Single-cell transcriptomic analysis reveals transcript enrichment in oxidative phosphorylation, fluid sheer stress, and inflammatory pathways in obesity-related glomerulopathy.

Obesity-related glomerulopathy (ORG) is an independent risk factor for chronic kidney disease and even progression to end-stage renal disease. Efforts have been undertaken to elucidate the mechanisms underlying the development of ORG and substantial advances have been made in the treatment of ORG, but relatively little is known about cell-specific changes in gene expression. To define the transcriptomic landscape at single-cell resolution, we analyzed kidney samples from four patients with ORG and three obese control subjects without kidney disease using single-cell RNA sequencing. We report for the first time that immune cells, including T cells and B cells, are decreased in ORG patients. Further analysis indicated that SPP1 was significantly up-regulated in T cells and B cells. This gene is related to inflammation and cell proliferation. Analysis of differential gene expression in glomerular cells (endothelial cells, mesangial cells, and podocytes) showed that these cell types were mainly enriched in genes related to oxidative phosphorylation, cell adhesion, thermogenesis, and inflammatory pathways (PI3K-Akt signaling, MAPK signaling). Furthermore, we found that the podocytes of ORG patients were enriched in genes related to the fluid shear stress pathway. Moreover, an evaluation of cell-cell communications revealed that there were interactions between glomerular parietal epithelial cells and other cells in ORG patients, with major interactions between parietal epithelial cells and podocytes. Altogether, our identification of molecular events, cell types, and differentially expressed genes may facilitate the development of new preventive or therapeutic approaches for ORG.

Comparison of orbital fibroblasts from Graves' ophthalmopathy and healthy control.

Graves' ophthalmopathy (GO) is an extrathyroidal manifestation of Graves' disease, Orbital fibroblasts (OFs) are recognized as key players in GO pathogenesis, involved in orbital inflammation, tissue remodeling, and fibrosis. This study offers a primary exploration of cell behavior and characteristics on OFs from GO (GO-OFs), and compared to OFs from healthy control (HC-OFs). Results reveal that GO-OFs exhibit delayed migration from tissue fragments, while no significant difference in cell proliferation is observed between GO-OFs and HC-OFs. Aberrant expression pattern of surface proteins Thy-1, TSHR, and IGF-1R suggests shared autoantigens and pathways between GO and GD, contributing to inflammation and fibrosis. Investigations into cytokine responses unveil elevated secretion of hyaluronic acid (HA) and prostaglandin E2 (PGE2) in GO-OFs, emphasizing their role in tissue remodeling. These findings deepen our understanding of OFs in GO pathogenesis, offering potential therapeutic avenues.

Helicobacter pylori causes gastric dysbacteriosis in chronic gastritis patients.

Gastric mucosal samples were procured and underwent the sequencing of 16S ribosomal RNA (16S rRNA) via Illumina high-throughput sequencing technology to explore the impact of Helicobacter pylori (H. pylori) infection on the composition of gastric flora in chronic gastritis (CG) patients. In the results, the operational taxonomic unit (OTU) analysis revealed an overlap of 5706 OTUs shared between the two groups. The top 5 abundance ranking (TOP5) phyla comprised Bacteroidetes, Proteobacteria, Firmicutes, Actinobacteria, and Epsilonbacteraeota, while the TOP5 genus was Lachnospiraceae_NK4A136_group, Helicobacter, Bacteroides, Klebsiella, and Pseudomonas. In the metabolic pathways at the Kyoto Encyclopedia of Genes and Genomes (KEGG)_L3 level, conspicuous variations across seven functions were observed between the H. pylori-positive (HP_Pos) and H. pylori-negative (HP_Neg) groups. Subsequently, functional gene enrichment in KEGG pathways was further validated through animal experimentation. In contrast to the mice in the HP_Neg group, those infected with H. pylori manifested an infiltration of inflammatory cells, an augmentation in gastric acid secretion, and conspicuously elevated scores regarding gastric activity, along with heightened levels of malondialdehyde. In conclusion, CG patients infected with H. pylori displayed a disorder in gastric flora, furnishing a theoretical basis for the prophylaxis of H. pylori infection and its associated pathogenic ramifications.

