A causal relationship between bone mineral density and breast cancer risk: a mendelian randomization study based on east Asian population.

BACKGROUND: Breast cancer (BC) poses significant burdens on women globally. While past research suggests a potential link between bone mineral density (BMD) and BC risk, findings remain inconsistent. Our study aims to elucidate the causal relationship between BMD and BC in East Asians using bidirectional Mendelian randomization (MR). METHODS: Genetic association data for bone mineral density T-scores (BMD-T) and Z-scores (BMD-Z) (Sample size = 92,615) and BC from two different sources (Sample size1 = 98,283; Sample size2 = 79,550) were collected from publicly available genome-wide association studies (GWAS). Single-nucleotide polymorphisms (SNPs) associated with BMD-T and BMD-Z as phenotype-related instrumental variables (IVs) were used, with BC as the outcome. As the primary means of causal inference, the inverse variance weighted (IVW) approach was employed. Heterogeneity analysis was conducted using Cochran's Q test, while MR-Egger regression analysis was implemented to assess the pleiotropic effects of the IVs. Sensitivity analyses were performed using methods such as MR-Egger, weighted median, and weighted mode to analyze the robustness and reliability of the results. The MR-PRESSO method and the RadialMR were used to detect and remove outliers. The PhenoScanner V2 website was utilized to exclude confounding factors shared between BMD and BC. Besides, the Bonferroni correction was also used to adjust the significance threshold. Then, the meta-analysis method was applied to combine the MR analysis results from the two BC sources. Finally, a reverse MR analysis was conducted. RESULTS: The results of the IVW method were consolidated through meta-analysis, revealing a positive correlation between genetically predicted BMD-T ([Formula: see text], [Formula: see text], [Formula: see text]) and BMD-Z ([Formula: see text],[Formula: see text], [Formula: see text]) with increased BC risk. The Cochran's [Formula: see text] test and MR-Egger regression suggested that neither of these causal relationships was affected by heterogeneity or horizontal pleiotropy. The sensitivity analyses supported the IVW results, indicating the robustness of the findings. Reverse MR analysis showed no causal relationship between BC and BMD. CONCLUSION: Our MR study results provide evidence for the causal relationship between BMD and BC risk in East Asian populations, suggesting that BMD screening is of great significance in detecting and preventing BC.

Interface Engineering via Manipulating Solvation Chemistry for Liquid Lithium-Ion Batteries Operated≥100 °C.

High-performance and temperature-resistant lithium-ion batteries (LIBs), which are able to operate at elevated temperatures (i.e., >60 °C) are highly demanded in various fields, especially in military or aerospace exploration. However, their applications were largely impeded by the poor electrochemical performance and unsatisfying safety issues, which were induced by the severe side reactions between electrolytes and electrodes at high temperatures. Herein, with the synergetic effects of solvation chemistry and functional additive in the elaborately designed weakly solvating electrolyte, a unique robust organic/inorganic hetero-interphase, composed of gradient F, B-rich inorganic components and homogeneously distributed Si-rich organic components, was successfully constructed on both cathodes and anodes, which would effectively inhibit the constant decomposition of electrolytes and dissolution of transition metal ions, thus highly enhancing the high-temperature electrochemical performance. As a result, both cathodes and anodes, without compromising their low-temperature performance, can operate at temperatures ≥100 °C, with excellent capacity retentions of 96.1 % after 500 cycles and 93.5 % after ≥200 cycles, respectively, at 80 °C. Ah-level LiCoO2||graphite full cells with a cut-off voltage of 4.3 V also exhibited superior temperature-resistance with a capacity retention of 89.9 % at temperature as high as 120 °C. Moreover, the fully charged pouch cells exhibited highly enhanced safety, demonstrating their potentials in practical applications at ultrahigh temperatures.

Hypotonic Challenge of Endothelial Cells Increases Membrane Stiffness with No Effect on Tether Force.

