Ginsenoside Rb1 attenuates doxorubicin induced cardiotoxicity by suppressing autophagy and ferroptosis.

Ginsenoside Rb1 (Rb1), an active component isolated from traditional Chinese medicine Ginseng, is beneficial to many cardiovascular diseases. However, whether it can protect against doxorubicin induced cardiotoxicity (DIC) is not clear yet. In this study, we aimed to investigate the role of Rb1 in DIC. Mice were injected with a single dose of doxorubicin (20 mg/kg) to induce acute cardiotoxicity. Rb1 was given daily gavage to mice for 7 days. Changes in cardiac function, myocardium histopathology, oxidative stress, cardiomyocyte mitochondrion morphology were studied to evaluate Rb1's function on DIC. Meanwhile, RNA-seq analysis was performed to explore the potential underline molecular mechanism involved in Rb1's function on DIC. We found that Rb1 treatment can improve survival rate and body weight in Dox treated mice group. Rb1 can attenuate Dox induced cardiac dysfunction and myocardium hypertrophy and interstitial fibrosis. The oxidative stress increase and cardiomyocyte mitochondrion injury were improved by Rb1 treatment. Mechanism study found that Rb1's beneficial role in DIC is through suppressing of autophagy and ferroptosis. This study shown that Ginsenoside Rb1 can protect against DIC by regulating autophagy and ferroptosis.

Ultra-antiwetting Membrane for Hypersaline Water Crystallization in Membrane Distillation.

Membrane distillation (MD) has great potential in the management of hypersaline water for zero liquid discharge (ZLD) due to its high salinity tolerance. However, the membrane wetting issue significantly restricts its practical application. In this study, a composite membrane tailored for extreme concentrations and even crystallization of hypersaline water is synthesized by coating a commercial hydrophobic porous membrane with a composite film containing a dense polyamide layer, a cation exchange layer (CEL), and an anion exchange layer (AEL). When used in direct contact MD for treating a 100 g L-1 NaCl hypersaline solution, the membrane achieves supersaturation of feed solution and a salt crystal yield of 38.0%, with the permeate concentration at <5 mg L-1. The composite membrane also demonstrates ultrahigh antiwetting stability in 360 h of long-term operation. Moreover, ion diffusion analysis reveals that the ultrahigh wetting resistance of the composite membrane is attributed to the bipolar AEL and CEL that eliminate ion crossover. The literature review elucidates that the composite membrane is superior to state-of-the-art membranes. This study demonstrates the great potential of the composite membrane for direct crystallization of hypersaline water, offering a promising approach to filling the gap between reverse osmosis and conventional thermal desalination processes for ZLD application.

Associations between accelerometer-measured physical activity and sedentary behaviour with physical function among older women: a cross-sectional study.

BACKGROUND: This study aimed to investigate the relationships between accelerometer-measured physical activity (PA) and sedentary behaviour (SB) with physical function (PF) among older Chinese women in the community. METHODS: The present study comprised 1,113 community-dwelling older females, with an average age of 65 ± 2 years. We employed a linear regression analysis to investigate the relationship between patterns of PA and SB with PF. PA variables consisted of total PA time, bouted PA time (a continuous PA that lasts equal to or more than 10 min), and sporadic PA time (a continuous PA that lasts less than 10 min). SB variables included total SB time, 30-min bout of SB (a continuous SB that lasts equal to or more than 30 min), and 60-min bout of SB (a continuous SB that lasts equal to or more than 60 min). PF variables comprised handgrip strength (HGS), one-legged stance test with eyes closed (OLSTEC), usual walking speed (UWS), maximum walking speed (MWS) and chair-stand time (CT). To explore the joint effects of moderate-to-vigorous-intensity PA (MVPA) and SB on PF, we divided the duration of SB and MVPA participation in older women into different combinations: low MVPA & high SB, low MVPA & low SB, high MVPA & high SB, high MVPA & low SB. RESULTS: The study revealed a significant association between 30-min bout of SB and CT, which remained after adjusting for total MVPA time (P = 0.021). Both total MVPA and bouted MVPA were found to be positively associated with better UWS, MWS, CT, and PF Z-score. When the combination of low MVPA & high SB was used as a reference, the regression coefficients for PF ascended by 1.32 (P < 0.001) in the high MVPA & high SB group and by 1.13 (P < 0.001) in the high MVPA & low SB group. CONCLUSIONS: A significant association was observed between poorer lower limb function and prolonged, uninterrupted SB in older women, rather than with the total SB time. Concurrently, the insufficient engagement in MVPA may also be a crucial factor contributing to poorer PF in older women. Engaging in longer durations and higher intensity of PA, such as bouts of MVPA lasting a minimum of 10 min or longer, may contribute to better PF.

