Frailty and psychiatric disorders: A bidirectional Mendelian randomization study.

BACKGROUND: The association between frailty and psychiatric disorders has been reported in observational studies. However, it is unclear whether frailty facilitates the appearance of psychiatric disorders or vice versa. Therefore, we conducted a bidirectional Mendelian randomization (MR) study to evaluate the causality. METHODS: Independent genetic variants associated with frailty index (FI) and psychiatric disorders were obtained from large genome-wide association studies (GWAS). The inverse variance weighted method was utilized as the primary method to estimate causal effects, followed by various sensitivity analyses. Multivariable analyses were performed to further adjust for potential confounders. RESULTS: The present MR study revealed that genetically predicted FI was significantly and positively associated with the risk of major depressive disorder (MDD) (odds ratio [OR] 1.79, 95 % confidence interval [CI] 1.48-2.15, P = 1.06 × 10-9), anxiety disorder (OR 1.61, 95 % CI 1.19-2.18, P = 0.002) and neuroticism (OR 1.38, 95 % CI 1.18-1.61, P = 3.73 × 10-5). In the reverse MR test, genetic liability to MDD (beta 0.232, 95 % CI 0.189-0.274, P = 1.00 × 10-26) and neuroticism (beta 0.128, 95 % CI 0.081-0.175, P = 8.61 × 10-8) were significantly associated with higher FI. Multivariable analyses results supported the causal association between FI and MDD and neuroticism. LIMITATIONS: Restriction to European populations, and sample selection bias. CONCLUSIONS: Our study suggested a bidirectional causal association between frailty and MDD neuroticism, and a positive correlation of genetically predicted frailty on the risk of anxiety disorder. Developing a deeper understanding of these associations is essential to effectively manage frailty and optimize mental health in older adults.

Fatigue database of complex metallic alloys.

The past few decades have witnessed rapid progresses in the research and development of complex metallic alloys such as metallic glasses and multi-principal element alloys, which offer new solutions to tackle engineering problems of materials such as the strength-toughness conflict and deployment in harsh environments and/or for long-term service. A fatigue database (FatigueData-CMA2022) is compiled from the literature by the end of 2022. Data for both metallic glasses and multi-principal element alloys are included and analyzed for their statistics and patterns. Automatic extraction and manual examination are combined in the workflow to improve the efficiency of processing, the quality of published data, and the reusability. The database contains 272 fatigue datasets of S-N (the stress-life relation), ε-N (the strain-life relation), and da/dN-ΔK (the relation between the fatigue crack growth rate and the stress intensity factor range) data, together with the information of materials, processing and testing conditions, and mechanical properties. The database and scripts are released in open repositories, which are designed in formats that can be continuously expanded and updated.

Causal effects of gut microbiota on sepsis: a two-sample Mendelian randomization study.

Background: Recent studies had provided evidence that the gut microbiota is associated with sepsis. However, the potential causal relationship remained unclear. Methods: The present study aimed to explore the causal effects between gut microbiota and sepsis by performing Mendelian randomization (MR) analysis utilizing publicly accessible genome-wide association study (GWAS) summary-level data. Gut microbiota GWAS (N = 18,340) were obtained from the MiBioGen study and GWAS-summary-level data for sepsis were gained from the UK Biobank (sepsis, 10,154 cases; 452,764 controls). Two strategies were used to select genetic variants, i.e., single nucleotide polymorphisms (SNPs) below the locus-wide significance level (1 × 10-5) and the genome-wide statistical significance threshold (5 × 10-8) were chosen as instrumental variables (IVs). The inverse variance weighted (IVW) was used as the primary method for MR study, supplemented by a series of other methods. Additionally, a set of sensitivity analysis methods, including the MR-Egger intercept test, Mendelian randomized polymorphism residual and outlier (MR-PRESSO) test, Cochran's Q test, and leave-one-out test, were carried out to assess the robustness of our findings. Results: Our study suggested that increased abundance of Deltaproteobacteria, Desulfovibrionales, Catenibacterium, and Hungatella were negatively associated with sepsis risk, while Clostridiaceae1, Alloprevotella, LachnospiraceaeND3007group, and Terrisporobacter were positively correlated with the risk of sepsis. Sensitivity analysis revealed no evidence of heterogeneity and pleiotropy. Conclusion: This study firstly found suggestive evidence of beneficial or detrimental causal associations of gut microbiota on sepsis risk by applying MR approach, which may provide valuable insights into the pathogenesis of microbiota-mediated sepsis and strategies for sepsis prevention and treatment.