Neferine Targeted the NLRC5/NLRP3 Pathway to Inhibit M1-type Polarization and Pyroptosis of Macrophages to Improve Hyperuricemic Nephropathy.

BACKGROUND: Neferine (Nef) has a renal protective effect. This research intended to explore the impact of Nef on hyperuricemic nephropathy (HN). METHODS: Adenine and potassium oxonate were administered to SD rats to induce the HN model. Bone marrow macrophages (BMDM) and NRK-52E were used to construct a transwell co-culture system. The polarization of BMDM and apoptosis levels were detected using immunofluorescence and flow cytometry. Renal pathological changes were detected using hematoxylin-eosin (HE) and Masson staining. Biochemical methods were adopted to detect serum in rats. CCK-8 and EDU staining were used to assess cell activity and proliferation. RT-qPCR and western blot were adopted to detect NLRC5, NLRP3, pyroptosis, proliferation, and apoptosis-related factor levels. RESULTS: After Nef treatment, renal injury and fibrosis in HN rats were inhibited, and UA concentration, urinary protein, BUN, and CRE levels were decreased. After Nef intervention, M1 markers, pyroptosis-related factors, and NLRC5 levels in BMDM stimulated with uric acid (UA) treatment were decreased. Meanwhile, the proliferation level of NRK-52E cells co-cultured with UA-treated BMDM was increased, but the apoptosis level was decreased. After NLRC5 overexpression, Nef-induced regulation was reversed, accompanied by increased NLRP3 levels. After NLRP3 was knocked down, the levels of M1-type markers and pyroptosis-related factors were reduced in BMDM. CONCLUSION: Nef improved HN by inhibiting macrophages polarized to M1-type and pyroptosis by targeting the NLRC5/NLRP3 pathway. This research provides a scientific theoretical basis for the treatment of HN.

The risk factors for arteriovenous fistula dysfunction in maintenance hemodialysis patients: A cross-sectional study.

INTRODUCTION: Arteriovenous fistula (AVF) dysfunction is a prevalent complication among maintenance hemodialysis patients. However, the factors influencing AVF patency remain unclear. To address this, we conducted a study aimed at identifying factors contributing to AVF dysfunction in this patient population. METHODS: The study compared clinical data, vascular calcification score, and laboratory data focusing on blood cell composition and coagulation in 100 maintenance hemodialysis patients in whom an AVF had been inserted from January through September of 2022. The patients were divided into a group in which the AVF functioned without issues and a group in which the AVF was dysfunctional, defined as not able to provide a blood flow of greater than 200 mL/min. FINDINGS: Patients in the 2 groups (56 in the dysfunctional AVF group and 44 in the group with satisfactory AVF function) were similar demographically. Compared with the normally functioning AVF group, the AVF dysfunction group exhibited significantly higher Agatston calcium scores (20.5 [1.28, 298] median [Q1, Q3] vs. 1.14 [0.00, 11.6]; p = 0.01), elevated triglyceride levels (1.1 [0.6, 1.2] mmol/L vs. 0.5 [0.3, 0.8]; p < 0.01), increased prothrombin activity (113 ± 22.1% vs. 99.4 ± 23.1; p < 0.01), lower prothrombin time (10.4 [9.8, 10.8] s vs. 11.0 [10.3, 11.5]; p < 0.01), higher red blood cell (RBC) counts (3.5 ± 0.7 · 1012/L vs. 3.0 ± 0.7; p < 0.01), and elevated hemoglobin levels (98.0 ± 21.8 g/L vs. 84.9 ± 24.2; p < 0.01). Higher C-reactive protein (20.2 [3.3, 20.2] mg/L vs. 17.8 [6.2, 17.8]; p = 0.01) and procalcitonin levels (0.9 [0.4, 0.9] ng/mL vs. 0.5 [0.2, 0.7]; p < 0.01) were also noted. Logistic regression analysis indicated that platelet/lymphocyte ratio, monocyte/lymphocyte ratio, and RBC count were factors associated with AVF dysfunction. Increased monocyte/lymphocyte ratio and RBC count correlated with higher risk, while a higher platelet/lymphocyte ratio was associated with lower risk. DISCUSSION: Arteriovenous fistula dysfunction in maintenance hemodialysis patients is associated with higher proportions of specific hematological parameters, particularly elevated RBC count, and altered platelet/lymphocyte and monocyte/lymphocyte ratios.

