways in neurons are reprogrammed, leading to their death. Consistently, we determined that PTPTRG can physically interact with VIRMA in mouse brains and PRKN is significantly upregulated in 5 × FAD mouse brain. Altogether, our findings demonstrate that PTPRG activates the m6A methyltransferase VIRMA to block mitophagy-mediated neuronal death in AD, which is a potential pathway, through which microglia and neuronal PTPRG modify neuronal connections in the brain during AD progression.

Tanshinone IIA is superior to paricalcitol in ameliorating tubulointerstitial fibrosis through regulation of VDR/Wnt/ß-catenin pathway in rats with diabetic nephropathy.

Glomerulosclerosis and tubulointerstitial fibrosis (TIF) are closely involved in the development of diabetic nephropathy (DN). Moreover, the development of TIF is closely related to epithelial-to-mesenchymal transition (EMT). Tanshinone IIA (Tan) has various pharmacological effects, especially the anti-fibrotic effect. And it is mainly used in the clinical treatment of cardiovascular diseases. Currently, the protective effect of Tan on DN and its possible mechanism have not been clearly elucidated. Our previous studies illustrated that Tan could improve the EMT of HK-2 cells induced by high glucose by regulating the vitamin D receptor (VDR)/Wnt/ß-catenin pathway. Here, we collected demographic information and laboratory results from the National Health and Nutrition Examination Survey (NHANES) database in order to investigate the relationship between VD and DN. Then, we established a DN model and treated DN rats with Tan and paricalcitol (Par) for 6 weeks. We subsequently compared the changes in general condition, renal function, pathological changes, and TIF-related protein expression levels of control rats, DN rats induced by STZ, DN rats with Tan at 5.4 mg/kg, DN rats with Tan at 10.8 mg/kg, and DN rats with Par at 0.054 µg/kg, to explore the effect and mechanism of Tan and Par on DN rats. The results showed that VD had a protective effect against DN in diabetic patients. And we found that Tan had a protective effect on renal fibrosis in DN rats, which was superior to Par in improving the symptoms of "three more and one less," reducing fasting blood glucose level, improving renal index, BUN/SCr, and UACR, reducing histopathological damage of kidney, and improving the expression of fibrosis-related proteins in kidney tissue by regulating VDR/Wnt/ß-catenin pathway. Tan was superior to Par in ameliorating tubulointerstitial fibrosis by regulating VDR/Wnt/ß-catenin pathway in rats with diabetic nephropathy.

Depression and anxiety symptoms among patients receiving maintenance hemodialysis: a single center cross-sectional study.

BACKGROUND: To investigate depression and anxiety and related factors among patients receiving maintenance hemodialysis (MHD). METHODS: This cross-sectional study included patients underwent MHD in 3/2022 at Jinshan Hospital affiliated to Fudan University. Depression and anxiety levels of patients were assessed using Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI), respectively. SF-36 was used to assess patients' quality of life. Multiple linear regression analysis was used to determine the variables associated with the scores of BDI/BAI. RESULTS: A total of 103 patients were included, 71 cases (68.93%) and 38 cases (36.89%) with depression and anxiety, respectively. The scores of almost all domains of the SF-36 showed a declining trend with increasing depression or anxiety among patients on MHD. Higher Charlson Comorbidity Index (CCI) (ß =0.066, 95%CI: 0.016-0.116, P = 0.010), lower educational status (ß = - 0.139, 95%CI: - 0.243- -0.036, P = 0.009), and number of oral medications (ß =0.177, 95%CI: 0.031-0.324, P = 0.018) were significantly associated with higher BDI scores. Longer dialysis duration (ß =0.098, 95%CI: 0.003-0.193, P = 0.044) and number of oral medications (ß =4.714, 95%CI: 1.837-7.590, P = 0.002) were significantly associated with higher BAI scores. CONCLUSIONS: Depression and anxiety may be likely to occur among patients undergoing MHD and impact their quality of life. Higher CCI, lower educational status and usage of multiple oral medications may be associated with depression, whereas longer dialysis duration and multiple oral medications may be associated with anxiety in MHD patients.

