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BACKGROUND: Mucopolysaccharidosis VII (MPS VII) is an ultra-rare, autosomal recessive, debilitating, progressive lysosomal storage disease caused by reduced activity of β-glucuronidase (GUS) enzyme. Vestronidase alfa (recombinant human GUS) intravenous enzyme replacement therapy is an approved treatment for patients with MPS VII. METHODS: This disease monitoring program (DMP) is an ongoing, multicenter observational study collecting standardized real-world data from patients with MPS VII (N ≈ 50 planned) treated with vestronidase alfa or any other management approach. Data are monitored and recorded in compliance with Good Clinical Practice guidelines and planned interim analyses of captured data are performed annually. Here we summarize the safety and efficacy outcomes as of 17 November 2022. RESULTS: As of the data cutoff date, 35 patients were enrolled: 28 in the Treated Group and seven in the Untreated Group. Mean (SD) age at MPS VII diagnosis was 4.5 (4.0) years (range, 0.0 to 12.4 years), and mean (SD) age at DMP enrollment was 13.9 (11.1) years (range, 1.5 to 50.2 years). Ten patients (29%) had a history of nonimmune hydrops fetalis. In the 23 patients who initiated treatment prior to DMP enrollment, substantial changes in mean excretion from initial baseline to DMP enrollment were observed for the three urinary glycosaminoglycans (uGAGs): dermatan sulfate (DS), -84%; chondroitin sulfate (CS), -55%; heparan sulfate (HS), -42%. Also in this group, mean reduction from initial baseline to months 6, 12, and 24 were maintained for uGAG DS (-84%, -87%, -89%, respectively), CS (-70%, -71%, -76%, respectively), and HS (+ 3%, -32%, and - 41%, respectively). All adverse events (AEs) were consistent with the known vestronidase alfa safety profile. No patients discontinued vestronidase alfa. One patient died. CONCLUSIONS: To date, the DMP has collected invaluable MPS VII disease characteristic data. The benefit-risk profile of vestronidase alfa remains unchanged and favorable for its use in the treatment of pediatric and adult patients with MPS VII. Reductions in DS and CS uGAG demonstrate effectiveness of vestronidase alfa to Month 24. Enrollment is ongoing.

Background: α-Klotho may involve in the occurrence and development of venous thromboembolism (VTE). However, the underlying relationship between circulating α-Klotho levels and VTE is still unclear. Methods: This two-sample Mendelian Randomization (MR) study aims to explore the causal associations of circulating α-Klotho levels with different types of venous thromboembolism. Data of exposure and outcomes were extracted from the genome-wide association study (GWAS) of the MRC Integrative Epidemiology Unit (MRC-IEU). The fixed inverse variance weighted (IVW), MR-Egger, MR-Robust Adjusted Profile Score (RAPS) and the weighted-median methods were utilized to investigate the causal associations of circulating α-Klotho levels with different types of VTE. The effect size was expressed as odds ratios (ORs) and 95% confidence intervals (CIs), and the False Discovery Rate (FDR) test was used for correction. The MR scatter plot and leave-one-out test were used for sensitivity analysis. In addition, reverse causal associations were assessed. Results: IVW estimates suggested that an elevated circulating α-Klotho level was associated with lower odds of deep vein thrombosis (DVT) of lower extremities (OR = 0.992, 95%CI: 0.986–0.998, P = 0.0074), pulmonary embolism (PE) (OR = 0.474, 95%CI: 0.255–0.881, P = 0.0183), and DVT of lower extremities combined with PE (OR = 0.984, 95%CI: 0.971–0.997, P = 0.0175). However, after the FDR correction, only negatively causal association between circulating α-Klotho level and increased odds of lower-extremity DVT was statistically significant (FDR P = 0.0296). Also, there were no reverse causal associations between the circulating α-Klotho levels and different types of VTE (all P > 0.05). Additionally, both the MR scatter plots and leave-one-out test results showed that these causal associations were relatively robust. Conclusion: An elevated circulating α-Klotho levels was associated with lower risk of DVT of lower extremities, PE, and DVT of lower extremities combined with PE, indicating α-Klotho has the potential to act as a target for early screening or treatment for VTE. However, the specific mechanism that α-Klotho influencing the occurrence of VTE still needed further exploration. [ABSTRACT FROM AUTHOR]

ERF56, a member of the APETALA2/ETHYLENE-RESPONSIVE FACTOR (AP2/ERF) transcription factor (TF) family, was reported to be an early nitrate-responsive TF in Arabidopsis. But the function of ERF56 in nitrate signaling remains not entirely clear. This study aimed to investigate the role of ERF56 in nitrate-dependent plant growth and nitrate signaling. We confirmed with reverse transcription quantitative PCR (RT-qPCR) that the transcription of ERF56 is quickly induced by nitrate. ERF56 overexpressors displayed decreased nitrate-dependent plant growth, while erf56 mutants exhibited increased plant growth. Confocal imaging demonstrated that ERF56 is localized into nuclei. Assays with the glucuronidase (GUS) reporter showed that ERF56 is mainly expressed at the region of maturation of roots and in anthers. The dual-luciferase assay manifested that the transcription of ERF56 is not directly regulated by NIN-LIKE PROTEIN 7 (NLP7). The transcriptome analysis identified 1038 candidate genes regulated by ERF56 directly. A gene ontology (GO) over-representation analysis showed that ERF56 is involved in the processes of water transport, inorganic molecule transmembrane transport, secondary metabolite biosynthesis, and cell wall organization. We revealed that ERF56 represses nitrate-dependent growth through regulating the processes of inorganic molecule transmembrane transport, the secondary metabolite biosynthesis, and cell wall organization. [ABSTRACT FROM AUTHOR]

Urinary steroid profiling after hydrolysis of conjugates is an emerging tool to differentiate aggressive adrenocortical carcinomas (ACC) from benign adrenocortical adenomas (ACA). However, the shortcomings of deconjugation are the lack of standardized and fully validated hydrolysis protocols and the loss of information about the originally conjugated form of the steroids. This study aimed to evaluate the quality of the deconjugation process and investigate novel diagnostic biomarkers in urine without enzymatic hydrolysis.24 h urine samples from 40 patients with ACC and 40 patients with ACA were analyzed by untargeted metabolomics using liquid chromatography-high-resolution mass spectrometry both unmodified and after hydrolysis with arylsulfatase/glucuronidase from Helix pomatia. Both approaches were compared regarding the differentiation of ACC vs. ACA via ROC analyses and to evaluate the hydrolyzation efficiency of steroid conjugates.Steroid glucuronides were fully deconjugated, while some disulfates and all monosulfates were still largely detectable after enzymatic hydrolysis, suggesting incomplete and variable deconjugation. In unhydrolyzed urine, steroid monosulfates showed the best differentiation between ACC and ACA (highest AUC=0.983 for C21H32O6S, followed by its isomer and two isomers with the molecular formula C21H32O7S). Moreover, several disulfates were highly abundant and increased in ACC compared to ACA.This work highlights the limitations of hydrolyzing steroid conjugates before analysis and shows a possible superiority of a direct analysis approach compared to a hydrolysis approach from a methodological point of view and regarding diagnostic accuracy. Several steroid conjugates were found as promising diagnostic biomarkers for differentiation between ACC and ACA. [ABSTRACT FROM AUTHOR]

Background: Childhood obesity is a major public health concern, being linked to an increased risk of metabolic disorders and cardiovascular disease. Even in childhood, obesity is associated with systemic low-grade inflammation, which is a critical factor in the development of atherosclerosis and a predictor of cardiovascular morbidity and mortality. Objectives: To describe the prevalence of obesity and examine the relationship between IL-6, TNF-α, adiponectin, leptin, the leptin/adiponectin (L/A) ratio, and Klotho levels with BMI in children. Methods: This cross-sectional study included children aged 10–14 years from La Rioja, Spain. Participants were selected based on BMI criteria for overweight (85th–95th percentiles) and obesity (>95th percentile). Socio-demographic and anthropometric data and blood samples were collected and analyzed for IL-6, TNF-α, adiponectin, leptin, and Klotho. Results: A total of 340 participants were included, with 276 (81.2%) classified as normal weight and 64 (18.8%) as overweight or obese. Mean age was similar between groups (p = 0.40). Obesity was more prevalent in males (59.4%, p = 0.048). Obese participants had higher mean birth weight (p = 0.003), current height (p = 0.04), BMI (p < 0.0001), and abdominal circumference (p < 0.0001). BMI correlated positively with leptin (r = 0.54, p = 0.0008) and the L/A ratio (r = 0.40, p = 0.025), showing sex-specific differences. Conclusions: This study underscores leptin and the L/A ratio as potential biomarkers of metabolic dysregulation in childhood obesity, particularly in females. Longitudinal studies are needed to confirm these findings and assess the clinical utility of these biomarkers in pediatric obesity management. [ABSTRACT FROM AUTHOR]

In this study, the potential role and interaction of the APOε and KLOTHO genes on the penetrance of fragile X-associated tremor/ataxia syndrome (FXTAS) and on the IQ trajectory were investigated. FXTAS was diagnosed based on molecular, clinical and radiological criteria. Males with the premutation (PM) over 50 years, 165 with and 34 without an FXTAS diagnosis, were included in this study and were compared based on their APO (ε2-ε3-ε4) and KLOTHO variant (KL-VS) genotypes. The effect of APOε4 on FXTAS stage and on diagnosis did not differ significantly by KL-VS genotype with interaction effect p = 0.662 and p = 0.91, respectively. In the FXTAS individuals with an APOε2 allele, a marginal significance was observed towards a larger decline in verbal IQ (VIQ) in individuals with an APOε4 allele compared to those without an APOε4 allele (p = 0.071). In conclusion, our findings suggest that the APOε4 and KL-VS genotypes alone or through their interaction effect do not appear to predispose to either FXTAS diagnosis or stage in male carriers of the PM allele. A further study is needed to establish the trend of IQ decline in the FXTAS individuals who carry APOε4 with APOε2 compared to those without APOε4.