Gut microbial network signatures of early colonizers in preterm neonates with extrauterine growth restriction.

BACKGROUND: Extrauterine growth restriction (EUGR) represents a prevalent condition observed in preterm neonates, which poses potential adverse implications for both neonatal development and long-term health outcomes. The manifestation of EUGR has been intricately associated with perturbations in microbial and metabolic profiles. This study aimed to investigate the characteristics of the gut microbial network in early colonizers among preterm neonates with EUGR. METHODS: Twenty-nine preterm infants participated in this study, comprising 14 subjects in the EUGR group and 15 in the normal growth (AGA) group. Meconium (D1) and fecal samples were collected at postnatal day 28 (D28) and 1 month after discharge (M1). Subsequently, total bacterial DNA was extracted and sequenced using the Illumina MiSeq system, targeting the V3-V4 hyper-variable regions of the 16S rRNA gene. RESULTS: The outcomes of principal coordinates analysis (PCoA) and examination of the microbial network structure revealed distinctive developmental trajectories in the gut microbiome during the initial three months of life among preterm neonates with and without EUGR. Significant differences in microbial community were observed at the D1 (P = 0.039) and M1 phases (P = 0.036) between the EUGR and AGA groups, while a comparable microbial community was noted at the D28 phase (P = 0.414). Moreover, relative to the AGA group, the EUGR group exhibited significantly lower relative abundances of bacteria associated with secretion of short-chain fatty acids, including Lactobacillus (P = 0.041) and Parabacteroides (P = 0.033) at the D1 phase, Bifidobacterium at the D28 phase, and genera Dysgonomonas (P = 0.042), Dialister (P = 0.02), Dorea (P = 0.042), and Fusobacterium (P = 0.017) at the M1 phase. CONCLUSION: Overall, the present findings offer crucial important insights into the distinctive gut microbial signatures exhibited by earlier colonizers in preterm neonates with EUGR. Further mechanistic studies are needed to establish whether these differences are the cause or a consequence of EUGR.

Characteristics and Prognostic Factors of SARS-CoV-2 Omicron Variant Infection in Hemodialysis Patients: A Single-Center Study in China.

INTRODUCTION: This study aimed to evaluate the characteristics and prognostic factors for coronavirus disease 2019 (COVID-19) patients on maintenance hemodialysis (HD). METHODS: All admitted HD patients who were infected with SARS-CoV-2 from December 1, 2022, to January 31, 2023, were included. Patients with pneumonia were further classified into the mild, moderate, severe, and critical illness. Clinical symptoms, laboratory results, radiologic findings, treatment, and clinical outcomes were collected. Independent risk factors for progression to critical disease and in-hospital mortality were determined by the multivariate regression analysis. The receiver operating characteristic analysis with the area under the curve was used to evaluate the predictive performance of developing critical status and in-hospital mortality. RESULTS: A total of 182 COVID-19 patients with HD were included, with an average age of the 61.55 years. Out of the total, 84 (46.1%) patients did not have pneumonia and 98 (53.8%) patients had pneumonia. Among patients with pneumonia, 48 (49.0%) had moderate illness, 26 (26.5%) severe illness, and 24 (24.5%) critical illness, respectively. Elder age [HR (95% CI): 1.07 (1.01-1.13), p <0.01], increased levels of lactate dehydrogenase (LDH) [1.01 (1.003-1.01), p <0.01], and C-reactive protein (CRP) [1.01 (1.00-1.01), p = 0.04] were risk factors for developing critical illness. Elder age [1.11 (1.03-1.19), p = 0.01], increased procalcitonin (PCT) [1.07 (1.02-1.12), p = 0.01], and LDH level [1.004 (1-1.01), p = 0.03] were factors associated with increased risk of in-hospital mortality. CONCLUSION: Age, CRP, PCT, and LDH can be used to predict negative clinical outcomes for HD patients with COVID-19 pneumonia.

A protective role of nintedanib in peritoneal fibrosis through H19-EZH2-KLF2 axis via impeding mesothelial-to-mesenchymal transition.