Regulation of cell volume is a fundamental property of all mammalian cells. Multiple signaling pathways are known to be activated by cell swelling and to contribute to cell volume homeostasis. Although cell mechanics and membrane tension have been proposed to couple cell swelling to signaling pathways, the impact of swelling on cellular biomechanics and membrane tension have yet to be fully elucidated. In this study, we use atomic force microscopy under isotonic and hypotonic conditions to measure mechanical properties of endothelial membranes including membrane stiffness, which reflects the stiffness of the submembrane cytoskeleton complex, and the force required for membrane tether formation, reflecting membrane tension and membrane-cytoskeleton attachment. We find that hypotonic swelling results in significant stiffening of the endothelial membrane without a change in membrane tension/membrane-cytoskeleton attachment. Furthermore, depolymerization of F-actin, which, as expected, results in a dramatic decrease in the cellular elastic modulus of both the membrane and the deeper cytoskeleton, indicating a collapse of the cytoskeleton scaffold, does not abrogate swelling-induced stiffening of the membrane. Instead, this swelling-induced stiffening of the membrane is enhanced. We propose that the membrane stiffening should be attributed to an increase in hydrostatic pressure that results from an influx of solutes and water into the cells. Most importantly, our results suggest that increased hydrostatic pressure, rather than changes in membrane tension, could be responsible for activating volume-sensitive mechanisms in hypotonically swollen cells.

Comparative transcriptomic and proteomic analyses reveal upregulated expression of virulence and iron transport factors of Aeromonas hydrophila under iron limitation.

BACKGROUND: Iron plays important roles in the growth, reproduction and pathogenicity of Aeromonas hydrophila. In this study, we detected and compared the mRNA and protein expression profiles of A. hydrophila under normal and iron restricted medium with 200 µM 2,2-Dipyridyl using RNA Sequencing (RNA-seq) and isobaric tags for relative and absolute quantification (iTRAQ) analyses. RESULTS: There were 1204 genes (601 up- and 603 down-regulated) and 236 proteins (90 up- and 146 down-regulated) shown to be differentially expressed, and 167 genes and proteins that showed consistent expression. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed that the differentially expressed genes and proteins were mainly involved in iron ion transport, protein activity, energy metabolism and virulence processes. Further validation of the RNA-seq and iTRAQ results by quantitative real-time PCR (qPCR) revealed that 18 of the 20 selected genes were consistently expressed. The iron-ion absorption and concentration of A. hydrophila under iron-limited conditions were enhanced, and most virulence factors (protease activity, hemolytic activity, lipase activity, and swimming ability) were also increased. Artificial A. hydrophila infection caused higher mortality in cyprinid Megalobrama amblycephala under iron-limited conditions. CONCLUSION: Understanding the responses of pathogenic Aeromonas hydrophila within the hostile environment of the fish host, devoid of free iron, is important to reveal bacterial infection and pathogenesis. This study further confirmed the previous finding that iron-limitation efficiently enhanced the virulence of A. hydrophila using multi-omics analyses. We identified differentially expressed genes and proteins, related to enterobactin synthesis and virulence establishment, that play important roles in addressing iron scarcity.

Molecular cloning and expression analysis of Megalobrama amblycephala transferrin gene and effects of exposure to iron and infection with Aeromonas hydrophila.

Transferrin (Tf) plays an important function in iron homeostasis and metabolism of organisms. In this study, we identified and characterized the Tf gene in Megalobrama amblycephala and evaluated its expression in basal conditions as well as after iron overload and experimental infection with Aeromonas hydrophila. Furthermore, we studied the iron binding properties of recombinant Tf. The full-length M. amblycephala Tf complementary DNA (cDNA) (GenBank accession no.: KX698308) of 2245 bp was cloned and contained a 1953 bp open reading frame (ORF) encoding 650 amino acid residues and flanked by a 68 bp 5' and a 204 bp 3' untranslated regions (UTR). Predicted conservative structure illustrated that M. amblycephala Tf consisted of two conservative Tf domains. Amino acid sequence alignment revealed that M. amblycephala Tf had high similarity with that of cyprinids deposited in Genbank, and phylogenetic analysis showed that M. amblycephala Tf clustered with Ctenopharyngodon idella and Hypophthalmichthys molitrix. Tissue expression pattern analyses demonstrated that the liver was the main Tf mRNA expressing organ, being significantly higher than other tissues (p < 0.05). In the liver, Tf mRNA expression in fish artificially injected with the pathogenic bacteria A. hydrophila was significantly upregulated, reaching a peak at 12 h post injection (hpi) and then decreasing afterward. The expression in FeCl3-injected fish showed a similar tendency, but reached a peak at 8 hpi. Meanwhile, fish serum iron significantly decreased following A. hydrophila injection, but increased to peak at 4 hpi and then decreased in FeCl3-injected fish. The recombinant M. amblycephala Tf showed iron binding capacity using CAS analysis. These results are helpful to understand the structure and regulation of expression of Tf, as well as the specific function of Tf for both immune responses and iron homeostasis.