Background: The Klotho gene is implicated in suppressing aging phenotypes and influencing age-related diseases. Previous studies have delved into its connection with different diseases, yet the association between Klotho and hearing loss has rarely been examined. A recent population study explored the relationship between serum Klotho and hearing loss, but it had certain limitations. This study aims to analyze the link between serum α-Klotho levels and hearing thresholds, as well as the risk of hearing loss. Methods: A total of 1,762 adults aged 40–69 years were selected from the 2011–2012 National Health and Nutrition Examination Survey (NHANES). Data on audiometry, serum α-Klotho levels, and relevant covariates were gathered. Statistical analyses, including linear and logistic regression, assessed the relationships of serum α-Klotho levels with hearing outcomes. Results: Increased serum α-Klotho levels were correlated with diminished hearing thresholds and a lower risk of hearing loss. Quartile analysis revealed a significant trend, where elevated α-Klotho levels were linked to better auditory outcomes. Adjusted models controlled for various covariates, affirming the robustness of the findings. Non-linear associations were not observed. Conclusion: This study provided novel evidence of a negative association between serum α-Klotho and hearing impairment in adults aged 40–69. Our results suggested a protective role of serum α-Klotho on adults with hearing loss. [ABSTRACT FROM AUTHOR]

Introduction: This study investigated the potential link between serum klotho levels and cognitive function in patients with non-alcoholic fatty liver disease (NAFLD). Materials and Methods: Utilizing NHANES data from 2011 to 2014, the research included 356 eligible participants. NAFLD was identified with the United States Fatty Liver Index (US-FLI), and cognition was measured by various tests including the Animal Fluency Test (AFT), Digit Symbol Substitution Test (DSST), Immediate Recall Test (IRT), and Delayed Recall Test (DRT). Weighted logistic regression and restricted cubic splines were employed to analyze the relationship between klotho levels and cognitive scores. Results: A significant nonlinear association was observed between klotho levels and the performance in DSST and Delayed Recall Test (DRT). After controlling for confounding factors, the study found a positive association between higher serum klotho levels and improved cognitive performance in both AFT and DSST. However, there was no significant relationship between klotho levels and the IRT or DRT, regardless of whether the natural logarithm or quartile was considered. Discussion: The findings suggest that a higher serum klotho level may be positively correlated with better cognitive performance in NAFLD patients. [ABSTRACT FROM AUTHOR]

Background and Objectives: Soluble alpha Klotho (s.Klotho) is an emerging marker for chronic kidney disease (CKD) prognosis. The objective was to study the association between s.Klotho and CKD‐related decrease in glomerular filtration rate (GFR), bone and vascular damage. Method: A total of 118 patients with CKD stage 2–4 were enrolled and 107 patients continued in the study. Clinical and laboratory parameters were recorded at time of enrollment and 12 months. A double sandwich ELISA for s.Klotho was recorded in controls (n = 25) and patients' serum samples at 6 months (n = 107) and 12 months (n = 102). Primary endpoints like 40% or more fall in GFR, a requirement for renal replacement therapy (RRT), and death with different grades of s.Klotho deficiency were studied. Results: Of the 107 patients (80 male and 27 female), mean s.Klotho was 3.46 ng/mL (02.3–04.2). The GFR fall was significantly different (p value < 0.0001) in the different grades of s.Klotho deficiency with Grade 4 s.Klotho deficiency (0.1–2.99 ng/mL) having the maximum fall of GFR at 9.2 mL/min/1.73 m2 (04.8–12.0) and minimum in Grade 2 (3–5.99 ng/mL) at 1.35 mL/min/1.73 m2 (03.0–02.75). The Ankle Brachial Pressure Index positively correlated with s.Klotho and the correlation coefficient was 0.536 (0.382–0.662) (p < 0.001). The carotid intimal medial thickness negatively correlated with s.Klotho and the correlation coefficient was −0.712 (95% CI: −0.797–−0.601, p < 0.001). All five deaths had s.Klotho Grade 4 (severe) deficiency. The event‐free survival rate was maximum (100%) in Grade 2 Klotho deficiency and lowest (55%) in Grade 4 s.Klotho deficiency. Conclusions: s.Klotho levels decreased significantly in patients with progressive kidney failure. s.Klotho levels significantly correlated with the presence of vascular disease. Death and need for RRT were significantly more in patients with severe s.Klotho deficiency. [ABSTRACT FROM AUTHOR]

Heart failure is a geriatric syndrome, often accompanied by a high disability rate, complex comorbidities, and a poor prognosis. This study aimed to assess the effect of Astragalus on the vitamin D- fibroblast growth factor 23/fibroblast growth factor receptor 1-KLOTHO axis in elderly heart failure patients using a bioinformatics approach. Thirteen active ingredients and 159 targets were identified based on network pharmacology, and 500 HF targets were obtained using GeneCards database. A predicted target set was established using 22 core targets, and a diagram of the active component-target network was constructed using Cytoscape software (version 3.7.2); a protein-protein interaction network was constructed for analysis, and the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment were analyzed using DAVID software. Bioinformatics analyses revealed that 22 targets were mainly involved in the Ras and PI3K-Akt signaling pathways. Molecular docking for fibroblast growth factor receptor 1 revealed that the active components HMM7 and HMM13 demonstrated better binding stability with the target gene. This study may help explain the molecular mechanism of effects on vitamin D- fibroblast growth factor 23/fibroblast growth factor receptor 1-KLOTHO axis and promote clinical application. [ABSTRACT FROM AUTHOR]

Introduction: The human gut microbiota influence critical functions including the metabolism of nutrients, xenobiotics, and drugs. Gut microbial β-glucuronidases (GUS) enzymes facilitate the removal of glucuronic acid from various compounds, potentially affecting anti-cancer drug efficacy and reactivating carcinogens. This review aims to comprehensively analyze and summarize studies on the role of gut microbial GUS in cancer and its interaction with anti-cancer treatments. Its goal is to collate and present insights that are directly relevant to patient care and treatment strategies in oncology. Methods: This scoping review followed PRISMA-ScR guidelines and focused on primary research exploring the role of GUS within the gut microbiota related to cancer etiology and anti-cancer treatment. Comprehensive literature searches were conducted in PubMed, Embase, and Web of Science. Results: GUS activity was only investigated in colorectal cancer (CRC), revealing increased fecal GUS activity, variations in the gut microbial composition, and GUS-contributing bacterial taxa in CRC patients versus controls. Irinotecan affects gastrointestinal (GI) health by increasing GUS expression and shifting gut microbial composition, particularly by enhancing the presence of GUS-producing bacteria, correlating with irinotecan-induced GI toxicities. GUS inhibitors (GUSi) can mitigate irinotecan's adverse effects, protecting the intestinal barrier and reducing diarrhea. Conclusion: To our knowledge, this is the first review to comprehensively analyze and summarize studies on the critical role of gut microbial GUS in cancer and anti-cancer treatment, particularly irinotecan. It underscores the potential of GUSi to reduce side effects and enhance treatment efficacy, highlighting the urgent need for further research to integrate GUS targeting into future anti-cancer treatment strategies. [ABSTRACT FROM AUTHOR]