BACKGROUND: Peritoneal fibrosis (PF), a common complication of long-term peritoneal dialysis, accounts for peritoneal ultrafiltration failure to develop into increased mortality. Nintedanib has previously been shown to protect against multi-organ fibrosis, including PF. Unfortunately, the precise molecular mechanism underlying nintedanib in the pathogenesis of PF remains elusive. METHODS: The mouse model of PF was generated by chlorhexidine gluconate (CG) injection with or without nintedanib administration, either with the simulation for the cell model of PF by constructing high-glucose (HG)-treated human peritoneal mesothelial cells (HPMCs). HE and Masson staining were applied to assess the histopathological changes of peritoneum and collagen deposition. FISH, RT-qPCR, western blot and immunofluorescence were employed to examine distribution or expression of targeted genes. Cell viability was detected using CCK-8 assay. Cell morphology was observed under a microscope. RNA immunoprecipitation (RIP) and chromatin immunoprecipitation (ChIP) assays were applied to validate the H19-EZH2-KLF2 regulatory axis. RESULTS: Aberrantly overexpressed H19 was observed in both the mouse and cell model of PF, of which knockdown significantly blocked HG-induced mesothelial-to-mesenchymal transition (MMT) of HPMCs. Moreover, loss of H19 further strengthened nintedanib-mediated suppressive effects against MMT process in a mouse model of PF. Mechanistically, H19 could epigenetically repressed KLF2 via recruiting EZH2. Furthermore, TGF-ß/Smad pathway was inactivated by nintedanib through mediating H19/KLF2 axis. CONCLUSION: In summary, nintedanib disrupts MMT process through regulating H19/EZH2/KLF2 axis and TGF-ß/Smad pathway, which laid the experimental foundation for nintedanib in the treatment of PF.

Risk factors for arteriovenous fistula dysfunction in hemodialysis patients: a retrospective study.

Arteriovenous fistula (AVF) is the first choice of vascular access in hemodialysis (HD) patients. However, the correlations between patient factors and the arteriovenous fistula patency remain unclear. Therefore, our study investigates the risk factors associated with AVF dysfunction in HD patients. A total of 233 end-stage renal disease (ESDR) patients who met the study inclusion criteria in the Nephrology Department of Hunan Provincial People's Hospital between December 2020 and June 2022 were included in this study. The baseline demographic, clinical and laboratory parameters were collected at the time of AVF creation and analyzed. Of the 233 ESRD patients, 146 (62.7%) were male and the mean age was 56.11 ± 12.14 (21-82) years. The patients were followed for a median time of 14 months. Kaplan-Meier analysis showed a 6-, 12- and 24-month post-placement survival of 87.1%, 82.8% and 80.7%, respectively. Univariate Cox regression analysis revealed weight (HR, 1.03; P = 0.03) as a predictor for the loss of vascular access functionality. In addition, multivariate Cox regression analysis further demonstrated that sex (HR, 3.41; P = 0.03), weight (HR 1.08; P < 0.01) and phosphorus level (HR: 3.03; P = 0.01) are independent risk factors for AVF dysfunction. AVF dysfunction is highly associated with several risk factors including weight, phosphorus level, and sex. Positive intervention strategies targeting these potential factors, such as weight loss or oral phosphate binders could improve the long-term success of AVF.

The Physicochemical Attributes, Volatile Compounds, and Antioxidant Activities of Five Plum Cultivars in Sichuan.

Plum (Prunus salicina Lindl.) is an important stone fruit crop in Sichuan that is increasingly in demand by consumers owing to its flavor and outstanding nutraceutical properties. The physicochemical characteristics, antioxidant capacity, and volatile profiles of five traditional and new plum cultivars in Sichuan were determined using high-performance liquid chromatography and gas chromatography time-of-flight mass spectrometry. The results showed that all plums exhibited an appropriate quality profile for fresh consumption; the new cultivar 'ZH' exhibited the highest soluble solids content, sugar-acid ratio, total phenolic content, total flavonoid content, and antioxidant capacity. High sugar-low acid properties were observed in five plum cultivars. Sucrose was the main sugar, while quinic acid and malic acid were the main organic acids. The plums were rich in volatile compounds and had specific volatile characteristics. A total of 737 volatiles were identified in the plum fruit, and orthogonal partial least-squares discriminant analysis was employed to screen 40 differential volatiles as markers for cultivar distinction. These findings offer comprehensive information on the physicochemical characteristics, antioxidant capacity, and volatile profiles of plums.