Description of a new Neoactinomyxum type actinosporean from the oligochaete Branchiura sowerbyi Beddard.

Actinosporean infection of oligochaetes living in the mud of a commercial gibel carp pond with myxosporean disease was studied. Six actinospore types were detected exclusively from the oligochaete Branchiura sowerbyi Beddard with very high prevalence (18%). Five out of the six types were identified as the same actinosporeans described in previous reports, the sixth actinosporean was identified as a new Neoactinomyxum type and described here based on morphological and molecular characterisation. Spore body of the actinospore was globular, much smaller than caudal processes. Three caudal processes were disc-like in apical view, hemispherical in side view, closer together and encircling the spore body. The number of sporoplasm cells was detected as eight in one specimen. The new actinosporean markedly differed from other Neoactinomyxum types in literature having much bigger caudal processes. DNA sequence analyses further confirmed the morphological identification, and revealed the actinosporean described here (KU641392) possessed less than 94% sequence similarity with myxozoans available in the GenBank database.

[Effect of Chinese Herbs Combined DHEA Pretreatment on Pregnancy Outcomes of Elderly Pa- tients with Normal Ovarian Reserve Undergoing IVF-ET].

Objective To observe the effect of Chinese herbs combined dehydroepiandrosterone (DHEA) pretreatment on pregnancy outcomes of elderly patients with normal ovarian function undergoing in vitro fertilization-embryo transfer ( IVF-ET). Methods Totally 233 IVF patients with normal ovarian function scheduled for IVF-ET, 36 -42 years old, were assigned to the combined group, the DHEA group, the control group according to random number table. Patients in the combined group (76 cases) were pretreated with Chinese herbs plus DHEA before IVF cycle for 8 weeks. Patients in the DHEA group (82 cases) were pretreated with DHEA before IVF cycle for 8 weeks. Those in the control group (75 cases) received no pretreatment. The number of retrieved oocytes , the fertilization rate, the rate of good quality embryos, the number of frozen embryos, clinical pregnancy rate, early spontaneous abortion rate, live birth rate, levels of anti-Mullerian hormone (AMH) , the cycle cancellation rate, endometrial thickness and estradiol (E2) level on human chorionic gonadotropin (hCG) injection day, the dosage and duration of Gn were observed in the 3 groups. Results The good quality embryo rate was significantly higher in the combined group and the DHEA group than in the control group (P <0. 05). Compared with the control group, the fertilization rate, the number of frozen embryos, the clinical pregnancy rate, and the live birth rate were higher; the early spontaneous abortion rate was lower in the two pretreatment groups (P > 0. 05). AMH increased more significantly in the two pretreatment groups after treatment (P <0. 05). There was no obvious change in the control group. The post-treatment number of retrieved oocytes, the cycle cancellation rate, E2 level and endometrial thickness on hCG injection day, the dosage and duration of Gn had no significant difference among the 3 groups (P >0. 05). Conclusion Pretreatment of Chinese herbs combined DHEA could improve the good quality embryo rate of elderly patients with normal ovarian re- serve, which might be associated with AMH.

The effect of supplementing with Saccharomyces boulardii on bismuth quadruple therapy for eradicating Helicobacter pylori: a systematic review and meta-analysis of randomized controlled trials.