Background Previous studies have extensively investigated traditional predictors of cardiovascular disease (CVD) development, progression, and prognosis. However, the influence of novel indicators such as Klotho, on CVD prevalence and prognosis in the general population remains unclear. Method This was an observational study that utilized cross-sectional and longitudinal methods to examine the general population in the National Health and Nutrition Examination Survey (NHANES) 2007-2016. The participants were divided into four groups according to the Klotho quartiles. Primary outcome was CVD [coronary artery disease (CAD), congestive heart failure, and stroke], secondary outcomes were all-cause mortality and cardiovascular mortality. Survey-weighted binary logistic regression analysis was used to analyze the association between Klotho and the prevalence of primary outcome, and the restricted cubic spline (RCS) curve was used to further analyze the nonlinear relationship. Subgroup analyses were conducted to investigate the association between Klotho values and CVD prevalence using survey-weighted binary logistic regression. The incidence of the secondary outcomes among four groups was assessed through Kaplan-Meier survival analysis. Additionally, the relationship between Klotho values and secondary endpoints was explored using survey-weighted Cox proportional hazards regression across various patient subpopulations. Results A total of 12,146 participants (56.8 ± 10.7 years, 48.5% male) were included in our study. The total incidence of CVD was 9.9% (n = 1201), of which 4.7% (n = 574) were CAD, 3.7% (n = 454) were congestive heart failure, and 4.1% (n = 497) were stroke. Binary logistics regression analysis showed that higher Klotho quartiles were associated with the decreased prevalence of CVD [Quartile 4 vs. Quartile 1: odds ratio (OR) (95% CI): 0.77 (0.64-0.93), P = 0.006] and congestive heart failure [Quartile 4 vs. Quartile 1: 0.75 (0.56-0.99), P = 0.048], However, no significant associations were found between Klotho levels and the outcomes of CAD or stroke. RCS curve illustrated a high Klotho value was negatively correlated with the prevalence of CVD (nonlinear P = 0.838), congestive heart failure (nonlinear P = 0.110) and stroke (nonlinear P = 0.972). No significant interactions were observed in any subgroups regarding the associations between Klotho and prevalence of CVD. After a median follow-up period of 93 months (range: from 1 to 160 months), there were 1228 cases (10.1%) of all-cause mortality in the general population, including 296 cases (2.4%) of cardiovascular mortality. The Kaplan-Meier curves indicated that lower Klotho levels were associated with a significant increase in all-cause mortality across the general population, CVD population, and non-CVD population. As Klotho levels decreased, there was also a notable rise in cardiovascular mortality in both the general population and the CVD population. In the overall population, Cox regression analyses demonstrated that higher Klotho values were associated with a decreased risk of both all-cause and cardiovascular mortality. And no significant interaction was observed in the CVD subgroup regarding the association between Klotho and mortality. Conclusion High Klotho level was associated with low prevalence of CVD and low risk of mortality in general population. [ABSTRACT FROM AUTHOR]

Background: The efficient use of softwood in biorefineries is hampered by its recalcitrance to enzymatic saccharification. In the present study, the fungus Thermothielavioides terrestris LPH172 was cultivated on three steam-pretreated spruce materials (STEX180°C/auto, STEX210°C/auto, and STEX210°C/H2SO4), characterized by different hemicellulose content and structure, as well as on untreated biomass. The aim of the study was to map substrate-induced changes in the secretome of T. terrestris grown on differently treated spruce materials and to evaluate the hydrolytic efficiency of the secretome as supplement for a commercial enzyme mixture. Results: The cultivation of T. terrestris was monitored by endo-cellulase, endo-xylanase, endo-mannanase, laccase, and peroxidase activity measurements. Proteomic analysis was performed on the secretomes induced by the spruce materials to map the differences in enzyme production. Growth of T. terrestris on STEX180°C/auto and STEX210°C/auto induced higher expression level of mannanases and mannosidases of the GH5_7 CAZy family compared to cultivation on the other materials. Cultivation on untreated biomass led to overexpression of GH47, GH76, and several hemicellulose debranching enzymes compared to the cultivation on the pretreated materials. T. terrestris grown on untreated, STEX180°C/auto and STEX210°C/auto induced three arabinofuranosidases of the GH43 and GH62 families; while growth on STEX210°C/H2SO4 induced a GH51 arabinofuranosidase and a GH115 glucuronidase. All secretomes contained five lytic polysaccharide monooxygenases of the AA9 family. Supplementation of Celluclast® + Novozym188 with the secretome obtained by growing the fungus grown on STEX180°C/auto achieved a twofold higher release of mannose from spruce steam-pretreated with acetic acid as catalyst, compared to the commercial enzyme cocktail alone. Conclusions: Minor changes in the structure and composition of spruce affect the composition of fungal secretomes, with differences in some classes explaining an increased hydrolytic efficiency. As demonstrated here, saccharification of spruce biomass with commercial enzyme cocktails can be further enhanced by supplementation with tailor-made secretomes. [ABSTRACT FROM AUTHOR]

Background: Metformin (Met) has been reported to play the key role in the pathogenesis of polycystic ovary syndrome (PCOS). However, the precise mechanisms underlying the actions of Met in PCOS remain incompletely understood. This study aimed to confirm the mechanism of Met interacting with a long non‐coding RNA LINC00548 in PCOS. Methods: Ovarian granulosa cells (OGCs) were incubated 500 nM dihydrotestosterone (DHT) to construct PCOS in vitro model and then were treated 20 μM Met. A series of cell experiments including Cell Counting Kit‐8, Terminal uridine nucleotide end labeling, and flow cytometry were performed to confirm the changes of OGC survival ability. Quantitative real‐time polymerase chain reaction was conducted to determine the levels of LINC00548, whereas Western blotting was applied to determine the levels of androgen receptor (AR) and klotho. Results: Met improved the cell viability and suppressed cell apoptosis in DHT‐treated OGCs. LINC00548 downregulated in DHT‐treated OGCs was upregulated by Met, and its overexpression further enhanced the positive effects of Met on the survival ability of DHT‐treated OGCs. In addition, Met could induce the upregulation of LINC00548 to suppress the activation of AR/klotho pathway in DHT‐treated OGCs. Conclusion: Overall, this study discovers that Met enhances the survival ability of OGCs in PCOS by elevating LINC00548 expression to suppress AR/klotho pathway. [ABSTRACT FROM AUTHOR]

Background: Klotho plays a pivotal role in human aging. Metabolic syndrome (MetS) is composed of multiple conditions that are also risk factors for cardiovascular disease and diabetes. We try to discuss gender-specific differences in Klotho and the associations between Klotho and MetS components. Materials and methods: The National Health and Nutrition Examination Survey database from cycle 2015–2016 was analyzed. MetS was defined according to the 2005 updated criteria by the American Heart Association and National Heart Lung and Blood Institute. Gender-specific differences in serum Klotho, and associations between Klotho level and MetS components were examined. Results: A total of 2475 participants (40–79 years old) with comprehensive data were included (52% women). In general, lower Klotho was associated with advanced age, male sex, tobacco use, elevated triglycerides, renal insufficiency, inflammation, low estradiol, and low sex hormone-binding globulin (SHBG). The correlation between MetS and Klotho was more obvious in women, mainly in waist circumference and triglyceride. There were no gender-specific differences in the associations between Klotho and renal dysfunction, but multivariate linear regression analysis showed gender differences in other factors associated with Klotho. Estradiol, SHBG, high-density lipoprotein cholesterol (HDL), and high-sensitivity C-reactive protein (CRP) were associated with Klotho levels independent of age and renal function in men, whereas in women, Klotho was independently associated with triglycerides and white blood cell count. Conclusion: Klotho levels had gender disparities regardless of age, renal function, and sex hormones. In the current cohort, triglycerides were the major component of MetS that was independently associated with serum Klotho levels, and the association was particularly seen in women. However, HDL was found to be the male-specific MetS component independently associated with Klotho. [ABSTRACT FROM AUTHOR]

Recent studies suggest an association between greater dietary inflammatory index (DII) and higher biological ageing. As α -Klotho has been considered as a longevity protein, we examined whether α -Klotho plays a role in the association between DII and ageing. We included 3054 participants from the National Health and Nutrition Examination Survey. The associations of DII with biological and phenotypic age were assessed by multivariable linear regression, and the mediating role of α -Klotho was evaluated by mediation analyses. Participants' mean age was 58·0 years (sd 11·0), with a median DII score of 1·85 and interquartile range from 0·44 to 2·79. After adjusting for age, sex, race/ethnicity, BMI, education, marital status, poverty income ratio, serum cotinine, alcohol, physical activity, a higher DII was associated with both older biological age and phenotypic age, with per DII score increment being associated with a 1·01-year increase in biological age (1·01 (95 % CI: 1·005, 1·02)) and 1·01-year increase in phenotypic age (1·01 (1·001, 1·02)). Negative associations of DII with α -Klotho (β = –1·01 pg/ml, 95 % CI: –1·02, –1·006) and α -Klotho with biological age (β = –1·07 years, 95 % CI: –1·13, –1·02) and phenotypic age (β = –1·03 years, 95 % CI: –1·05, –1·01) were found. Furthermore, α -Klotho mediated 10·13 % (P < 0·001) and 9·61 % (P < 0·001) of the association of DII with biological and phenotypic age, respectively. Higher DII was associated with older biological and phenotypic age, and the potential detrimental effects could be partly mediated through α -Klotho. [ABSTRACT FROM AUTHOR]

Background: The triglyceride-glucose (TyG) index is recognized as a robust indicator for evaluating insulin resistance (IR). Despite the well-documented anti-aging biological functions of Klotho protein, its correlation with the TyG index remains unexplored. Methods: A cross-sectional analysis was conducted involving participants from the National Health and Nutrition Examination Surveys (NHANES) 2007–2016. The TyG index was computed using laboratory data, while serum Klotho concentrations was determined using ELISA kit. After adjusting potential confounding variables, multivariate regression models were employed to evaluate the association between the TyG index and Klotho protein levels among middle-aged and elderly females and males separately. Additionally, smooth curve fitting and segmented regression model were applied to investigate potential threshold effects and identify the inflection point. Results: A total of 6,573 adults qualified for inclusion, comprising 3,147 (47.88%) males and 3,426 (52.12%) females. Multivariate regression analysis revealed that females with a higher TyG index exhibited significantly lower serum Klotho concentrations (β=-83.41, 95% CI: -124.23 to -42.60, P < 0.0001). This association was not statistically significant in males (β = 15.40, 95% CI: -19.16 to 49.95, P = 0.3827). Subgroup analyses revealed a significant interaction effect by diabetes status in females (P-interaction = 0.0121), where non-diabetic females showed a stronger negative association between TyG index and serum Klotho levels compared to diabetic females. In the female group, when TyG index was divided into quartiles, individuals in the highest quartile of TyG index exhibited reduced levels of Klotho protein (Q4: -88.77 pg/ml) compared to those in the lowest quartile (Q1) after full adjustment (P = 0.0041). Segmented regression analysis indicated a turning point value of 9.4 in females. Notably, a 1-unit increase in TyG index was significantly associated with a decrease in Klotho levels by -111.43 pg/ml (95% CI: -157.34 to -65.52, P < 0.0001) when TyG index was below 9.4, while above this threshold, the association was not significant (Log likelihood ratio test: 0.009). Conclusions: The findings highlight a non-linear correlation between the TyG index and serum Klotho concentrations among females, indicative of a saturation effect. This relationship was particularly pronounced in non-diabetic women. In contrast, no statistically significant association was observed in male participants. [ABSTRACT FROM AUTHOR]