Efficient Photosynthesis of Hydrogen Peroxide by Cyano-Containing Covalent Organic Frameworks from Water, Air and Sunlight.

The insufficient exciton (e- -h+ pair) separation/transfer and sluggish two-electron water oxidation are two main factors limiting the H2 O2 photosynthetic efficiency of covalent organic frameworks (COFs) photocatalysts. Herein, we present an alternative strategy to simultaneously facilitate exciton separation/transfer and reduce the energy barrier of two-electron water oxidation in COFs via a dicyano functionalization. The in situ characterization and theoretical calculations reveal that the dicyano functionalization improves the amount of charge transfer channels between donor and acceptor units from two in COF-0CN without cyano functionalization to three in COF-1CN with mono-cyano functionalization and four in COF-2CN with dicyano functionalization, leading to the highest separation/transfer efficiency in COF-2CN. More importantly, the dicyano group activates the neighbouring C atom to produce the key *OH intermediate for effectively reducing the energy barrier of rate-determining two-electron water oxidation in H2 O2 photosynthesis. The simultaneously enhanced exciton separation/transfer and two-electron water oxidation in COF-2CN result in high H2 O2 yield (1601 µmol g-1 h-1 ) from water and oxygen without using sacrificial reagent under visible-light irradiation. COF-2CN can effectively yield H2 O2 in water with wide pH range, in different real water samples, in scaled-up reactor under natural sunlight irradiation, and in continuous-flow reactor for consecutively producing H2 O2 solution for water decontamination.

[Spatio-temporal Evolution and Driving Factors of Ecological Environment Quality in the Huaihe River Basin Based on RSEI].

Clarifying the spatio-temporal evolution of the ecological environment quality of a watershed and its response to the natural environment and human factors are crucial for policy implementation in the ecological environment of the watershed. Using the Google earth engine（GEE） to establish a remote sensing ecological index （RSEI）, the spatio-temporal changes in the ecological environment quality of the Huaihe River Basin from 2002 to 2022 were evaluated combined with trend analysis, variation coefficient, and Hurst index. The main driving factors of spatial differentiation of RSEI were explored using the geographic detector. The results showed that： ① In the past 21 years, RSEI of the Huaihe River Basin had generally improved, but it showed a gradual upward-downward trend. Overall, the area of poor and less poor grades decreased, the area of medium grades increased, and the area of good and excellent grades increased. The improved area accounted for 55.93%, and the degraded area accounted for 22.01%. ② In terms of spatial distribution, RSEI gradually deteriorated from east to west （except in the northwest and southwest marginal mountainous areas）. The stability was better in the east and worse in the western and central areas. In the future, the ecological quality change in the basin was prone to be anti-sustainable and mainly improved. ③ Factor detection results showed that the spatial differentiation of RSEI in the basin was mainly driven by vegetation factors, followed by altitude. The interaction between two factors enhanced the driving force for RSEI spatial differentiation, in which the interaction between vegetation factor and elevation had the strongest driving force for RSEI spatial differentiation, reaching 86.3%.

The relationship between accelerometer-based physical activity, sedentary behavior, and seven common geriatric syndromes: a two-sample Mendelian randomization study.

Introduction: To investigate the causal associations between accelerometer-based physical activity (PA), sedentary behavior (SB), and seven common geriatric syndromes (GSs) (frailty, falls, delirium, urinary incontinence, dysphagia, hearing loss, and visual impairment) by Mendelian randomization (MR) analysis. Methods: Instrumental variables from a genome-wide association study were used for MR analysis. The exposure factors were three PA phenotypes (average acceleration, overall activity, and moderate-intensity activity) and one SB phenotype (SB). The outcome variables were seven common GSs. The inverse variance weighted (IVW) method was utilized for the primary MR analysis. Additionally, sensitivity, pleiotropy, and heterogeneity analyses were subsequently conducted to assess the robustness of the present study's findings. Results: According to the primary MR results obtained using the IVW method, genetically predicted PA (average acceleration) decreased the risk of two GSs (frailty, p = 0.01; dysphagia, p = 0.03). Similarly, overall activity decreased the risk of two GSs (frailty, p = 0.01; delirium, p = 0.03), and moderate-intensity activity reduced the risk of three GSs (urinary incontinence, p = 0.04; hearing loss, p = 0.02; visual impairment, p = 0.01). Furthermore, SB was causally correlated with a greater risk for three GSs (frailty, p = 0.03; fall, p = 0.01; dysphagia, p = 0.04). Conclusion: This study provided evidence that accelerometer-based PA may be causally associated with a lower risk of GSs, while SB may increase the risk of GSs.

A novel deep intronic variant introduce dystrophin pseudoexon in Becker muscular dystrophy: A case report.