Creating a Thermostable ß-Glucuronidase Switch for Homogeneous Immunoassay by Disruption of Conserved Salt Bridges at Diagonal Interfaces.

Escherichia coli ß-glucuronidase (GUS) has been used as a reporter enzyme in molecular biology and engineered as an enzyme switch for the development of homogeneous biosensors. In this study, we developed a thermostable GUS enzyme switch based on the thermostable GUS mutant TR3337 by disrupting a conserved salt bridge (H514-E523) between the diagonal subunits of its homotetramer. A combinatorial library (240 variants) was screened using a novel high-throughput strategy, which led to the identification of mutant DLW (H514D/M516L/Y517W) as a functional enzyme switch in a caffeine-recognizing immunosensor. Molecular dynamics simulations were performed to predict the topology change around position 514, and a side-chain flip of D514 (repulsion with E523) was observed in the DLW mutant. Up to 1.8-fold of signal-to-background ratio was confirmed when measured at up to 45 °C, thereby highlighting the DLW mutant as a versatile tool for developing thermostable immunosensors for in vitro and in cellulo applications.

Causal association of lipoprotein-associated phospholipids on the risk of sepsis: a Mendelian randomization study.

Background: Many previous studies have revealed a close relationship between lipoprotein metabolism and sepsis, but their causal relationship has, until now, remained unclear. Therefore, we performed a two-sample Mendelian randomization analysis to estimate the causal relationship of lipoprotein-associated phospholipids with the risk of sepsis. Materials and methods: A two-sample Mendelian randomization (MR) analysis was performed to investigate the causal relationship between lipoprotein-associated phospholipids and sepsis based on large-scale genome-wide association study (GWAS) summary statistics. MR analysis was performed using a variety of methods, including inverse variance weighted as the primary method, MR Egger, weighted median, simple mode, and weighted mode as complementary methods. Further sensitivity analyses were used to test the robustness of the data. Results: After Bonferroni correction, the results of the MR analysis showed that phospholipids in medium high-density lipoprotein (HDL; ORIVW = 0.82, 95% CI 0.71-0.95, P = 0.0075), large HDL (ORIVW = 0.92, 95% CI 0.85-0.98, P = 0.0148), and very large HDL (ORMR Egger = 0.83, 95% CI 0.72-0.95, P = 0.0134) had suggestive causal relationship associations with sepsis. Sensitivity testing confirmed the accuracy of these findings. There was no clear association between other lipoprotein-associated phospholipids and sepsis risk. Conclusions: Our MR analysis data suggestively showed a correlation between higher levels of HDL-associated phospholipids and reduced risk of sepsis. Further studies are required to determine the underlying mechanisms behind this relationship.

Activation of Transcription Factor EB Alleviates Tubular Epithelial Cell Injury via Restoring Lysosomal Homeostasis in Diabetic Nephropathy.

Disruption of lysosomal homeostasis contributes to the tubulopathy of diabetic nephropathy; however, its underlying mechanisms remain unclear. Herein, we report that decreased activity of transcription factor EB (TFEB) is responsible for the disturbed lysosome biogenesis and clearance in this pathological process. This was confirmed by the findings that insufficient lysosomal replenishment and damaged lysosomal clearance coincided with TFEB inactivation, which was mediated by mTOR hyperactivation in the renal tubular epithelial cells (TECs) of diabetic nephropathy. Furthermore, either TFEB overexpression or pharmacological activation of TFEB enhanced lysosomal clearance via promoting lysosomal biogenesis and protected TECs by reducing apoptosis in vitro. In addition, pharmacological activation of TFEB attenuated renal tubule injury, apoptosis, and inflammation in db/db mice. In conclusion, diabetes-induced mTOR activation represses TFEB function, thereby perturbing lysosomal homeostasis through impairing lysosomal biogenesis and clearance in TECs. Moreover, TFEB activation protects TECs from diabetic injuries via restoring lysosomal homeostasis.

Prenylated coumarins from the fruits of Artocarpus heterophyllus with their potential anti-inflammatory and anti-HIV activities.

A phytochemical investigation on the fruits of Artocarpus heterophyllus led to the isolation and characterisation of a new prenylated coumarin, artoheteronin (1), together with six known analogues (2-7). The chemical structure of 1 was elucidated using extensive spectral methods and the known compounds (2-7) were identified by comparing their spectral data with those reported in the literature. All known compounds (2-7) were isolated from the genus Artocarpus for the first time. The anti-inflammatory and anti-HIV activities of all isolated prenylated coumarins (1-7) were assessed in vitro. As a result, compounds 1-7 displayed notable inhibitory effects against nitric oxide (NO) production induced by lipopolysaccharide in mouse macrophage RAW 264.7 cells in vitro with the IC50 values in range of 0.58 ± 0.06 to 6.29 ± 0.12 µM. Meanwhile, compounds 1-7 exhibited notable anti-HIV-1 reverse transcriptase (RT) activities possessing EC50 values in the range of 0.18 to 9.12 µM.