Cognitive dysfunction in aging is a major biomedical challenge. Whether treatment with klotho, a longevity factor, could enhance cognition in human-relevant models such as in nonhuman primates is unknown and represents a major knowledge gap in the path to therapeutics. We validated the rhesus form of the klotho protein in mice showing it increased synaptic plasticity and cognition. We then found that a single administration of low-dose, but not high-dose, klotho enhanced memory in aged nonhuman primates. Systemic low-dose klotho treatment may prove therapeutic in aging humans.

Background: Thyroid hormone is the key endocrine regulator of growth, development, metabolism, and other bodily functions. α-Klotho has been involved in the aging process and acts as an endocrine factor involved in the regulation of various metabolic processes in humans. However, the relationship between α-Klotho and thyroid profile has not been uniformly recognize. Objective: To determine the relationship between α-Klotho and thyroid profile in adult individuals. Methods: Population data of 4614 adult individuals were obtained from the NHANES database during the period of 2007–2012. Weighted multivariable regression analysis was performed using a general linear model with serum α-Klotho as the independent variable and thyroid profile as the dependent variables, respectively. The generalized additive model was used for smoothing curve fitting and threshold effect analysis. Results: α-Klotho was associated with a slightly higher FT3, TT3 and TT4 level in unadjusted and adjusted regression models. However, a higher α-Klotho level was associated with a lower TSH level. After α-Klotho was grouped as quantiles with reference (Q1), α-Klotho still showed a statistically significant positive correlation with FT3 and TT3 levels in Q2, Q3 and Q4. In addition, α-Klotho was positively corrected with TT4, but negatively associated with TSH in Q4. Conclusions: Serum soluble α-Klotho was positively associated with FT3, TT3 and TT4, but negatively correlated with TSH. The significant effect of α-Klotho on thyroid profile suggests its potential as a predictive marker of thyroid functions, indicating its possible involvement in the regulation of thyroid hormone secretion. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) has become the primary cause of end-stage renal disease (ESRD), causing an urgent need for preventive strategies for DKD. Astragaloside I (ASI), a bioactive saponin extracted from Astragalus membranaceus (Fisch.) Bunge has been demonstrated to possess a variety of biological activities. This study investigates the therapeutic potential of ASI in DKD and the underlying molecular mechanism using db/db mice in vivo and high glucose (HG)-induced SV40-MES-13 cells in vitro. The results indicated that ASI significantly ameliorated renal dysfunction and mitigated the pathological alterations in the renal tissues of db/db mice. Moreover, ASI was found to reduce the levels of renal fibrosis makers and suppress the activation of TGF-β1/Smad2/3 pathway in both db/db mice and HG-induced SV40-MES-13 cells. Furthermore, ASI downregulated HDAC3 expression, upregulated Klotho expression, and enhanced Klotho release. ASI is directly bound to HDAC3, and the beneficial effects of ASI on Klotho/TGF-β1/Smad2/3-mediciated renal fibrosis in DKD were reversed by the HDAC3 agonist ITSA-1. In conclusion, ASI attenuates renal fibrosis in DKD, and may act through concurrently inhibiting HDAC3 and TGF-β1, thereby regulating HDAC3-mediciated Klotho/TGF-β1/Smad2/3 pathway. [ABSTRACT FROM AUTHOR]

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Renal fibrosis is an unavoidable end result of all forms of progressive chronic kidney diseases (CKD). Discovery of efficacious drugs against renal fibrosis is in crucial need. In a preliminary study we found that a derivative of artemisinin, dihydroartemisinin (DHA), exerted strong renoprotection, and reversed renal fibrosis in adenine-induced CKD mouse model. In this study we investigated the anti-fibrotic mechanisms of DHA, particularly its specific target in renal cells. Renal fibrosis was induced in mice by unilateral ureteral obstruction (UUO) or oral administration of adenine (80 mg · kg-1), the mice received DHA (30 mg · kg-1 · d-1, i.g.) for 14 or 21 days, respectively. We showed that DHA administration markedly attenuated the inflammation and fibrotic responses in the kidneys and significantly improved the renal function in both the renal fibrosis mouse models. In adenine-treated mice, DHA was more effective than 5-azacytidine against renal fibrosis. The anti-fibrotic effects of DHA were also observed in TGF-β1-treated HK-2 cells. In order to determine the target protein of DHA, we conducted pull-down technology coupled with shotgun proteomics using a small-molecule probe based on the structure of DHA (biotin-DHA). As a results, DNA methyltransferase 1 (DNMT1) was identified as the anti-fibrotic target of DHA in 3 different types of renal cell lines (HK-2, HEK293 and 3T3). We demonstrated that DHA directly bound to Asn 1529 and Thr 1528 of DNMT1 with a Kd value of 8.18 μM. In primary mouse renal tubular cells, we showed that DHA (10 μM) promoted DNMT1 degradation via the ubiquitin-proteasome pathway. DHA-reduced DNMT1 expression effectively reversed Klotho promoter hypermethylation, which led to the reversal of Klotho protein loss in the kidney of UUO mice. This subsequently resulted in inhibition of the Wnt/β-catenin and TGF-β/Smad signaling pathways and consequently conferred renoprotection in the animals. Knockdown of Klotho abolished the renoprotective effect of DHA in UUO mice. Our study reveals a novel pharmacological activity for DHA, i.e., renoprotection. DHA exhibits this effect by targeting DNMT1 to reverse Klotho repression. This study provides an evidence for the possible clinical application of DHA in the treatment of renal fibrosis.

Primary intrahepatic stones (PIS) is a refractory disease with a high incidence rate in Southwest China, which greatly affects the life of patients. Metabolites, such as β-glucuronidase produced by chronic biliary tract infection, play an important role in the formation of pigmented stones. In addition to exogenous β-glucuronidase produced by bacteria, endogenous β-glucuronidase produced by intrahepatic bile duct cells also plays an important role in the formation of stones. This article analyzes the research advances in the role of β-glucuronidase in the pathogenesis of PIS, in order to provide a possible method for the prevention and treatment of PIS. [ABSTRACT FROM AUTHOR]

Cognitive deficits are a major biomedical challenge-and engagement of the brain in stimulating tasks improves cognition in aged individuals (Wilson et al., 2002; Gates et al., 2011) and rodents (Aidil-Carvalho et al., 2017), through unknown mechanisms. Whether cognitive stimulation alters specific metabolic pathways in the brain is unknown. Understanding which metabolic processes are involved in cognitive stimulation is important because it could lead to pharmacologic intervention that promotes biological effects of a beneficial behavior, toward the goal of effective medical treatments for cognitive deficits. Here we show using male mice that cognitive stimulation induced metabolic remodeling of the mouse hippocampus, and that pharmacologic treatment with the longevity hormone α-klotho (KL), mediated by its KL1 domain, partially mimicked this alteration. The shared, metabolic signature shared between cognitive stimulation and treatment with KL or KL1 closely correlated with individual mouse cognitive performance, indicating a link between metabolite levels and learning and memory. Importantly, the treatment of mice with KL1, an endogenous circulating factor that more closely mimicked cognitive stimulation than KL, acutely increased synaptic plasticity, a substrate of cognition. KL1 also improved cognition, itself, in young mice and countered deficits in old mice. Our data show that treatments or interventions mimicking the hippocampal metabolome of cognitive stimulation can enhance brain functions. Further, we identify the specific domain by which klotho promotes brain functions, through KL1, a metabolic mimic of cognitive stimulation.SIGNIFICANCE STATEMENT Cognitive deficits are a major biomedical challenge without truly effective pharmacologic treatments. Engaging the brain through cognitive tasks benefits cognition. Mimicking the effects of such beneficial behaviors through pharmacological treatment represents a highly valuable medical approach to treating cognitive deficits. We demonstrate that brain engagement through cognitive stimulation induces metabolic remodeling of the hippocampus that was acutely recapitulated by the longevity factor klotho, mediated by its KL1 domain. Treatment with KL1, a close mimic of cognitive stimulation, enhanced cognition and countered cognitive aging. Our findings shed light on how cognition metabolically alters the brain and provide a plausible therapeutic intervention for mimicking these alterations that, in turn, improves cognition in the young and aging brain.