Entrepreneurship education on entrepreneurial intention: The moderating role of the personality and family economic status.

This study investigates the impact of entrepreneurship education on college students' entrepreneurial intentions, as well as the moderating effects of personality and family economic status on the relationship between entrepreneurship education and entrepreneurial intention, respectively. We tested our hypotheses using a sample of college students in Tianjin, China, and analyzed the data of 326 questionnaires containing validated measures. The results show that entrepreneurship education has a positive impact on college students' entrepreneurial intentions; proactive personality negatively moderates this relationship; and family economic status positively moderates it. However, the moderating effect of narcissistic personality has not been verified. This study is unique and innovative as it brings new insights to this stream of literature by introducing the roles of the personality and family economic status in the relationship between entrepreneurship education and entrepreneurial intention. Our analysis provides important empirical evidence about the negative moderating effect of proactive personality and the positive moderating effect of family economic status on the relationship between entrepreneurship education and entrepreneurial intention, introducing insights into the heterogeneity of the effect of entrepreneurship education.

Effect of Ultrafine Fly Ash and Water Glass Content on the Performance of Phosphorus Slag-Based Geopolymer.

Phosphorus slag (PS), an industrial waste slag, has been used in geopolymers because it is rich in silicon and calcium. The poor performance of phosphorus slag-based geopolymer is due to its aluminum deficiency. In this work, low-calcium fly ash, treated by a wet-grinding process, named wet-grinding ultrafine fly ash (WUFA) was used as an Al supplement to replace some of the phosphorus slag, and the wet-grinding, ultrafine fly ash-phosphorus slag (WUFA-PS)-based geopolymer was prepared. The effects of the substitution amount of WUFA and the activator dosage on the hydration properties, mechanical properties, pore structure and SEM of the WUFA-PS geopolymer were discussed in detail. The results indicate that WUFA and more activators contribute to the Al and high alkalinity environment, which positively induces the production of more geopolymer gels, thus releasing more heat and optimizing the pore structure of the matrix. The compressive strength increased by up to 28.1%. The enhanced performance of the WUFA-PS-based geopolymer may also arise from the filling effect and activity improvement of WUFA. This study has proved the feasibility of preparing a geopolymer by blending wet-grinding ultrafine fly ash and phosphorus slag and has provided references for the ratio and performance evaluation of WUFA-PS-based geopolymer concrete.

Using Physical Organic Chemistry Knowledge to Predict Unusual Metabolites of Synthetic Phenolic Antioxidants by Cytochrome P450.

Biotransformation, especially by human CYP450 enzymes, plays a crucial role in regulating the toxicity of organic compounds in organisms, but is poorly understood for most emerging pollutants, as their numerous "unusual" biotransformation reactions cannot retrieve examples from the textbooks. Therefore, in order to predict the unknown metabolites with altering toxicological profiles, there is a realistic need to develop efficient methods to reveal the "unusual" metabolic mechanism of emerging pollutants. Combining experimental work with computational predictions has been widely accepted as an effective approach in studying complex metabolic reactions; however, the full quantum chemical computations may not be easily accessible for most environmentalists. Alternatively, this work practiced using the concepts from physical organic chemistry for studying the interrelationships between structure and reactivity of organic molecules, to reveal the "unusual" metabolic mechanism of synthetic phenolic antioxidants catalyzed by CYP450, for which the simple pencil-and-paper and property-computation methods based on physical organic chemistry were performed. The phenol-coupling product of butylated hydroxyanisole (BHA) (based on spin aromatic delocalization) and ipso-addition quinol metabolite of butylated hydroxytoluene (BHT) (based on hyperconjugative effect) were predicted as two "unusual" metabolites, which were further confirmed by our in vitro analysis. We hope this easily handled approach will promote environmentalists to attach importance to physical organic chemistry, with an eye to being able to use the knowledge gained to efficiently predict the fates of substantial unknown synthesized organic compounds in the future.