Explore the changes of intestinal flora in patients with coronavirus disease 2019 based on bioinformatics.

Background: Studies have revealed that there were significant changes in intestinal flora composition in patients with coronavirus disease 2019 (COVID-19) compared to non-COVID-19 patients, regardless of whether they were treated with medication. Therefore, a comprehensive study of the intestinal flora of COVID-19 patients is needed to further understand the mechanisms of COVID-19 development. Methods: In total, 20 healthy samples and 20 COVID-19 samples were collected in this study. Firstly, alpha diversity and beta diversity were analyzed to assess whether there were difference in species richness and diversity as well as species composition between COVID-19 and control groups. The observed features index, Evenness index, PD index, and Shannon index were utilized to measure alpha diversity. The principal coordinates analysis (PCoA) and non-metric multidimensional scaling (NMDS) were performed to analyzed beta diversity. Linear discriminant analysis Effect Size (LEfSe) was utilized to analyze the variability in the abundance of bacterial taxa from different classification levels. The random forest (RF), Least absolute shrinkage and selection operator (LASSO), and univariate logistic regression were utilized to identify key Amplicon Sequence Variant (ASVs). Finally, the relevant networks of bacterial taxa were created in COVID-19 and control groups, separately. Results: There were more species in the control group than in COVID-19 group. The observed features index, Shannon index, and Evenness index in the control groups were markedly higher than in the COVID-19 group. Therefore, there were marked variations in bacterial taxa composition between the COVID-19 and control groups. The nine bacterial taxa were significantly more abundant in the COVID-19 group, such as g-Streptococcus, f-Streptococcaceae, o-Lactobacillales, c-Bacilli and so on. In the control group, 26 bacterial taxa were significantly more abundant, such as c-Clostrjdia, o-Oscillospirales, f-Ruminococcaceae, etc. The 5 key ASVs were obtained through taking the intersection of the characteristic ASVs obtained by the three algorithms, namely ASV6, ASV53, ASV92, ASV96, and ASV105, which had diagnostic value for COVID-19. The relevance network in the control group was more complex compared to the COVID-19 group. Conclusion: Our findings provide five key ASVs for diagnosis of COVID-19, providing a scientific reference for further studies of COVID-19.

Exosomes in Diabetic Kidney Disease.

Background: Diabetic kidney disease (DKD) is a major complication of diabetes mellitus and a common cause of end-stage kidney disease. The incidence of DKD is rising worldwide and associated with increased morbidity and premature mortality, indicating an urgent need to further explore the underlying pathogenesis and potential biomarkers. Exosomes are nanoscale vesicles secreted by all cell types that play an essential role in cellular homeostasis and intercellular communications by transferring molecular cargoes between different cells. Summary: Emerging evidence indicates that exosomes are both a crucial signaling mediator and a potential biomarker of DKD. On the one hand, exosomes released by various kidney resident cells facilitate the cell-cell crosstalk as a contributing factor in DKD; on the other hand, exosomes can be detected from urine and blood and have emerged as promising noninvasive biomarkers for DKD. Key Messages: Herein, we highlight the recent advances in research on the role of exosomes from different kidney resident cells in DKD. We further discuss the potential use of urine exosomes as biomarkers and therapeutic agents.

Heparin-induced thrombocytopenia after switching from unfractionated heparin to low-molecular-weight heparin: A case report and literature review.

Heparin-induced thrombocytopenia (HIT) is a severe, potentially life-threatening adverse drug reaction. It is an antibody-mediated process involving platelet activation. Heparin and low-molecular-weight heparin (LMWH) are routinely used in uremic patients undergoing hemodialysis. Here, we report a case of HIT that occurred in a hemodialysis patient after she switched from heparin to the LMWH nadroparin for anticoagulation during hemodialysis. The clinical features, incidence, mechanism, and treatment of HIT are discussed.

Preventive effects of Mycobacterium tuberculosis DNA vaccines on the mouse model with latent tuberculosis infection.