Emerging research supports that triclosan (TCS), an antimicrobial agent found in thousands of consumer products, exacerbates colitis and colitis-associated colorectal tumorigenesis in animal models. While the intestinal toxicities of TCS require the presence of gut microbiota, the molecular mechanisms involved have not been defined. Here we show that intestinal commensal microbes mediate metabolic activation of TCS in the colon and drive its gut toxicology. Using a range of in vitro, ex vivo, and in vivo approaches, we identify specific microbial β-glucuronidase (GUS) enzymes involved and pinpoint molecular motifs required to metabolically activate TCS in the gut. Finally, we show that targeted inhibition of bacterial GUS enzymes abolishes the colitis-promoting effects of TCS, supporting an essential role of specific microbial proteins in TCS toxicity. Together, our results define a mechanism by which intestinal microbes contribute to the metabolic activation and gut toxicity of TCS, and highlight the importance of considering the contributions of the gut microbiota in evaluating the toxic potential of environmental chemicals.

BackgroundKlotho is a longevity and neuroprotective hormone encoded by the KLOTHO gene, and heterozygosity for the KL-VS variant confers a protective effect against neurodegenerative disease.ObjectiveTest whether klotho concentrations in serum or cerebrospinal fluid (CSF) vary as a function of KLOTHO KL-VS genotype, determine whether circulating klotho concentrations from serum and CSF differ from one another, and evaluate whether klotho levels are associated with Alzheimer's disease risk factors.MethodsCirculating klotho was measured in serum (n = 1,116) and CSF (n = 183) of cognitively intact participants (aged 62.4 ± 6.5 years; 69.5% female). KLOTHO KL-VS zygosity (non-carrier; heterozygote; homozygote) was also determined. Linear regression was used to test whether klotho hormone concentration varied as a function of KL-VS genotype, specimen source, and demographic and clinical characteristics.ResultsSerum and CSF klotho were higher in KL-VS carriers than non-carriers. Klotho concentration was higher in CSF than in serum. Females had higher serum and CSF klotho, while younger age was associated with higher klotho in CSF.ConclusionIn a cohort enriched for risk for Alzheimer's disease, heterozygotic and homozygotic carriers of the KL-VS allele, females, and younger individuals have higher circulating klotho. Fluid source, KL-VS genotype, age, and sex should be considered in analyses of circulating klotho on brain health.

Objective. This study aims to explore the relationships between serum indoxyl sulfate (IS) and Klotho protein levels with vascular calcification in patients with chronic kidney disease (CKD) stages 3–5. Methods. From December 2021 to January 2023, a total of 108 CKD patients in stages 3–5 were enrolled in this cross-sectional investigation. Demographic information and routine clinical biochemistry test results were gathered. Serum levels of IS and Klotho were quantified through enzyme-linked immunosorbent assays. Furthermore, multislice spiral computed tomography was employed to evaluate vascular calcification. The association between serum IS or Klotho levels and abdominal aorta calcification was assessed using univariate analysis and logistic regression analyses. Results. With the progression of CKD stages, serum creatinine, phosphorus, intact parathyroid hormone (iPTH), serum IS, and abdominal aortic calcification exhibited incremental trends, while serum calcium and Klotho protein levels showed a diminishing trend, with statistically significant differences (P < 0. 05). Significant differences were observed in age, blood phosphorus, calcium, total parathyroid hormone, serum IS, and Klotho protein levels between patients with and without aortic calcification (P < 0. 05). Logistic regression analysis demonstrated that advanced age, high IS level, and low Klotho protein level were independent risk factors for abdominal aortic calcification in CKD patients (P < 0. 05). Conclusion. This study indicates elevated serum IS levels and decreased Klotho protein levels in CKD patients. High IS level and low Klotho level were independent risk factors for abdominal aortic calcification. [ABSTRACT FROM AUTHOR]

We aimed to investigate the effect of three types of exercise interventions on memory (i.e., immediate memory (IM), long‐term memory (LTM), and recognition). We also investigated whether exercise‐induced changes in circulating S‐Klotho and 1,25‐dihydroxivitamin D (1,25(OH)2D) levels were related to those observed in memory in healthy middle‐aged sedentary adults. A 12‐week randomized controlled trial was performed with a parallel‐group design. Seventy‐four participants (45–65 years old: 53% women) were randomly assigned to (1) no exercise (control) group, (2) concurrent training based on the international physical activity recommendations (PAR) group, (3) high‐intensity interval training (HIIT) group, or (4) HIIT plus whole‐body electromyostimulation (HIIT‐EMS) group. Memory outcomes were assessed using the Wechsler Memory Scale‐third edition. S‐Klotho plasma levels were determined according to a solid‐phase sandwich enzyme‐linked immunosorbent assay kit while 1,25(OH)2D plasma levels were measured using a DiaSorin‐Liaison immunochemiluminometric analyzer. IM‐Verbal Paired Associates (IM‐VPA) and IM‐Logical Memory (IM‐LM) were improved in both the HIIT and HIIT‐EMS groups compared with the control group (all p ≤ 0.045). Exercise‐induced changes in S‐Klotho plasma levels were positively associated with those observed in IM, LTM, and recognition (all p ≤ 0.007), whereas exercise‐induced changes in 1,25(OH)2D plasma levels were directly related to changes in IM and LTM (all p ≤ 0.048). In conclusion, a 12‐week HIIT intervention with or without WB‐EMS seems to be the most effective exercise program to improve IM. The significant and positive associations between exercise‐induced changes in S‐Klotho and 1,25(OH)2D levels with those observed in memory outcomes suggest that these factors may be potentially related to exercise‐induced improvements of memory in middle‐aged adults. [ABSTRACT FROM AUTHOR]

Genus Niallia has recently been separated taxonomic group from the Bacillus based on conserved signature indels in the genome. Unlike bioremediation, its role in plant biomass hydrolysis has not garnered considerable attention. The present study investigates the genomic potential of a novel Niallia sp. CRN 25 for applications in lignocellulose hydrolysis, significant enzyme production, and bioremediation. The CRN 25 strain exhibits xylosidase, cellobiosidase, α-arabinosidase, and α-D-galactosidase activity as 0.03 U/ml whereas β-D-glucosidase and glucuronidase as 0.06 U/ml and 0.01 U/ml, respectively. Further genome sequencing reveals nine copies of GH43 gene coding for hemicellulose-specific xylanase enzyme attached to the CBM 6 domain for increased processivity. The presence of β-glucosidase and β-galactosidase indicates the possible application of CRN 25 in facilitating the valorization of plant biomass into value-added products. Apart from this, genes of FMN-dependent NADH-azoreductase, cytochrome P450, and nitrate reductase, playing a crucial role in bioremediation processes, were annotated. Biosynthetic gene clusters (BGCs), responsible for synthesizing specialized metabolites of terpenes and lasso peptides, were also found in the genome. Conclusively genomic sketch of Niallia sp. CRN 25 reveals versatile metabolic potential for diverse environmental applications. [ABSTRACT FROM AUTHOR]

Gluconacetobacter diazotrophicus lives inside plant tissue cells in the form of colonies and excretes about half of the fixed nitrogen, which offers potential power that improves plant growth. The aim of this study is to find the interaction of glucuronidase (GUS)- labeled G. diazotrophicus with spinach seedlings and the detection of GUS genes using X-gluc dye (5-bromo-4-chloro-3-indolyl-β-Dglucuronic acid). The GUS protocol is used to detect GUS-labeled G. diazotrophicus in spinach seedling tissues by chemical detection using X-gluc dye. The results show that the spinach seedlings are successfully infected with GUS-labeled G. diazotrophicus, with the survival of the seedlings throughout their growth period and an improvement in the growth of pollinated seedlings. The outcomes of the microscopic inspection of the root slices reveal the presence of bacterial cells at the root tips and their concentration in the area of the cell walls of the peripheral cells. Furthermore, the findings of microscopic examinations of longitudinal sections for cotyledons show the presence of a number of bacteria within epidermal cell walls. This indicates that the determinants of the interaction between these bacteria and spinach seedlings are suitable for the expression of the gene responsible for the formation of the nitrogenase enzyme. [ABSTRACT FROM AUTHOR]

Unisexual flowers provide a useful system for studying plant sex determination. In cucumber (Cucumis sativus L.), three major Mendelian loci control unisexual flower development, Female (F), androecious [a; 1-aminocyclopropane-1-carboxylate {ACC} synthase 11, acs11], and Monoecious (M; ACS2), referred to here as the Female, Androecious, Monoecious (FAM) model, in combination with two genes, gynoecious (g, the WIP family C2H2 zinc finger transcription factor gene WIP1) and the ethylene biosynthetic gene ACC oxidase 2 (ACO2). The F locus, conferring gynoecy and the potential for increasing fruit yield, is defined by a 30.2-kb tandem duplication containing three genes. However, the gene that determines the Female phenotype, and its mechanism, remains unknown. Here, we created a set of mutants and revealed that ACS1G is responsible for gynoecy conferred by the F locus. The duplication resulted in ACS1G acquiring a new promoter and expression pattern; in plants carrying the F locus duplication, ACS1G is expressed early in floral bud development, where it functions with ACO2 to generate an ethylene burst. The resulting ethylene represses WIP1 and activates ACS2 to initiate gynoecy. This early ACS1G expression bypasses the need for ACS11 to produce ethylene, thereby establishing a dominant pathway for female floral development. Based on these findings, we propose a model for how these ethylene biosynthesis genes cooperate to control unisexual flower development in cucumber.