Cadinane-type sesquiterpenes with potential anti-inflammatory and anti-HIV activities from the stems and leaves of Mappianthus iodoides.

Eight cadinane-type sesquiterpenes, including a new cadinane-type sesquiterpene, named as mappianiodene (1), and seven known analogues (2-8), were isolated and identified from the stems and leaves of Mappianthus iodoides. The chemical structure and absolute configurations of 1 was elucidated by extensive spectral methods and the known compounds were identified by comparing their experimental spectral data with the reported spectral data in the literature. The anti-inflammatory and anti-HIV activities of those isolated cadinane-type sesquiterpenes were tested. As a result, cadinane-type sesquiterpenes 1-8 displayed notable inhibitory effects on NO (nitric oxide) production with IC50 values equivalent to that of the hydrocortisone. Moreover, compounds 1-8 exhibited pronounced anti-HIV-1 reverse transcriptase (RT) activities with the EC50 values in range of 0.17 to 9.28 µM.

High expression of RNF169 is associated with poor prognosis in pancreatic adenocarcinoma by regulating tumour immune infiltration.

Background: Pancreatic adenocarcinoma (PAAD) is a highly deadly and aggressive tumour with a poor prognosis. However, the prognostic value of RNF169 and its related mechanisms in PAAD have not been elucidated. In this study, we aimed to explore prognosis-related genes, especially RNF169 in PAAD and to identify novel potential prognostic predictors of PAAD. Methods: The GEPIA and UALCAN databases were used to investigate the expression and prognostic value of RNF169 in PAAD. The correlation between RNF169 expression and immune infiltration was determined by using TIMER and TISIDB. Correlation analysis with starBase was performed to identify a potential regulatory axis of lncRNA-miRNA-RNF169. Results: The data showed that the level of RNF169 mRNA expression in PAAD tissues was higher than that in normal tissues. High RNF169 expression was correlated with poor prognosis in PAAD. In addition, analysis with the TISIDB and TIMER databases revealed that RNF169 expression was positively correlated with tumour immune infiltration in PAAD. Correlation analysis suggested that the long non-coding RNA (lncRNA) AL049555.1 and the microRNA (miRNA) hsa-miR-324-5p were involved in the expression of RNF169, composing a potential regulatory axis to control the progression of PAAD. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that RNF169 plays a role in PAAD through pathways such as TNF, Hippo, JAK-STAT and Toll-like receptor signaling. Conclusion: In summary, the upregulation of RNF169 expression mediated by ncRNAs might influence immune cell infiltration in the microenvironment; thus, it can be used as a prognostic biomarker and a potential therapeutic target in PAAD.

[Chemical constituents from Morinda citrifolia and their inhibitory activities on proliferation of synoviocytes in vitro].

The chemical constituents from the stems and leaves of Morinda citrifolia were isolated and purified by column chromatography methods with silica gel, ODS, Sephadex LH-20 and preparative high performance liquid chromatography(HPLC). The structures of the isolated compounds were identified by physicochemical properties and spectroscopic analysis, as well as comparisons with the data reported in literature. 17 compounds were isolated from the 90% ethanol extract of the stems and leaves of M. citrifolia, and were identified as 9,10-dihydroxy-4, 7-megastigmadien-3-one(1), 5,12-epoxy-6,9-hydroxy-7-megastigmen-3-one(2), fukinone(3), ß-eudesmol(4), sarmentol F(5), 4, 5-dihydroblumenol A(6), 3-hydroxy-ß-ionone(7), aristol-8-en-1-one(8), ergosta-7-en-3ß-ol(9), ergosta-7-ene-3ß,5α,6ß-triol(10),(22E)-5α,8α-epidioxyergosta-6,22-dien-3ß-ol(11), olivil(12), 4-epi-larreatricin(13), chushizisin Ⅰ(14), rabdosia acid A(15), glycerol monolinoleate(16) and(9Z,12Z,15Z)-2,3-dihydroxypropyl octadeca-trienoate(17). All compounds were isolated from M. citrifolia for the first time. All isolated compounds were evaluated for their anti-rheumatoid arthritis activities via examining their inhibitory activities on the proliferation of synoviocytes in vitro using MTS met-hod. Compounds 1-11 showed significant anti-rheumatoid arthritis activities, displaying the inhibitory effects on the proliferation of MH7 A synovial fibroblast cell with the IC_(50) values ranging from(38.69±0.86) to(203.45±1.03) µmol·L~(-1).