Background and objective: It remains uncertain if the addition of Saccharomyces boulardii (S. boulardii) to bismuth quadruple therapy (BQT) recommended in the current guidelines can enhance the Helicobacter pylori (H. pylori) eradication rate and decrease the incidence of adverse events. We therefore conducted a meta-analysis of randomized controlled trials (RCTs) to address this issue. Methods: We performed comprehensive searches in PubMed, Embase, Web of Science, and Cochrane library databases from the inception of the databases through to November 1, 2023. A meta-analysis was conducted to determine the pooled relative risk (RR) with 95% confidence intervals (CI) using a random-effects model. We utilized the revised Cochrane Risk of Bias Tool to assess the risk of bias of included studies. Results: A total of six RCTs (1,404 patients) included in this meta-analysis. The results of the intention-to-treat analysis showed that the combination of S. boulardii with BQT had a higher eradication rate than BQT alone (87.0% versus 83.3%), with a pooled RR of 1.05 (95% CI: 1.00-1.10, p = 0.03). In the per-protocol analysis, however, there was no statistical significance between the two groups in the eradication rate (93.7% versus 91.0%, RR = 1.03, 95% CI: 1.00-1.06, p = 0.07). The combination of S. boulardii and BQT had a significantly lower rate of overall adverse events (22% vs. 39%, RR = 0.56, 95% CI: 0.44-0.70, p < 0.00001), diarrhea (7.9% vs. 25.7%, RR = 0.29, 95% CI: 0.17-0.48, p < 0.00001), constipation (2.9% vs. 8.4%, RR = 0.35, 95% CI: 0.14-0.88, p = 0.03) and abdominal distention (4.9% vs. 12.7%, RR = 0.41, 95% CI: 0.23-0.72, p = 0.002) than BQT alone. For the assessment of risk of bias, five studies were deemed to have some concerns, while one study was judged to have a low risk. Conclusion: Current evidence suggests that supplementation with S. boulardii in BQT may not have a major effect on the H. pylori eradication rate, but significantly reduces the incidence of overall adverse events, diarrhea, abdominal distention and constipation. Combining S. Boulardii with BQT can help alleviate symptoms, potentially improving patient adherence. Systematic review registration: https://osf.io/n9z7c.

Transcriptome-Based Analysis of the Mechanism of Action of Metabolic Disorders Induced by Waterborne Copper Stress in Coilia nasus.

To reveal the effects of waterborne copper stress on gene expression changes, molecular pathways, and physiological functions in Coilia nasus, juvenile fish were equally divided into two experimental groups, and the copper levels were 1.61 ± 0.03 mg/L (copper-exposed group) and 0 mg/L (control group), respectively. After 4 h, gill tissue samples were collected for transcript sequencing analysis, and two libraries were constructed from the copper treatment group (Cu) and the control group (C) and sequenced using Illumina sequencing technology. The results showed that approximately 40.2-46.0 M clean reads were obtained from each library, and the percentage of uniquely mapped transcripts ranged from 80.57 to 84.93%. A total of 3915 differentially expressed genes (DEGs) were identified under waterborne copper stress, among which 1300 genes were up-regulated, and 2615 genes were down-regulated. Twelve DEGs were randomly selected for quantitative RT-PCR (qRT-PCR) analysis, and the results confirmed that the transcriptome analysis was reliable. Furthermore, the DEGs were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and the results showed that most of the DEGs were involved in metabolic pathways, including steroid biosynthesis, glutathione metabolism, and peroxisome proliferator-activated receptor (PPAR) signaling pathways. Furthermore, due to the waterborne copper levels, gsk-3ß was significantly up-regulated, while other metabolism-related genes (tor, pi3k, lpl, aqp7, fabp3) were significantly down-regulated. In addition, the copper-exposed group significantly reduced the expression of some immunity genes (ifn-γ, stat1, cxcl10, and tgf-ß), and enhanced the expression of il-1ß and tnf-α. In summary, these results indicated that copper causes metabolic disorders and insufficient energy supply in the body, and induces oxidative stress, which results in reduced immune functions.

Role of Cholecystokinin (cck) in Feeding Regulation of Largemouth Bass (Micropterus salmoides): Peptide Activation and Antagonist Inhibition.