Background: About a quarter of the world's population with latent tuberculosis infection (LTBI) are the main source of active tuberculosis. Bacillus Calmette Guerin (BCG) cannot effectively control LTBI individuals from developing diseases. Latency-related antigens can induce T lymphocytes of LTBI individuals to produce higher IFN-γ levels than tuberculosis patients and normal subjects. Herein, we firstly compared the effects of M. tuberculosis (MTB) ag85ab and 7 latent DNA vaccines on clearing latent MTB and preventing its activation in the mouse LTBI model. Methods: A mouse LTBI model was established, and then immunized respectively with PBS, pVAX1 vector, Vaccae vaccine, ag85ab DNA and 7 kinds of latent DNAs (including rv1733c, rv2660c, rv1813c, rv2029c, rv2628, rv2659c and rv3407) for three times. The mice with LTBI were injected with hydroprednisone to activate the latent MTB. Then, the mice were sacrificed for the bacterial count, histopathological examination, and immunological evaluation. Results: Using chemotherapy made the MTB latent in the infected mice, and then using hormone treatment reactivated the latent MTB, indicating that the mouse LTBI model was successfully established. After the mouse LTBI model was immunized with the vaccines, the lung colony-forming units (CFUs) and lesion degree of mice in all vaccines group were significantly decreased than those in the PBS group and vector group (P<0.0001, P<0.05). These vaccines could induce antigen-specific cellular immune responses. The number of IFN-γ effector T cells spots secreted by spleen lymphocytes in the ag85ab DNA group was significantly increased than those in the control groups (P<0.05). In the splenocyte culture supernatant, IFN-γ and IL-2 levels in the ag85ab, rv2029c, and rv2659c DNA groups significantly increased (P<0.05), and IL-17A levels in ag85ab and rv2659c DNA groups also significantly increased (P<0.05). Compared with the PBS and vector groups, the proportion of CD4+CD25+FOXP3+ regulatory T cells in spleen lymphocytes of ag85ab, rv2660c, rv2029c, and rv3407 DNA groups were significantly reduced (P<0.05). Conclusions: MTB ag85ab and 7 kinds of latent DNA vaccines showed immune preventive efficacies on a mouse model of LTBI, especially the rv2659c, and rv1733c DNA. Our findings will provide candidates for the development of new multi-stage vaccines against TB.

Tamlana laminarinivorans sp. nov. and Tamlana sargassicola sp. nov., two novel species isolated from Sargassum, show genomic and physiological adaptations for a Sargassum-associated lifestyle.

The genus Tamlana from the Bacteroidota currently includes six validated species. Two strains designated PT2-4T and 62-3T were isolated from Sargassum abundant at the Pingtan island coast in the Fujian Province of China. 16S rRNA gene sequence analysis showed that the closest described relative of strains PT2-4T and 62-3T is Tamlana sedimentorum JCM 19808T with 98.40 and 97.98% sequence similarity, respectively. The 16S rRNA gene sequence similarity between strain PT2-4T and strain 62-3T was 98.68 %. Furthermore, the highest average nucleotide identity values were 87.34 and 88.97 % for strains PT2-4T and 62-3T, respectively. The highest DNA-DNA hybridization (DDH) value of strain PT2-4T was 35.2 % with strain 62-3T, while the DDH value of strain 62-3T was 37.7 % with T. sedimentorum JCM 19808T. Growth of strains PT2-4T and 62-3T occurs at 15-40 °C (optimum, 30 °C) with 0-4 % (w/v) NaCl (optimum 0-1 %). Strains PT2-4T and 62-3T can grow from pH 5.0 to 10.0 (optimum, pH 7.0). The major fatty acids of strains PT2-4T and 62-3T are iso-C15 : 0 and iso G-C15 : 1. MK-6 is the sole respiratory quinone. Genomic and physiological analyses of strains PT2-4T and 62-3T showed corresponding adaptive features. Significant adaptation to the growth environment of macroalgae includes the degradation of brown algae-derived diverse polysaccharides (alginate, laminarin and fucoidan). Notably, strain PT2-4T can utilize laminarin, fucoidan and alginate via specific carbohydrate-active enzymes encoded in polysaccharide utilization loci, rarely described for the genus Tamlana to date. Based on their distinct physiological characteristics and the traits of utilizing polysaccharides from Sargassum, strains PT2-4T and 62-3T are suggested to be classified into two novel species, Tamlana laminarinivorans sp. nov. and Tamlana sargassicola sp. nov. (type strain PT2-4T=MCCC 1K04427T=KCTC 92183T and type strain 62-3T=MCCC 1K04421T=KCTC 92182T).