Most pathogenic DMD variants are detectable and interpretable by standard genetic testing for dystrophinopthies. However, approximately 1∼3% of dystrophinopthies patients still do not have a detectable DMD variant after standard genetic testing, most likely due to structural chromosome rearrangements and/or deep intronic pseudoexon-activating variants. Here, we report on a boy with a suspected diagnosis of Becker muscular dystrophy (BMD) who remained without a detectable DMD variant after exonic DNA-based standard genetic testing. Dystrophin mRNA studies and genomic Sanger sequencing were performed in the boy, followed by in silico splicing analyses. We successfully detected a novel deep intronic disease-causing variant in the DMD gene (c.2380 + 3317A > T), which consequently resulting in a new dystrophin pseudoexon activation through the enhancement of a cryptic donor splice site. The patient was therefore genetically diagnosed with BMD. Our case report further emphasizes the significant role of disease-causing splicing variants within deep intronic regions in genetically undiagnosed dystrophinopathies.

Clinical and genetic interpretation of uncertain DMD missense variants: evidence from mRNA and protein studies.

BACKGROUND: Pathogenic missense variants in the dystrophin (DMD) gene are rarely reported in dystrophinopathies. Most DMD missense variants are of uncertain significance and their pathogenicity interpretation remains complicated. We aimed to investigate whether DMD missense variants would cause aberrant splicing and re-interpret their pathogenicity based on mRNA and protein studies. METHODS: Nine unrelated patients who had an elevated serum creatine kinase level with or without muscle weakness were enrolled. They underwent a detailed clinical, imaging, and pathological assessment. Routine genetic testing and muscle-derived mRNA and protein studies of dystrophin and sarcoglycan genes were performed in them. RESULTS: Three of the 9 patients presented with a Duchenne muscular dystrophy (DMD) phenotype and the remaining 6 patients had a suspected diagnosis of Becker muscular dystrophy (BMD) or sarcoglycanopathy based on their clinical and pathological characteristics. Routine genetic testing detected only 9 predicted DMD missense variants in them, of which 6 were novel and interpreted as uncertain significance. Muscle-derived mRNA studies of sarcoglycan genes didn't reveal any aberrant transcripts in them. Dystrophin mRNA studies confirmed that 3 predicted DMD missense variants (c.2380G > C, c.4977C > G, and c.5444A > G) were in fact splicing and frameshift variants due to aberrant splicing. The 9 DMD variants were re-interpreted as pathogenic or likely pathogenic based on mRNA and protein studies. Therefore, 3 patients with DMD splicing variants and 6 patients with confirmed DMD missense variants were diagnosed with DMD and BMD, respectively. CONCLUSION: Our study highlights the importance of muscle biopsy and aberrant splicing for clinical and genetic interpretation of uncertain DMD missense variants.

A novel biomarker of fibrofatty replacement in dystrophinopathies identified by integrating transcriptome, magnetic resonance imaging, and pathology data.

BACKGROUND: We aimed to analyse genome-wide transcriptome differences between Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) patients and identify biomarkers that correlate well with muscle magnetic resonance imaging (MRI) and histological fibrofatty replacement in both patients, which have not been reported. METHODS: One hundred and one male patients with dystrophinopathies (55 DMD and 46 BMD) were enrolled. Muscle-derived genome-wide RNA-sequencing was performed in 31 DMD patients, 29 BMD patients, and 11 normal controls. Fibrofatty replacement was scored on muscle MRI and histological levels in all patients. A unique pipeline, single-sample gene set enrichment analysis combined with Spearman's rank correlations (ssGSEA-Cor) was developed to identify the most correlated gene signature for fibrofatty replacement. Quantitative real-time PCR (qRT-PCR) analysis, western blot analysis, and single-nucleus RNA-sequencing (snRNA-seq) were performed in the remaining patients to validate the most correlated gene signature. RESULTS: Comparative transcriptomic analysis revealed that 31 DMD muscles were characterized by a significant increase of inflammation/immune response and extracellular matrix remodelling compared with 29 BMD muscles (P < 0.05). The ssGSEA-Cor pipeline revealed that the gene set of CDKN2A and CDKN2B was the most correlated gene signature for fibrofatty replacement (histological rs  = 0.744, P < 0.001; MRI rs  = 0.718, P < 0.001). Muscle qRT-PCR confirmed that CDKN2A mRNA expression in both 15 DMD (median = 25.007, P < 0.001) and 12 BMD (median = 5.654, P < 0.001) patients were significantly higher than that in controls (median = 1.101), while no significant difference in CDKN2B mRNA expression was found among DMD, BMD, and control groups. In the 27 patients, muscle CDKN2A mRNA expression respectively correlated with muscle MRI (rs  = 0.883, P < 0.001) and histological fibrofatty replacement (rs  = 0.804, P < 0.001) and disease duration (rs  = 0.645, P < 0.001) and North Star Ambulatory Assessment total scores (rs  = -0.698, P < 0.001). Muscle western blot analysis confirmed that both four DMD (median = 2.958, P < 0.05) and four BMD (median = 1.959, P < 0.01) patients had a significantly higher level of CDKN2A protein expression than controls (median = 1.068). The snRNA-seq analysis of two DMD muscles revealed that CDKN2A was mainly expressed in fibro-adipogenic progenitors, satellite cells, and myoblasts. CONCLUSIONS: We identify CDKN2A expression as a novel biomarker of fibrofatty replacement, which might be a new target for antifibrotic therapy in dystrophinopathies.