This study investigated the role of cholecystokinin (cck) in the feeding regulation of largemouth bass (Micropterus salmoides) via peptide activation and antagonist inhibition. The results show that the cck gene was expressed in various tissues, with the highest expression level occurring in the brain. Feeding, continuous feeding, and refeeding after fasting could significantly improve the mRNA levels of cck in the brain. Moreover, the activation of cck via injecting an exogenous CCK peptide could inhibit feed intake by regulating the mRNA levels of anorexigenic and feed-promoting factors in the brain and intestine. Furthermore, the CCK peptide reduced feed intake; however, the presence of an antagonist (Ly225910-CCK1R and devazepide-CCK2R) could reverse this effect through regulating the mRNA levels of anorexigenic and feed-promoting factors in the brain and intestine. Treatment with devazepide + CCK (CCK2R) reversed feed intake more effectively than Ly225910 + CCK (CCK1R) treatment. In summary, cck could regulate the feed intake of largemouth bass through regulating feeding-related genes in the brain and intestine. In addition, cck required binding with the receptor to inhibit feed intake more effectively in largemouth bass, and the binding effect of CCK1R was better than that of CCK2R.

Excessive Replacement of Fish Meal by Soy Protein Concentrate Resulted in Inhibition of Growth, Nutrient Metabolism, Antioxidant Capacity, Immune Capacity, and Intestinal Development in Juvenile Largemouth Bass (Micropterus salmoides).

This study investigated the effects of replacing 0% (SPC0), 25% (SPC25), 50% (SPC50), 75% (SPC75), and 100% (SPC100) of fish meal (FM) with soy protein concentrate (SPC) on the growth, nutritional metabolism, antioxidant capacity, and inflammatory factors in juvenile largemouth bass (Micropterus salmoides) (17.03 ± 0.01 g). After 56 days of culturing, various growth parameters including FW, WGR, and SGR were not significantly different among SPC0, SPC25, and SPC50 groups; however, they were significantly higher than those in SPC75 and SPC100 groups. Conversely, significantly lower FCR were determined for the SPC0, SPC25, and SPC50 groups compared with that for the SPC100 group; specifically, no significant difference among SPC0, SPC25, and SPC50 groups was found. Moreover, compared with SPC75 and SPC100 groups, a significantly higher FI was observed in the SPC0 group, whereas a significantly lower SR was observed in SPC100 compared with that in SPC0 and SPC25 groups. Compared with the SPC0 group, significantly lower mRNA levels of tor, rps6, 4ebp1, pparγ, and fas were found in SPC75 and SPC100. Additionally, the mRNA levels of cpt were significantly higher in SPC0, SPC25, and SPC50 groups than in SPC75 and SPC100 groups. Moreover, the mRNA levels of scd and acc remained unchanged for all the groups. Replacement of FM with SPC did not significantly affect the mRNA levels of gk, pk, and pepck. Compared with the SPC0 group, significantly decreased activities of CAT were observed in the SPC50, SPC75, and SPC100 groups, and significantly decreased activities of GSH-Px were observed in the SPC75 and SPC100 groups. In addition, significantly lower activity of SOD was observed in SPC100 compared with the other groups. Moreover, compared with the other groups, the SPC75 and SPC100 groups had significantly decreased and increased contents of GSH and MDA, respectively, while significantly lower mRNA levels of nrf2, cat, sod, and gsh-px were found in SPC50, SPC75, and SPC100; however, significantly higher mRNA levels of keap1 were observed in SPC75 and SPC100 groups. Additionally, significantly higher mRNA levels of il-8 and nf-κb were found in the SPC50, SPC75, and SPC100 groups compared with the SPC0 group. Conversely, significantly lower mRNA levels of il-10 and significantly higher mRNA levels of tnf-α were found in the SPC75 and SPC100 groups compared with the other groups. Compared with the SPC0 group, mucosal thickness and villus height were significantly decreased in the SPC75 and SPC100 groups. Collectively, SPC replacing 50% FM did not affect its growth of juvenile largemouth bass. However, SPC replacing 50% or more FM might inhibit antioxidant capacity and immune capacity to even threaten the SR, resulting in impaired intestinal development in replacing FM level of 75% or more.