Klotho-VS heterozygosity (KL-VShet) is associated with reduced risk of Alzheimer's disease (AD). However, whether KL-VShet is associated with lower levels of pathologic tau, i.e., the key AD pathology driving neurodegeneration and cognitive decline, is unknown. Here, we assessed the interaction between KL-VShet and levels of beta-amyloid, a key driver of tau pathology, on the levels of PET-assessed neurofibrillary tau in 551 controls and patients across the AD continuum. KL-VShet showed lower cross-sectional and longitudinal increase in tau-PET per unit increase in amyloid-PET when compared to that of non-carriers. This association of KL-VShet on tau-PET was stronger in Klotho mRNA-expressing brain regions mapped onto a gene expression atlas. KL-VShet was related to better memory functions in amyloid-positive participants and this association was mediated by lower tau-PET. Amyloid-PET levels did not differ between KL-VShet carriers versus non-carriers. Together, our findings provide evidence to suggest a protective role of KL-VShet against amyloid-related tau pathology and tau-related memory impairments in elderly humans at risk of AD dementia.

Litchi (Litchi chinensis Sonn.) is a type of commercially prevalent subtropical and tropical fruit. Since litchi has a highly heterozygous genetic background and a long reproductive cycle, conventional breeding methods (such as hybridization) have limited ability to nurture new litchi cultivars. Here, an efficient and stable Agrobacterium tumefaciens-mediated genetic transformation of embryogenic callus was established in 'Feizixiao' litchi. Transgenic materials were verified using polymerase chain reaction (PCR) analysis, b-glucuronidase (GUS) assay, and green fluorescent protein (GFP) assay. To implement the technology of the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/associated protein 9 (CRISPR/Cas9) technology in 'Feizixiao' litchi and verify the validity of these transformation systems, the litchi polyphenol oxidase gene (LcPPO, JF926153) was knocked out. Various categories of mutations, covering base insertions, deletions, and substitutions, were found in transgenic materials via sequence analysis. The transformation system achieved high feasibility and efficiency, and the system of CRISPR/Cas9 was successfully employed to edit genes in 'Feizixiao' litchi. This work provides an essential foundation for investigating the functions of genes and accelerating litchi genetic improvement. [ABSTRACT FROM AUTHOR]

Background: Osteoporosis is a degenerative disease defined by low bone mineral density, has a high prevalence, and causes fractures at multiple sites throughout the body, greatly affecting the quality of patients. α-Klotho is an endocrine factor involved in the regulation of various metabolic processes in humans, and its role in bone metabolism has attracted widespread attention. The relationship between α-klotho and bone mineral density has not been uniformly recognized, and no large-scale correlation analysis has been conducted in the middle-aged and elderly population. Objective: To determine the relationship between α-klotho and bone mineral density in middle-aged and elderly people. Methods: Population data of 3120 individuals aged 40–79 years were obtained from the NHANES database for the period 2011–2016. Regression analysis was performed using a general linear model with serum α-klotho as the independent variable and total bone mineral density, thoracic bone mineral density, lumbar bone mineral density, pelvic bone mineral density, and trunk bone mineral density as the dependent variables, respectively. The generalized additive model was also used for smoothing curve fitting and threshold effect analysis. Results: Serum α-klotho was positively correlated with total bone mineral density at lg (Klotho) < 2.97 and with thoracic bone mineral density at lg (Klotho) > 2.69 (β = 0.05, p = 0.0006), and negatively correlated (β = −0.27, p = 0.0341) with lumbar bone mineral density at lg (Klotho) < 2.69. It also positively correlated with trunk bone mineral density (β = 0.027, p = 0.03657) and had no segmental effect but did not correlate with pelvic bone mineral density. The positive association of serum α-klotho with those aged 40–49 years, female, non-Hispanic White, and without hypertension was clearer. In the population with diabetes, a significantly positive association between total (β = 0.15, p = 0.01), thoracic (β = 0.23, p = 0.0404), and lumbar (β = 0.22, p = 0.0424) bone mineral density and α-klotho was observed. Conclusions: α-Klotho has different relationships with total, thoracic, lumbar, and trunk bone mineral density. Among them, the positive correlation between α-klotho and trunk bone mineral density is more valuable for predicting osteoporosis. The significant effect of α-klotho on bone mineral density in diabetes patients suggests its potential as a predictive marker of diabetes progression. [ABSTRACT FROM AUTHOR]

Background Endothelial dysfunction (ED) has a well-known role in promoting vascular inflammation in Behçet disease (BD). α-klotho is involved in regulation of endothelial function, and its reduction has been reported to be associated with ED.  Objective To assess serum α-klotho in patients with BD, compared with healthy control individuals. Methods In a cross-sectional study, 55 patients with BD and 30 age- and sex-matched healthy controls were enrolled, and their serum levels of α-klotho were measured. Results Common clinical symptoms in patients with BD were oral aphthous ulcers, uveitis, and genital ulcers. Median (IQR) serum α-klotho levels in the BD and control groups were 0.30 (0.20–0.70) and 1.00 (0.70–2.52) ng/mL, respectively. The difference was statistically significant (P  = .005). No significant correlation was observed between serum α-klotho and age (r  = 0.194; P  = .14). Serum α-klotho levels in patients with uveitis were significantly lower. Conclusion α-klotho may have a role in the pathogenesis of ED and is a potential biomarker for uveitis in BD. [ABSTRACT FROM AUTHOR]

Key messageA family of repetitive proline-rich proteins interact with acidic pectins and play distinct roles in legume root cell walls affecting cortical and vascular structure. A proline-rich protein (PRP) family, composed of tandemly repeated Pro-Hyp-Val-X-Lys pentapeptide motifs, is found primarily in the Leguminosae. Four distinct size classes within this family are encoded by seven tightly linked genes: MtPRP1, MtPRP2 and MtPRP3, and four nearly identical MtPRP4 genes. Promoter fusions to β-glucuronidase showed strong expression in the stele of hairy roots for all 4 PRP genes tested, with additional expression in the cortex for PRP1, PRP2 and PRP4. All except MtPRP4 are strongly expressed in non-tumorous roots, and secreted and ionically bound to root cell walls. These PRPs are absent from root epidermal cell walls, and PRP accumulation is highly localized within the walls of root cortical and vascular tissues. Within xylem tissue, PRPs are deposited in secondary thickenings where it is spatially exclusive to lignin. In newly differentiating xylem, PRPs are deposited in the regularly spaced paired-pits and pit membranes that hydraulically connect neighboring xylem elements. Hairpin-RNA knock-down constructs reducing PRP expression in Medicago truncatula hairy root tumors disrupted cortical and vascular patterning. Immunoblots showed that the knockdown tumors had potentially compensating increases in the non-targeted PRPs, all of which cross-react with the anti-PRP antibodies. However, PRP3 knockdown differed from knockdown of PRP1 and PRP2 in that it greatly reduced viability of hairy root tumors. We hypothesize that repetitive PRPs interact with acidic pectins to form block-copolymer gels that can play distinct roles in legume root cell walls.

Abstract Background Previous studies have revealed that some Auxiliary Activity family 9 (AA9) lytic polysaccharide monooxygenases (LPMOs) oxidize and degrade certain types of xylans when incubated with mixtures of xylan and cellulose. Here, we demonstrate that the xylanolytic activities of two xylan-active LPMOs, TtLPMO9E and TtLPMO9G from Thermothielavioides terrestris, strongly depend on the presence of xylan substitutions. Results Using mixtures of phosphoric acid-swollen cellulose (PASC) and wheat arabinoxylan (WAX), we show that removal of arabinosyl substitutions with a GH62 arabinofuranosidase resulted in better adsorption of xylan to cellulose, and enabled LPMO-catalyzed cleavage of this xylan. Furthermore, experiments with mixtures of PASC and arabinoglucuronoxylan from spruce showed that debranching of xylan with the GH62 arabinofuranosidase and a GH115 glucuronidase promoted LPMO activity. Analyses of mixtures with PASC and (non-arabinosylated) beechwood glucuronoxylan showed that GH115 action promoted LPMO activity also on this xylan. Remarkably, when WAX was incubated with Avicel instead of PASC in the presence of the GH62, both xylan and cellulose degradation by the LPMO9 were impaired, showing that the formation of cellulose–xylan complexes and their susceptibility to LPMO action also depend on the properties of the cellulose. These debranching effects not only relate to modulation of the cellulose–xylan interaction, which influences the conformation and rigidity of the xylan, but likely also affect the LPMO–xylan interaction, because debranching changes the architecture of the xylan surface. Conclusions Our results shed new light on xylanolytic LPMO9 activity and on the functional interplay and possible synergies between the members of complex lignocellulolytic enzyme cocktails. These findings will be relevant for the development of future lignocellulolytic cocktails and biomaterials.