Tanshinone IIA attenuates high glucose-induced epithelial-to-mesenchymal transition in HK-2 cells through VDR/Wnt/ß-catenin signaling pathway.

INTRODUCTION: The progression of diabetic kidney disease (DKD) is closely related to renal tubular epithelial- to-mesenchymal transition (EMT) and tubulointerstitial fibrosis. Tanshinone IIA (TSIIA), extracted from a traditional Chinese medicine named Salvia miltiorrhiza, has been proved to have anti-fibrosis effects. The aim of this study was to investigate the effect of TSIIA on high glucose-induced EMT in human proximal tubular cells (HK-2 cells) and its possible mechanism. MATERIAL AND METHODS: The proliferation of cells exposed to different concentrations of glucose was measured by light microscopy and CCK-8 test. The cells were stimulated with 30 mM glucose and different concentrations of TSIIA (5 µM or 10 µM) for 48 h. Vitamin D receptor (VDR)-siRNA was used to transfect cells, and high glucose and TSIIA treatment were further used to treat cells. The expression of alpha smooth muscle actin (a-SMA) mRNA was detected by qPCR to ensure successful induction of EMT, and the expression of VDR mRNA was detected by qPCR to ensure successful transfection of VDR-siRNA. Protein expression of a-SMA, E-cadherin, VDR, b-catenin and glycogen synthase kinase 3b (GSK-3b) was detected by Western blot analysis. RESULTS: The results showed that high glucose concentration inhibited cell proliferation and promoted EMT in HK-2 cells. TSIIA could reverse high glucose-induced EMT by increasing the level of VDR protein and inhibiting the levels of b-catenin and GSK-3b proteins suggestive of a negative correlation between VDR and the Wnt/b-catenin pathway. After VDR-siRNA transfection and incubation of cells at high glucose concentration, the inhibitory effect of VDR on the expression of b-catenin and GSK-3b of Wnt pathway was suppressed and the b-catenin pathway was activated. When VDR level was restored by TSIIA, the inhibitory effect of VDR on the pathway was also restored and the activation of the pathway was suppressed. CONCLUSIONS: TSIIA was able to attenuate high glucose-induced EMT in HK-2 cells by up-regulating VDR levels, which might be related to the inhibitory effect of VDR on the Wnt pathway.

The Effects of Rhubarb for the Treatment of Diabetic Nephropathy in Animals: A Systematic Review and Meta-analysis.

Background: Rhubarb, also known as Da Huang, is a traditional Chinese medicine, and it was often used as a laxative in the past. Recently, multiple studies have applied rhubarb to treat diabetic nephropathy (DN). Anthraquinones, including emodin and rhein, have been extracted from rhubarb and used to explore the effective components and possible mechanisms of rhubarb for DN. Evaluating the efficacy of rhubarb may provide a scientific reference for the clinical application of rhubarb for the treatment of DN. Objective: 1) To evaluate the efficacy of rhubarb in the treatment of DN; 2) To identify the most effective ingredient of rhubarb for DN; 3) To explore the specific mechanism of rhubarb in treating DN. Methods: Data sources: related studies were identified by searching Cochrane Library, Ovid-EMBASE, PubMed, SinoMed, WanFang, VIP, CNKI, and other Chinese magazines. Assessment and analysis: SYRCLE's risk of bias tool for animal studies was used to assess the quality of articles. The meta-analysis was performed in accordance with the Cochrane Handbook for Systematic Reviews of Interventions. Data analysis adopted RevMan 5.3 and STATA 12.0 software. This study was published in the register with PROSPERO, number CRD42020204701. Results: Aggregated data were collected from 27 eligible studies. The results illustrated an intense improvement in the following outcomes in rhubarb-treated animals with DN (p < 0.05): blood glucose, serum creatinine (Scr), blood urea nitrogen (BUN), albumin creatinine ratio (ACR), urine protein (UP), urinary albumin excretion (UAE), renal index (two kidneys weight/body weight, KW/BW), tubulointerstitial injury index (TII), transforming growth factor-beta1 (TGF-ß1) mRNA and protein, alpha-smooth muscle actin (α-SMA) protein, and E-cadherin (E-cad) protein. Of these, DN animals with rhubarb exhibited a significantly higher level of E-cad protein. In addition, the level of the other outcomes mentioned above decreased significantly, while there was no significant association between the intervention and nephrin protein (p > 0.05). Conclusion: This systematic review and meta-analysis demonstrated that rhubarb has a positive therapeutic effect on animals with DN, which may provide confidence and some theoretical reference for clinical application to a certain extent.