New insights into multi-strategies of sludge granulation in up-flow anaerobic sludge blanket reactors from community succession and interaction.

This study aimed to elucidate the multiple strategies employed by anaerobes during granulation in a laboratory upflow anaerobic sludge blanket reactor, based on microbial succession and interactions. The anaerobic granulation process featured staged dominance of microbial genera, corresponding well with the environmental traits. Across the stages (selection, seeding, expansion, and maturation), chemotaxis attraction of nitrogen and/or carbon sources and flagellar motion were the primary strategy of microbial assembly. The second messengers - cyclic adenosine and guanosine monophosphates - partially regulated the agglomeration of filamentous Euryachaeota and Chloroflexi as the inner cores, while quorum sensing mediated the expansion of granules prior to maturation. Antagonism or competition governed the interactions within the phylogenetic molecular ecological network during sludge granulation, which were largely driven by the low-abundance (<1%) taxa. These new insights suggest that better engineering solutions to enhance chemotaxis attraction and species selection could achieve more efficient anaerobic granular sludge processes.

Rapid self-heating synthesis of Fe-based nanomaterial catalyst for advanced oxidation.

Iron-based catalysts are promising candidates for advanced oxidation process-based wastewater remediation. However, the preparation of these materials often involves complex and energy intensive syntheses. Further, due to the inherent limitations of the preparation conditions, it is challenging to realise the full potential of the catalyst. Herein, we develop an iron-based nanomaterial catalyst via soft carbon assisted flash joule heating (FJH). FJH involves rapid temperature increase, electric shock, and cooling, the process simultaneously transforms a low-grade iron mineral (FeS) and soft carbon into an electron rich nano Fe0/FeS heterostructure embedded in thin-bedded graphene. The process is energy efficient and consumes 34 times less energy than conventional pyrolysis. Density functional theory calculations indicate that the electron delocalization of the FJH-derived heterostructure improves its binding ability with peroxydisulfate via bidentate binuclear model, thereby enhancing ·OH yield for organics mineralization. The Fe-based nanomaterial catalyst exhibits strong catalytic performance over a wide pH range. Similar catalysts can be prepared using other commonly available iron precursors. Finally, we also present a strategy for continuous and automated production of the iron-based nanomaterial catalysts.

Mechanisms of Rhizoma Coptidis against type 2 diabetes mellitus explored by network pharmacology combined with molecular docking and experimental validation.

This study systematically explored the underlying mechanism of Rhizoma Coptidis against type 2 diabetes mellitus (T2DM) by using network pharmacology and molecular docking and experimental validation. We retrieved and screened active compounds of Rhizoma Coptidis and corresponding T2DM-related targets across multiple databases. PPI networks of the genes were constructed using STRING, and the core targets were screened via topological analysis. GO and KEGG enrichment analyses were performed by using DAVID. Finally, molecular docking and experimental studies were performed after bioinformatic analysis for verification. There were 14 active compounds and 19 core targets of Rhizoma Coptidis-T2DM, of which quercetin was identified as the main compound and IL6, VEGFA and TNF were the most significant core targets. GO and KEGG enrichment analyses showed that Rhizoma Coptidis ameliorated T2DM by regulating multiple biological processes and pathways. Docking studies indicated that IL6, VEGFA and TNF could stably bind with all active compounds of Rhizoma Coptidis. The results of our experiments revealed that Rhizoma Coptidis could inhibit the expression of IL6 and TNFα and enhance islet cell viability. This study suggests anti-inflammatory therapeutic effects of Rhizoma Coptidis on T2DM, thereby providing a scientific basis and new insight for further research on the antidiabetic effect of Rhizoma Coptidis.

Efficacy and safety of Huangkui capsule for diabetic nephropathy: A protocol for systematic review and meta-analysis.