Background: Osteoporosis (OP) is one of the diseases that endanger the health of the elderly population. Klotho protein is a hormone with anti-aging effects. A few studies have discussed the relationship between Klotho and OP. However, there is still a lack of research on larger populations. This study aims to evaluate the association between OP and Klotho in American postmenopausal women. Methods: This is a retrospective study. We searched the National Health and Nutrition Examination Survey (NHANES) database and collected data of 3 survey cycles, finally involving 871 postmenopausal women over 50 years old in the present study. All participants took dual-energy X-ray absorptiometry examination and serum Klotho testing at the time of investigation. After adjusting the possible confounding variables, a multivariate regression model was employed to estimate the relationship between OP and Klotho proteins. Besides, the P for trend and restricted cubic spline (RCS) were applied to examine the threshold effect and calculate the inflection point. Results: Factors influencing the occurrence of OP included age, ethnicity, body mass index and Klotho levels. Multivariate regression analysis indicated that the serum Klotho concentration was lower in OP patients than that in participants without OP (OR[log2Klotho] = 0.568, P = 0.027). The C-index of the prediction model built was 0.765, indicating good prediction performance. After adjusting the above-mentioned four variables, P values for trend showed significant differences between groups. RCSs revealed that when the Klotho concentration reached 824.09 pg/ml, the risk of OP decreased drastically. Conclusion: Based on the analysis of the data collected from the NHANES database, we propose a correlation between Klotho and postmenopausal OP. A higher serum Klotho level is related to a lower incidence of OP. The findings of the present study can provide guidance for research on diagnosis and risk assessment of OP. [ABSTRACT FROM AUTHOR]

Background: Periodontitis is an inflammatory disease characterized by inflammation and progressive destruction of periodontal tissues including alveolar bone. α-klotho protein is a multifunctional protein related to age-related diseases, inflammatory diseases, and bone metabolism-related diseases. However, large-sample epidemiological research evidence on the correlation between α-Klotho and the aggravation of periodontitis stages is still lacking. Methods: Cross-sectional study data of participants aged between 40 and 79 years in the National Health and Nutrition Examination Survey 2013‒2014 were selected and analyzed. The stages of periodontitis of the participants were determined according to the 2018 World Workshop Classification of Periodontal and Peri-implant Diseases. The serum α-Klotho levels in people with periodontitis in different stages were evaluated. Then the correlation between serum α-Klotho levels and different stages of periodontitis was analyzed by multiple linear regression (stepwise regression method). Results: A total of 2378 participants were included in the study. The serum α-Klotho levels in people with stage I/II, III and IV periodontitis were 896.16 ± 304.84, 871.08 ± 266.42 and 840.52 ± 286.24 pg/mL, respectively. The levels of α-Klotho in people with stage IV periodontitis were significantly lower than those in people with stage I/II and III periodontitis. Linear regression analysis results showed that compared to stage I/II periodontitis, serum α-Klotho levels were significantly negatively correlated with stage III (B ± SE = -37.28 ± 16.00, 95% CI: -68.66 ~ -25.91, P = 0.020) and stage IV (B ± SE = -69.37 ± 16.11, 95% CI: -100.97 ~ -37.77, P < 0.001) periodontitis. Conclusion: The serum α-Klotho levels were negatively correlated with the severity of periodontitis. With the aggravation of periodontitis stages, the serum α-Klotho levels gradually decreased. [ABSTRACT FROM AUTHOR]

Background: The effect of different dosing regimens of cholecalciferol supplementation on bone biomarkers has not been studied in children with chronic kidney disease (CKD). Methods: This is a post hoc analysis of a multi-center randomized controlled trial which included children with CKD stages 2–4 with vitamin D deficiency (25-hydroxy vitamin D (25OHD) < 30 ng/ml) randomized 1:1:1 to receive an equivalent dose of oral cholecalciferol as daily, weekly or monthly treatment. Markers of bone formation (bone alkaline phosphatase (BAP), procollagen I N terminal peptide (PINP)), bone resorption (tartarate-resistant acid phosphatase 5b (TRAP), C terminal telopeptide (CTX)), and osteocyte markers (intact fibroblast growth factor 23 (iFGF23), sclerostin) and soluble klotho were measured at baseline and after 3 months of intensive replacement therapy. The change in biomarkers and ratio of markers of bone formation to resorption were compared between treatment arms. BAP and TRAP were expressed as age- and sex-specific z-scores. Results: 25OHD levels increased with cholecalciferol supplementation, with 85% achieving normal levels. There was a significant increase in the BAP/TRAP ratio (p = 0.04), iFGF23 (p = 0.004), and klotho (p = 0.002) with cholecalciferol therapy, but this was comparable across all three therapy arms. The BAPz was significantly higher in the weekly arm (p = 0.01). The change in 25OHD (Δ25OHD) inversely correlated with ΔPTH (r = − 0.4, p < 0.001). Conclusions: Although cholecalciferol supplementation was associated with a significant increase in bone formation, the three dosing regimens of cholecalciferol supplementation have a comparable effect on the bone biomarker profile, suggesting that they can be used interchangeably to suit the patient's needs and optimize adherence to therapy. [ABSTRACT FROM AUTHOR]

Background: Human periodontal ligament stem cells (hPDLSCs) have a superior ability to promote the formation of new bones and achieve tissue regeneration. However, mesenchymal stem cells (MSCs) are placed in harsh environments after transplantation, and the hostile microenvironment reduces their stemness and hinders their therapeutic effects. Klotho is an antiaging protein that participates in the regulation of stress resistance. In our previous study, we demonstrated the protective ability of Klotho in hPDLSCs. Methods: A cranial bone defect model of rats was constructed, and the hPDLSCs with or without Klotho pretreatment were transplanted into the defects. Histochemical staining and micro-computed tomography were used to detect cell survival, osteogenesis, and immunoregulatory effects of hPDLSCs after transplantation. The in vitro capacity of hPDLSCs was measured by a macrophage polarization test and the inflammatory level of macrophages. Furthermore, we explored autophagy activity in hPDLSCs, which may be affected by Klotho to regulate cell homeostasis. Results: Pretreatment with the recombinant human Klotho protein improved cell survival after hPDLSC transplantation and enhanced their ability to promote bone regeneration. Furthermore, Klotho pretreatment can promote stem cell immunomodulatory effects in macrophages and modulate cell autophagy activity, in vivo and in vitro. Conclusion: These findings suggest that the Klotho protein protects hPDLSCs from stress after transplantation to maintain stem cell function via enhancing the immunomodulatory ability of hPDLSCs and inhibiting cell autophagy. [ABSTRACT FROM AUTHOR]

Objectives: The rate of biological aging is influenced by various factors such as genetics, environment, and diet. The dietary inflammatory index (DII) is strongly associated with various chronic diseases. The aim of this study was to investigate the association between DII and biological aging in US adults using quantitative indicators. Methods: Based on data from the National Health and Nutrition Examination Survey (NHANES) 1999–2018, weighted multiple linear regression models, generalized weighted models, and smoothed fitted curves were used to investigate the linear and nonlinear relationships of DII with four biological markers of aging (biological age, phenotypic age, telomere length, and serum klotho concentration). Results: A total of 35,575 adult participants with complete data were included in the study. After adjusting for all confounders, significant positive correlations were found between DII with biological age [0.070 (0.045, 0.095)] and phenotypic age [0.421 (0.371, 0.471)], with an increase of 0.07 and 0.42 years in biological age and phenotypic age, respectively, for each increase in DII score. The negative correlations between DII with telomere length [ – 0.005 (– 0.008, – 0.002)] and klotho [ – 3.874 (– 7.409, – 0.338)] were significant only in partially adjusted models and differed across subgroups. Conclusions: In the current study, higher DII scores (greater pro-inflammatory dietary potential) were associated with biological aging. These findings may contribute to the development of aging prevention strategies through dietary interventions. [ABSTRACT FROM AUTHOR]

New findingsWhat is the central question of this study? Does modulating the expression of Klotho affect myogenesis following acute injury of healthy, non-senescent muscle? What is the main finding and its importance? Klotho can accelerate muscle growth following acute injury of healthy, adult mice, which supports the possibility that increased delivery of Klotho could have therapeutic value for improving repair of damaged muscle.AbstractSkeletal muscle injuries activate a complex programme of myogenesis that can restore normal muscle structure. We tested whether modulating the expression of klotho influenced the response of mouse muscles to acute injury. Our findings show that klotho expression in muscle declines at 3 days post-injury. That reduction in klotho expression coincided with elevated expression of targets of Wnt signalling (Ccnd1; Myc) and increased MyoD+ muscle cell numbers, reflecting the onset of myogenic cell differentiation. klotho expression subsequently increased at 7 days post-injury with elevated expression occurring primarily in inflammatory lesions, which was accompanied by reduced expression of Wnt target genes (Ccnd1: 91%; Myc: 96%). Introduction of a klotho transgene maintained high levels of klotho expression over the course of muscle repair and attenuated the increases in Ccnd1 and Myc expression that occurred at 3 days post-injury. Correspondingly, transgene expression reduced Wnt signalling in Pax7+ cells, reflected by reductions in Pax7+ cells expressing active β-catenin, and reduced the numbers of MyoD+ cells at 3 days post-injury. At 21 days post-injury, muscles in klotho transgenic mice showed increased Pax7+ and decreased myogenin+ cell densities and large increases in myofibre size. Likewise, treating myogenic cells in vitro with Klotho reduced Myod expression but did not affect Pax7 expression. Muscle inflammation was only slightly modulated by increased klotho expression, initially reducing the expression of M2-biased macrophage markers Cd163 and Cd206 at 3 days post-injury and later increasing the expression of pan-macrophage marker F480 and Cd68 at 21 days post-injury. Collectively, our study shows that Klotho modulates myogenesis and that increased expression accelerates muscle growth after injury.