Association between healthy lifestyle and memory decline in older adults: 10 year, population based, prospective cohort study.

OBJECTIVE: To identify an optimal lifestyle profile to protect against memory loss in older individuals. DESIGN: Population based, prospective cohort study. SETTING: Participants from areas representative of the north, south, and west of China. PARTICIPANTS: Individuals aged 60 years or older who had normal cognition and underwent apolipoprotein E (APOE) genotyping at baseline in 2009. MAIN OUTCOME MEASURES: Participants were followed up until death, discontinuation, or 26 December 2019. Six healthy lifestyle factors were assessed: a healthy diet (adherence to the recommended intake of at least 7 of 12 eligible food items), regular physical exercise (≥150 min of moderate intensity or ≥75 min of vigorous intensity, per week), active social contact (≥twice per week), active cognitive activity (≥twice per week), never or previously smoked, and never drinking alcohol. Participants were categorised into the favourable group if they had four to six healthy lifestyle factors, into the average group for two to three factors, and into the unfavourable group for zero to one factor. Memory function was assessed using the World Health Organization/University of California-Los Angeles Auditory Verbal Learning Test, and global cognition was assessed via the Mini-Mental State Examination. Linear mixed models were used to explore the impact of lifestyle factors on memory in the study sample. RESULTS: 29 072 participants were included (mean age of 72.23 years; 48.54% (n=14 113) were women; and 20.43% (n=5939) were APOE ε4 carriers). Over the 10 year follow-up period (2009-19), participants in the favourable group had slower memory decline than those in the unfavourable group (by 0.028 points/year, 95% confidence interval 0.023 to 0.032, P<0.001). APOE ε4 carriers with favourable (0.027, 95% confidence interval 0.023 to 0.031) and average (0.014, 0.010 to 0.019) lifestyles exhibited a slower memory decline than those with unfavourable lifestyles. Among people who were not carriers of APOE ε4, similar results were observed among participants in the favourable (0.029 points/year, 95% confidence interval 0.019 to 0.039) and average (0.019, 0.011 to 0.027) groups compared with those in the unfavourable group. APOE ε4 status and lifestyle profiles did not show a significant interaction effect on memory decline (P=0.52). CONCLUSION: A healthy lifestyle is associated with slower memory decline, even in the presence of the APOE ε4 allele. This study might offer important information to protect older adults against memory decline. TRIAL REGISTRATION: ClinicalTrials.gov NCT03653156.

Mutation of conserved residues in the laminarinase Lam1092 increases the antioxidant activity of the laminarin product hydrolysates.

Laminarinases from the glycoside hydrolase 16 (GH16) family are hydrolases that break ß-1,3-glycosidic bonds in laminarin, which is the major storage polysaccharide present in brown algae or microalgae. We explored a laminarinase from the marine Flavobacteriaceae species Tamlana sp. PT2-4 at the structural and functional levels. Based on a homology model of Lam1092-substrate interactions, the large active groove crossing Lam1092 was deemed a reasonable pathway for the bent substrates for hydrolysis. Eight residues (Gly361, Asn364, Arg400, His466, Asp449, Glu452, Ser477 and Thr538) were selected for mutagenesis based on the interactions of Lam1092 in complex with Lam4/Lam6. Ultimately, we generated eight mutants of Lam1092, and the antioxidant activities of the hydrolysates of two mutants (G361A and H466A) showed significant improvement. These results show that the antioxidant activity of laminarin can be improved by laminarinase mutation, which will be beneficial for developing efficient approaches to engineer the substrate specificity of laminarinases and improve the application of bioactive laminarioligosaccharides.

miR-128-3p inhibits high-glucose-induced peritoneal mesothelial cells fibrosis via PAK2/SyK/TGF-ß1 axis.