BACKGROUND: Diabetic nephropathy (DN) is 1 of the most serious complications of diabetes mellitus and the leading cause of end-stage renal disease in the world. Huangkui capsule, extracted from Abelmoschus manihot (L.) medic (AM), has been widely used to treat DN. However, there is no consensus on the efficacy of Huangkui capsule for DN. This study aims to perform meta-analysis to systematically review the efficacy and safety of Huangkui capsule. METHODS: The following 9 electronic databases will be comprehensively searched: PubMed, web of science, MEDLINE, Embase, Cochrane Library, China National Knowledge Infrastructure, Chinese Scientific Journals Database, Wanfang data, and Chinese BioMedicine Literature Database. The retrieval time is from their inception to May 2021. According to the inclusion and exclusion criteria, 2 reviewers independently completed the study selection, data extraction, risk of bias assessment, and data synthesis. Review Manager Version 5.3 software will be used to conduct meta-analysis. RESULTS: This study provides a high-quality synthesis to assess the efficacy of Huangkui capsule for treating diabetic nephropathy. CONCLUSION: The result of this systematic review will provide objective evidence-based basis to judge the effectiveness and safety of Huangkui capsule on diabetic nephropathy.

Dynamic Role of Phospholipases A2 in Health and Diseases in the Central Nervous System.

Phospholipids are major components in the lipid bilayer of cell membranes. These molecules are comprised of two acyl or alkyl groups and different phospho-base groups linked to the glycerol backbone. Over the years, substantial interest has focused on metabolism of phospholipids by phospholipases and the role of their metabolic products in mediating cell functions. The high levels of polyunsaturated fatty acids (PUFA) in the central nervous system (CNS) have led to studies centered on phospholipases A2 (PLA2s), enzymes responsible for cleaving the acyl groups at the sn-2 position of the phospholipids and resulting in production of PUFA and lysophospholipids. Among the many subtypes of PLA2s, studies have centered on three major types of PLA2s, namely, the calcium-dependent cytosolic cPLA2, the calcium-independent iPLA2 and the secretory sPLA2. These PLA2s are different in their molecular structures, cellular localization and, thus, production of lipid mediators with diverse functions. In the past, studies on specific role of PLA2 on cells in the CNS are limited, partly because of the complex cellular make-up of the nervous tissue. However, understanding of the molecular actions of these PLA2s have improved with recent advances in techniques for separation and isolation of specific cell types in the brain tissue as well as development of sensitive molecular tools for analyses of proteins and lipids. A major goal here is to summarize recent studies on the characteristics and dynamic roles of the three major types of PLA2s and their oxidative products towards brain health and neurological disorders.

Data Analysis Model Design of Health Service Monitoring System for China's Elderly Population: The Proposal of the F-W Model Based on the Collaborative Governance Theory of Healthy Aging.

In the era of artificial intelligence, big data and 5G, health care for elderly people is facing an important digital transformation. The objective of this study is to design the data analysis module of the elderly health service monitoring system (HSMS) and attempt to put forward a new healthy aging (HA) model that is applicable not only to the individual HA, but also to the regional HA system. Based on the HA theory of collaborative governance, we divided the elderly HSMS into four modules, including physical health, mental health, ability of daily activity, and social participation. Then, factors that influence HA were assessed by stepwise logistic regression to build the analysis model, using the public micro-panel data of the China Health and Retirement Longitudinal Survey (CHARLS). Age (odds ratio (OR) = 1.55 (95% confidence interval (CI): 1.06-2.27)), living in urban areas (OR = 1.57 (95% CI: 1.03-2.39)), being literate (OR = 1.51 (95% CI: 1.01-2.23)), expecting to get long-term health care in the future from their grown children (OR = 1.69 (95% CI: 1.10-2.61)) and having literate grown children (OR = 2.01 (95% CI: 0.26-0.97)) had a significant positive impact on HA of elderly people. Therefore, the F-W (factors and weighs, also family and welfare) model is proposed in this paper. The outcomes can contribute with designing HSMS for different provinces and several different regions in China and leave a door open to improve the model and algorithm application for HSMS in the future studies.

Effects of Docosahexaenoic Acid and Its Peroxidation Product on Amyloid-ß Peptide-Stimulated Microglia.