Anti-inflammatory steroids from the fruits of Artocarpus heterophyllus.

A phytochemical study on the fruits of Artocarpus heterophyllus caused the isolation of a previously undescribed steroid, artoheterophoid (1), together with seven known analogues (2 - 8). The chemical structure of 1 was elucidated on the basis of comprehensive spectroscopic methods and the known compounds (2 - 8) were identified by comparing their spectroscopic data with those reported in the literatures. All known compounds (2-8) were separated from A. heterophyllus for the first time. All isolated compounds (1-8) were assessed for their anti-inflammatory activities in vitro by measuring the inhibitory effect against nitric oxide (NO) production induced by lipopolysaccharide in mouse macrophage RAW 264.7 cells. Compounds 1-8 displayed remarkable inhibitory effects against NO production with the IC50 values in the range of 0.72 ± 0.07 to 5.93 ± 0.12 µM.

Prenylated chromones and flavonoids from Artocarpus heterophyllus with their potential antiproliferative and anti-inflammatory activities.

Two new prenylated chromones, artoheterophines A (1) and B (2), five known prenylated chromones (3-7), as well as five known biogenetically related prenylated flavonoids (8-12) were isolated and characterized from the stems and leaves of A. heterophyllus. Their chemical structures were unambiguously determined through comprehensive spectral data analyses. The antiproliferative and anti-inflammatory effects of all these isolated prenylated chromones and flavonoids were evaluated in vitro. As a result, compounds 1-12 showed notable inhibitory effects against various human cancer cell lines with IC50 values ranging from 0.36 ± 0.02 to 22.09 ± 0.16 µM. Meanwhile, compounds 1-12 exhibited significant inhibitory activities on nitric oxide (NO) production holding IC50 values in the range of 0.48 ± 0.05-19.87 ± 0.21 µM. These research results suggest that the isolation and characterization of these prenylated chromones (1-7) and flavonoids (8-12) holding significant antiproliferative and anti-inflammatory activities could be significant to the discovery and development of new natural anti-tumor and anti-inflammatory drugs. The findings also provides a phytochemical evidence for further development and utilization of the stems and leaves of A. heterophyllus in health and pharmaceutical products.

Culturable bacteria resident on lettuce might contribute to accumulation of human noroviruses.

Human noroviruses (HuNoVs) are the primary non-bacterial pathogens causing acute gastroenteritis worldwide. Attachment and invasion of HuNoVs are thought to involve histo-blood group antigens (HBGAs). Romaine lettuce, which is usually consumed raw, is a common food-related vehicle for HuNoVs transmission. This study investigated the possibility that bacteria resident on the surface of lettuce leaves contribute to norovirus adherence to this food. To test this hypothesis, bacteria were isolated from romaine lettuce and screened to evaluate whether they produced any polysaccharides with structures resembling HBGAs. Twenty-seven bacterial isolates were screened and 18, belonging to 13 different genera, were found to produce HBGAs-like polysaccharides that were recognized by monoclonal antibodies specific to type A, B, H and Lewis a, b, x and y. One bacterial isolate, belonging to the genus Pseudomonas was further investigated because it produced polysaccharides with the widest range of HBGA types, including type B, H and Lewis a, b and x. The Pseudomonas HBGAs-like polysaccharides were found to be extracellular and their production was enhanced when the bacteria were cultured in oligotrophic medium. HuNoVs capture assays revealed that GI.1, GI.8, and GII.2, GII.3, GII.4, GII.6, GII.12, GII.17 genotypes can be bind to Pseudomonas HBGAs-like polysaccharides. The direct evidence of bacterial production HBGAs-like polysaccharides demonstrates one possible mechanism driving accumulation of HuNoVs on lettuce.

Prospects of and limitations to the clinical applications of genistein.

Genistein is an isoflavone derived from soy-rich products, which is known to exhibit several beneficial biological effects, such as anti-tumor activity, improvement of glucose metabolism, and reduction of the frequency of peri-menopausal hot flashes, and thus has potential for clinical application. Certain limitations and side effects, such as low bioavailability, biological estrogenic activity, and detrimental effects on thyroid function, have restricted its clinical applications to some extent. Recently, it has been reported that fermentation, use of micromicelles, and modification of its chemical structure can enhance the bioavailability of genistein. Moreover, the modification of its molecular structure may also eliminate its biological estrogenic activity and adverse effects on thyroid function. In this review, we summarize the clinical application prospects and limitations of genistein, as well as the plausible solutions to overcome its low bioavailability, phytoestrogenic activity, and adverse effects on thyroid function.