Targeting the ALS/FTD-associated A-DNA kink with anthracene-based metal complex causes DNA backbone straightening and groove contraction.

The use of a small molecule compound to reduce toxic repeat RNA transcripts or their translated aberrant proteins to target repeat-expanded RNA/DNA with a G4C2 motif is a promising strategy to treat C9orf72-linked disorders. In this study, the crystal structures of DNA and RNA-DNA hybrid duplexes with the -GGGCCG- region as a G4C2 repeat motif were solved. Unusual groove widening and sharper bending of the G4C2 DNA duplex A-DNA conformation with B-form characteristics inside was observed. The G4C2 RNA-DNA hybrid duplex adopts a more typical rigid A form structure. Detailed structural analysis revealed that the G4C2 repeat motif of the DNA duplex exhibits a hydration shell and greater flexibility and serves as a 'hot-spot' for binding of the anthracene-based nickel complex, NiII(Chro)2 (Chro = Chromomycin A3). In addition to the original GGCC recognition site, NiII(Chro)2 has extended specificity and binds the flanked G:C base pairs of the GGCC core, resulting in minor groove contraction and straightening of the DNA backbone. We have also shown that Chro-metal complexes inhibit neuronal toxicity and suppresses locomotor deficits in a Drosophila model of C9orf72-associated ALS. The approach represents a new direction for drug discovery against ALS and FTD diseases by targeting G4C2 repeat motif DNA.

Predicting malignancy of pulmonary ground-glass nodules and their invasiveness by random forest.

BACKGROUND: The purpose of this study was to develop a predictive model that could accurately predict the malignancy of the pulmonary ground-glass nodules (GGNs) and the invasiveness of the malignant GGNs. METHODS: The authors built two binary classification models that could predict the malignancy of the pulmonary GGNs and the invasiveness of the malignant GGNs. RESULTS: Results of our developed model showed random forest could achieve 95.1% accuracy to predict the malignancy of GGNs and 83.0% accuracy to predict the invasiveness of the malignant GGNs. CONCLUSIONS: The malignancy and invasiveness of pulmonary GGNs could be predicted by random forest.

An aptamer and functionalized nanoparticle-based strip biosensor for on-site detection of kanamycin in food samples.

A lateral flow strip biosensor for fast, sensitive, low-cost and on-site detection of kanamycin was developed by using kanamycin-specific aptamer-modified gold nanoparticles (AuNPs-apt) as a probe and oligonucleotide DNA1-modified silver nanoparticles (AgNPs-DNA1) as a signal amplification element. Through the complementary sequences of DNA1 and the aptamer, the AgNP-DNA1-apt-AuNPs complex can be formed and further captured on the test zone of the strip, where a capture probe DNA2 complementary to the 3'-terminal of DNA1 was immobilized. In the presence of kanamycin, it can competitively bind to the aptamer, and then inhibit the formation of the complex and the accumulation of AuNPs on the test zone. AuNPs-apt can finally be captured on the control zone via the specific binding between biotin and streptavidin. The assay avoids multiple incubation and washing steps and can be completed within 10 min. By observing the color change of the test zone, a qualitative detection for kanamycin can be achieved by the naked eye, with the visual limit of 35 nM. Meanwhile, a linear detection range of 1-30 nM with a low detection limit of 0.0778 nM for quantitative analysis can be achieved by using a scanning reader. The lateral flow strip biosensor exhibited high specificity and stability. Moreover, it was applied to detect kanamycin in various food samples, indicating its great potential in field testing.