AIM: To elucidate the mechanism of miR-128-3p in peritoneal fibrosis (PF). METHODS: Peritoneal mesothelial cells (PMCs) were dealt with high glucose (HG) for 3 days. The expressions of miR-128-3p, p21-activated kinase 2 (PAK2), spleen tyrosine kinase (SyK), and transforming growth factor-ß1 (TGF-ß1) were detected with quantitative real-time reverse transcription polymerase chain reaction. The levels of IL-1ß, TNF-α, IL-6, and monocyte chemotactic protein-1 in supernatant were measured by ELISA. Proteins of TGF-ß1, SyK, PAK2, α-SMA, collagen I, vimentin, ERK/AP-1, and IκBα/NF-κB pathway related proteins were measured by Western blot. The correlation between miR-128-3p and PAK2 was found by bioinformatics analysis and luciferase reporter gene analysis. RESULTS: miR-128-3p was decreased while PAK2, SyK, and TGF-ß1 were increased in HG-induced PMCs. Moreover, miR-128-3p inhibited HG-induced fibrosis and inflammation in PMCs by targeting PAK2. PAK2 activated SyK, which induced TGF-ß1 expression through ERK/AP-1 and IκBα/NF-κB pathways to promote HG-induced fibrosis of PMCs. CONCLUSION: miR-128-3p inhibited HG-induced PMCs fibrosis via PAK2/SyK/TGF-ß1 axis.

Effects of Purine Metabolism-Related LINC01671 on Tumor Heterogeneity in Kidney Renal Clear Cell Carcinoma.

BACKGROUND: Renal cell carcinoma has several subtypes, with kidney renal clear cell carcinoma (KIRC) being the most common and heterogeneous. Purine metabolism is associated with cancer progression. However, the role of purine metabolism-related long non-coding RNAs (lncRNAs) in KIRC remains unknown. METHODS: KIRC were grouped into Cluster-1 and Cluster-2 based on purine genes. Limma package was used to identify differentially expressed lncRNAs between two classes of purine genes. Single-factor screening was used followed by random forest dimensionality reduction and Lasso method to screen lncRNAs. A risk score model (Purine Score) containing the 3 lncRNAs was developed using the Lasso method. RESULTS: A total of 22 differentially expressed lncRNAs were identified. These were reduced to a final set of three (LINC01671, ARAP1-AS1 and LINC02747). Age and metastasis (M) were identified as independent prognostic factors for KIRC using univariate and multivariate Cox analysis. An abnormal immune cell response was also associated with patient survival. The Purine Score correlated with abnormal expression of immune checkpoint genes. Genetic analysis of KIRC found somatic mutations in TP53, TRIOBP, PBRM1, PKHD1, VHL, NPHP3, TLN2, CABIN1, ABCC6, XIRP2, and CHD4. In vitro cell experiments showed that knockdown of LINC01671 promoted the proliferation and migration of 786-O cells, while inhibiting apoptosis. Overexpression of LINC01671 inhibited the proliferation and migration of CAKI-1 cells, while promoting apoptosis. Gene Set Enrichment Analysis (GSEA) analysis revealed that LINC01671 was significantly enriched in the MAPK, NF-kappa B, mTOR, PI3K-Akt, and Wnt signaling pathways. CONCLUSIONS: LINC01671 may be a novel prognostic marker with important therapeutic value for KIRC.

Treatment of membranous nephropathy with crescent nephritis by rituximab: A case report.

BACKGROUND: Crescent formation is rare in primary membranous nephropathy (MN). The mechanism of crescent formation is unknown and the treatments are tentative. PATIENT CONCERNS: A 71-year-old woman presented with nephrotic syndrome, hematuria, and rapidly progressive kidney dysfunction. DIAGNOSIS: Kidney biopsy was performed, and the diagnosis was MN in combination with crescentic glomerulonephritis. Circulating anti-PLA2R was detected of a high level. INTERVENTIONS: The patient received rituximab besides corticosteroids. OUTCOMES: The patient achieved complete remission of proteinuria and recovery of kidney function. CONCLUSION: Our case suggests that there is a pathologic feature of MN and crescents in the absence of known immunologic factors as well as rituximab could serve as an effective cure and could be considered in serious MN conditions.