Growing evidence suggests that docosahexaenoic acid (DHA) exerts neuroprotective effects, although the mechanism(s) underlying these beneficial effects are not fully understood. Here we demonstrate that DHA, but not arachidonic acid (ARA), suppressed oligomeric amyloid-ß peptide (oAß)-induced reactive oxygen species (ROS) production in primary mouse microglia and immortalized mouse microglia (BV2). Similarly, DHA but not ARA suppressed oAß-induced increases in phosphorylated cytosolic phospholipase A2 (p-cPLA2), inducible nitric oxide synthase (iNOS), and tumor necrosis factor-α (TNF-α) in BV2 cells. LC-MS/MS assay indicated the ability for DHA to cause an increase in 4-hydroxyhexenal (4-HHE) and suppress oAß-induced increase in 4-hydroxynonenal (4-HNE). Although oAß did not alter the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, exogenous DHA, ARA as well as low concentrations of 4-HHE and 4-HNE upregulated this pathway and increased production of heme oxygenase-1 (HO-1) in microglial cells. These results suggest that DHA modulates ARA metabolism in oAß-stimulated microglia through suppressing oxidative and inflammatory pathways and upregulating the antioxidative stress pathway involving Nrf2/HO-1. Understanding the mechanism(s) underlying the beneficial effects of DHA on microglia should shed light into nutraceutical therapy for the prevention and treatment of Alzheimer's disease (AD).

Azelnidipine Attenuates the Oxidative and NFκB Pathways in Amyloid-ß-Stimulated Cerebral Endothelial Cells.

Cerebral amyloid angiopathy (CAA), a condition depicting cerebrovascular accumulation of amyloid ß-peptide (Aß), is a common pathological manifestation in Alzheimer's disease (AD). In this study, we investigated the effects of Azelnidipine (ALP), a dihydropyridine calcium channel blocker known for its treatment of hypertension, on oligomeric Aß (oAß)-induced calcium influx and its downstream pathway in immortalized mouse cerebral endothelial cells (bEND3). We found that ALP attenuated oAß-induced calcium influx, superoxide anion production, and phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and calcium-dependent cytosolic phospholipase A2 (cPLA2). Both ALP and cPLA2 inhibitor, methylarachidonyl fluorophosphate (MAFP), suppressed oAß-induced translocation of NFκB p65 subunit to nuclei, suggesting that cPLA2 activation and calcium influx are essential for oAß-induced NFκB activation. In sum, our results suggest that calcium channel blocker could be a potential therapeutic strategy for suppressing oxidative stress and inflammatory responses in Aß-stimulated microvasculature in AD.

Cytosolic Phospholipase A2 Facilitates Oligomeric Amyloid-ß Peptide Association with Microglia via Regulation of Membrane-Cytoskeleton Connectivity.

Cytosolic phospholipase A2 (cPLA2) mediates oligomeric amyloid-ß peptide (oAß)-induced oxidative and inflammatory responses in glial cells. Increased activity of cPLA2 has been implicated in the neuropathology of Alzheimer's disease (AD), suggesting that cPLA2 regulation of oAß-induced microglial activation may play a role in the AD pathology. We demonstrate that LPS, IFNγ, and oAß increased phosphorylated cPLA2 (p-cPLA2) in immortalized mouse microglia (BV2). Aß association with primary rat microglia and BV2 cells, possibly via membrane-binding and/or intracellular deposition, presumably indicative of microglia-mediated clearance of the peptide, was reduced by inhibition of cPLA2. However, cPLA2 inhibition did not affect the depletion of this associated Aß when cells were washed and incubated in a fresh medium after oAß treatment. Since the depletion was abrogated by NH4Cl, a lysosomal inhibitor, these results suggested that cPLA2 was not involved in the degradation of the associated Aß. To further dissect the effects of cPLA2 on microglia cell membranes, atomic force microscopy (AFM) was used to determine endocytic activity. The force for membrane tether formation (Fmtf) is a measure of membrane-cytoskeleton connectivity and represents a mechanical barrier to endocytic vesicle formation. Inhibition of cPLA2 increased Fmtf in both unstimulated BV2 cells and cells stimulated with LPS + IFNγ. Thus, increasing p-cPLA2 would decrease Fmtf, thereby increasing endocytosis. These results suggest a role of cPLA2 activation in facilitating oAß endocytosis by microglial cells through regulation of the membrane-cytoskeleton connectivity.