BackgroundThe hormone klotho, encoded by the gene klotho, is primarily expressed in the kidney and choroid plexus of the brain. Higher klotho concentrations have been linked to better physical performance; however, it is unknown whether klotho relates to frailty status in older adults.MethodsPlasma klotho was measured in 774 participants aged ≥65 years enrolled in InCHIANTI, a prospective cohort study comprising Italian adults. Frailty status was assessed at 3 and 6 years after enrollment. Frailty was defined as presence of at least three out of five criteria of unintentional weight loss, exhaustion, sedentariness, muscle weakness, and slow walking speed; prefrailty was defined as presence of one or two criteria; and robustness was defined as zero criteria. We assessed whether plasma klotho concentrations measured at the 3-year visit related to frailty.ResultsEach additional natural logarithm of klotho (pg/mL) was associated with lower odds of frailty versus robustness after adjustment for covariates (odds ratio [OR] 0.46; 95% confidence interval 0.21, 0.98; p-value = .045). Higher klotho was particularly associated with lower odds of exhaustion (OR 0.57; 95% CI 0.36, 0.89; p-value = .014). Participants with higher klotho also had lower estimated odds of weight loss and weakness, but these findings were not statistically significant.ConclusionsHigher plasma klotho concentrations were associated with lower likelihoods of frailty and particularly exhaustion. Future studies should investigate modifiable mechanisms through which klotho may affect the frailty syndrome.

Background and Purpose: Opioids are commonly used for the management of cancer‐associated pain and chemotherapy‐induced diarrhoea. The chemotherapeutic irinotecan (CPT‐11) causes severe gastrointestinal (GI) toxicity due to deconjugation of inactive metabolite SN‐38 glucuronide (SN‐38G) by bacterial β‐glucuronidases to the active 7‐ethyl‐10‐hydroxycamptothecin (SN‐38). Opioids are known to cause gut microbial dysbiosis, this study evaluated whether CPT‐11 anti‐tumour efficacy and GI toxicity are exacerbated by opioid co‐administration. Experimental Approach: Eight‐week‐old C57BL/6 male mice were co‐administration with CPT‐11 ± opioid. 16S rRNA sequencing was used for gut microbiome analysis. LC–MS analyses of plasma and intestinal extracts were performed to investigate the pharmacokinetic profile of CPT‐11. Histological analysis and quantitative real‐time polymerase chain reaction were used to determine the severity of intestinal tissue damage. Human liver microsome In vitro assay was performed to confirm the effects of opioids on CPT‐11 metabolism. Key Results: Gut microbiome analysis showed that morphine treatment induced enrichment of β‐glucuronidase‐producing bacteria in the intestines of CPT‐11‐treated mice, resulting in SN‐38 accumulation and exacerbation of GI toxicity in the small intestine. Oral administration of both antibiotics and glucuronidase inhibitor protected mice against GI toxicity induced with CPT‐11 and morphine co‐administration, implicating a microbiome‐dependent mechanism. Additionally, morphine and loperamide decreased the plasma concentration of SN‐38 and compromised CPT‐11 anti‐tumour efficacy, this seemed to be microbiome independent. Conclusion and Implications: Gut microbiota play a significant role in opioid and chemotherapeutic agent drug–drug interactions. Inhibition of gut microbial glucuronidase may also prevent adverse GI effects of CPT‐11 in patients on opioids. [ABSTRACT FROM AUTHOR]

Located within the brain's ventricles, the choroid plexus produces cerebrospinal fluid and forms an important barrier between the central nervous system and the blood. For unknown reasons, the choroid plexus produces high levels of the protein klotho. Here, we show that these levels naturally decline with aging. Depleting klotho selectively from the choroid plexus via targeted viral vector-induced knockout in Klotho flox/flox mice increased the expression of multiple proinflammatory factors and triggered macrophage infiltration of this structure in young mice, simulating changes in unmanipulated old mice. Wild-type mice infected with the same Cre recombinase-expressing virus did not show such alterations. Experimental depletion of klotho from the choroid plexus enhanced microglial activation in the hippocampus after peripheral injection of mice with lipopolysaccharide. In primary cultures, klotho suppressed thioredoxin-interacting protein-dependent activation of the NLRP3 inflammasome in macrophages by enhancing fibroblast growth factor 23 signaling. We conclude that klotho functions as a gatekeeper at the interface between the brain and immune system in the choroid plexus. Klotho depletion in aging or disease may weaken this barrier and promote immune-mediated neuropathogenesis.

Aggregated metastatic cancer cells, referred to as circulating tumor cell (CTC) clusters, are present in the blood of cancer patients and contribute to cancer metastasis. However, the origin of CTC clusters, especially intravascular aggregates, remains unknown. Here, we employ suspension culture methods to mimic CTC cluster formation in the circulation of breast cancer patients. CTC clusters generated using these methods exhibited an increased metastatic potential that was defined by the overexpression of heparanase (HPSE). Heparanase induced FAK- and ICAM-1-dependent cell adhesion, which promoted intravascular cell aggregation. Moreover, knockdown of heparanase or inhibition of its activity with JG6, a heparanase inhibitor, was sufficient to block the formation of cell clusters and suppress breast cancer metastasis. Our data reveal that heparanase-mediated cell adhesion is critical for metastasis mediated by intravascular CTC clusters. We also suggest that targeting the function of heparanase in cancer cell dissemination might limit metastatic progression.

BackgroundKlotho serum levels reflect nutritional state in adults including obesity and anorexia. The relationship between cord blood klotho levels at birth and parameters of growth including anthropometrics are not known.MethodsWe evaluated the relationship between cord blood klotho, leptin and adipocyte hormones and infant, child and maternal anthropometrics and maternal depression in a cohort of 73 children. Non-parametric tests were used to assess differences between dichotomous and categorical predictors and klotho levels and Spearman's rank coefficients were used to assess the relationship between klotho levels and continuous predictors. A multivariable log transformed linear regression model was used to test for independent predictors of serum klotho levels.ResultsMean klotho levels were 2864.9±1409.7 (pg/mL) in cord blood and we found no relationship with infant sex, delivery specifics including gestational age or anthropometrics at birth. There was similarly no association between klotho levels at birth and future obesity at age 2. Leptin levels at birth were inversely associated with klotho levels in multivariable models after adjusting for other covariates (p

Purpose: Aging is the primary risk factor for cognitive decline. Serum klotho, as an anti-aging protein, may be involved in cognitive decline. Thus, we aim to explorer the correlation between serum klotho and cognitive performance among an older adult population in the United States. Methods: We performed a cross-sectional study using data from NHANES 2011-2014. Serum klotho was analyzed by ELISA. Cognitive function was measured by Establish a Registry for Alzheimer's Disease (CERAD) test, Animal Fluency test and Digit Symbol Substitution Test (DSST) score. The relationship between serum klotho and cognition was analyzed by a multivariable regression model. Results: A total of 2,171 participants aged 60-79 years were included. Median serum klotho concentration was 851.52 pg./ml (SD = 294.07). We also categorized serum klotho concentrates into quartiles. After fully adjusting pertinent variables, compared to those with lowest klotho levels (206.3-658.4 pg./ml), individuals with highest klotho concentrates (983.3-3,456 pg./ml) had a higher CERAD score [ß (95%CI): 0.97 (0.25, 1.69) p = 0.008] and DSST score [ß (95%CI): 1.86 (0.25, 3.47), p = 0.024]. Conclusion: Our findings indicated that, among the general population of American older adults, serum klotho concentrates may serve as a marker of cognitive health. The benefits of klotho on aging process and neurodegenerative disorders should be paid more attention. [ABSTRACT FROM AUTHOR]

We show that the knockout of a sugar transporter gene OsSWEET15 led to a significant drop in rice fertility with around half of the knockout mutant's spikelets bearing blighted or empty grains. The rest of the spikelets bore fertile grains with a slightly reduced weight. Notably, the ovaries in the blighted grains of the ossweet15 mutants expanded after flowering but terminated their development before the endosperm cellularization stage and subsequently aborted. β- glucuronidase (GUS) and Green Fluorescent Protein (GFP) reporter lines representing the OsSWEET15 expression showed that the gene was expressed in the endosperm tissues surrounding the embryo, which supposedly supplies nutrients to sustain embryo development. These results together with the protein's demonstrated sucrose transport capacity and plasma membrane localization suggest that OsSWEET15 plays a prominent role during the caryopsis formation stage, probably by releasing sucrose from the endosperm to support embryo development. By contrast, the empty grains were probably caused by the reduced pollen viability of the ossweet15 mutants. Investigation of ossweet11 mutant grains revealed similar phenotypes to those observed in the ossweet15 mutants. These results indicate that both OsSWEET15 and OsSWEET11 play important and similar roles in rice pollen development, caryopsis formation and seed-setting, in addition to their function in seed-filling that was demonstrated previously. [ABSTRACT FROM AUTHOR]