Asiatic acid protects against cisplatin-induced acute kidney injury via anti-apoptosis and anti-inflammation.

Cisplatin is a well-known chemotherapeutic drug applied for the treatment of numerous human cancers. However, the use of cisplatin in clinic is limited by certain serious side effects, such as nephrotoxicity. Unfortunately, there is currently no effective therapeutic approach to prevent cisplatin-induced AKI. Increasing evidence suggests that apoptosis of tubular epithelial cells and renal inflammation mainly determine the progression and outcome of cisplatin-induced AKI. Asiatic acid (AA) has been reported have the functions of anti-inflammation and anti-apoptosis, etc. But the effects of AA on kidney injury induced by cisplatin are still not known. The current study aimed to determine the potential renoprotective effects of AA on kidney injury induced by cisplatin. Twenty-four C57BL/6 male mice were randomly divided into four groups: normal control (CON), cisplatin-induced AKI (CIS), AKI with 50 mg/kg AA pretreatment (CIS + AA50), and AKI with 100 mg/kg AA pretreatment (CIS + AA100). Mice were anesthetized and sacrificed at 72 h after the cisplatin injection. Blood and kidney samples were collected for analyses. Compared with CON mice, cisplatin-treated mice exhibited severe tubular necrosis and elevated serum creatinine level. However, AA pretreatment (50 mg/kg or 100 mg/kg) markedly suppressed the elevated serum creatinine, blood urea nitrogen and histological changes. Moreover, AA pretreatment notably downregulated tubular expression of kidney injury molecule-1 (KIM-1) and the number of apoptotic cells, and upregulated the expression of the apoptosis inhibitor survivin and promoted tubular proliferation as evidenced by an increase in the number of proliferating cell nuclear antigen-positive cells. In addition, AA suppressed the enhanced mRNA expression of proinflammatory cytokines IL-1ß, TNF-α, MCP-1 and caspase-1 in the kidneys. Furthermore, AA pretreatment inhibited NF-κB activation and the inflammatory response, which may result from Smad7 up-regulation. In conclusion, AA protects against cisplatin-induced AKI via anti-apoptosis and anti-inflammation.

Massive Proteinuria-Induced Injury of Tubular Epithelial Cells in Nephrotic Syndrome is Not Exacerbated by Furosemide.

BACKGROUND/AIMS: Massive proteinuria, a significant sign of nephrotic syndrome (NS), has the potential to injure tubular epithelial cells (TECs). Furosemide is widely used for the treatment of edema, a common manifestation of NS. However, whether furosemide treatment affects massive proteinuria-induced TEC injury in patients with NS is unknown. METHODS: The effect of furosemide on TEC damage was investigated in vitro. In addition, a clinical study was conducted to study whether the short-term treatment of nephrotic edema with furosemide could exacerbate TEC injury. RESULTS: The proliferation of in vitro human kidney-2 (HK-2) cells exposed to massive urinary protein (8 mg/mL) significantly decreased (P<0.05), while the levels of kidney injury molecule-1 (Kim-1) and neutrophil gelatinase associated lipocalin (NGAL) in the supernatants significantly increased (P<0.05). Importantly, furosemide treatment did not further increase the expression of Kim-1 and NGAL in HK-2 cells upregulated by massive proteinuria. For the clinical study, 26 patients with NS, all prescribed the recommended dosage of prednisone (1 mg/kg/day), were randomly assigned to two groups. One group (n=13) received furosemide (60-120 mg/day, intravenously) for 1 week; the remaining participants (control group) did not receive furosemide or any other diuretics. The results showed that the 24-h urine volume in the furosemide-treated group was slightly, but not significantly, higher than that in the control group (P>0.05). In addition, serum levels of BUN, Scr, Cys C, and urinary Kim-1 and NGAL were not significantly different between the two groups (all P>0.05). Twenty-three patients underwent a renal biopsy. Of these, 22 patients exhibited vacuolar degeneration of the TECs; 8 patients showed brush border membrane shedding of the TECs; and 12 patients showed protein casts. However, there were no significant differences between the two groups (all P>0.05). CONCLUSION: In summary, massive proteinuria induced the injury of TECs in patients with NS, and furosemide treatment did not aggravate this injury.