A new pseudoexon activation due to ultrarare branch point formation in Duchenne muscular dystrophy.

Deep-intronic variants that create or enhance a splice site are increasingly reported as a significant cause of monogenic diseases. However, deep-intronic variants that activate pseudoexons by affecting a branch point are extremely rare in monogenic diseases. Here, we describe a novel deep-intronic DMD variant that created a branch point in a Duchenne muscular dystrophy (DMD) patient. A 7.0-year-old boy was enrolled because he was suspected of DMD based on his clinical, muscle imaging, and pathological features. Routine genetic testing did not discover a pathogenic DMD variant. We then performed muscle-derived dystrophin mRNA analysis and detected an aberrant pseudoexon-containing transcript. Further genomic Sanger sequencing and bioinformatic analyses revealed a novel deep-intronic splicing variant in DMD (NM_004006.2:c.5325+1759G>T), which created a new branch point sequence and thus activated a new dystrophin pseudoexon (NM_004006.2:r.5325_5326ins5325+1779_5325+1855). Our study highlights the significant role of branch point alterations in the pathogenesis of monogenic diseases.

Pyruvate dehydrogenase kinase regulates macrophage polarization in metabolic and inflammatory diseases.

Macrophages are highly heterogeneous and plastic, and have two main polarized phenotypes that are determined by their microenvironment, namely pro- and anti-inflammatory macrophages. Activation of pro-inflammatory macrophages is closely associated with metabolic reprogramming, especially that of aerobic glycolysis. Mitochondrial pyruvate dehydrogenase kinase (PDK) negatively regulates pyruvate dehydrogenase complex activity through reversible phosphorylation and further links glycolysis to the tricarboxylic acid cycle and ATP production. PDK is commonly associated with the metabolism and polarization of macrophages in metabolic and inflammatory diseases. This review examines the relationship between PDK and macrophage metabolism and discusses the mechanisms by which PDK regulates macrophage polarization, migration, and inflammatory cytokine secretion in metabolic and inflammatory diseases. Elucidating the relationships between the metabolism and polarization of macrophages under physiological and pathological conditions, as well as the regulatory pathways involved, may provide valuable insights into the etiology and treatment of macrophage-mediated inflammatory diseases.

Research progress on low carbohydrate diet in the control of overweight and obesity / 预防医学

@#Overweight and obesity are main risk factors for chronic metabolic diseases, and are strongly associated with the increased risk of premature death. Low carbohydrate diet (LCD) has been proven to effectively control body weight and fat mass in overweight and obese patients by short-term (≤6 months) dietary intervention studies. The mechanisms include regulation of energy metabolism, anti-inflammatory, antioxidant, alteration in expression of lipid metabolic-related genes and modulation of intestinal flora. However, the conclusions are inconsistent on whether LCD can cause durable weight loss and reduce the risk of overweight and obesity. This review summarizes the current research progress on the mechanisms, epidemiological studies, intervention studies and potential risks of LCD in controlling overweight and obesity, providing a reference for the future research and clinical application.

The effect of aspartame on accelerating caspase-dependent apoptosis of pancreatic islet via ZIPK/STAT3/caspase 3 signaling pathway

Aspartame (ASP) as an important sugar substitute is widely used in pharmaceutical and food processing. Here, we compared the effects of ASP and sucrose on mice pancreatic islet cells in vivo and observed that ASP with the condition of high concentration and long-term exposure (HASP) could cause insulin secretion (500 mg/kg for 1 month). Next, we conducted iTRAQ mass spectrometry to profile the global phosphoproteome and found that phosphorylation of zipper-interacting protein kinase (ZIPK) in murine pancreatic islet tissues were induced at Thr197, Thr242, Thr282, and Ser328 by high-sucrose (HS) treatment, but only induced at Thr197 and Ser328 by HASP treatment. Simultaneously, phosphorylation of STAT3 could be induced at Tyr705 and Ser727 by HS but not by HASP. Furthermore, presence of activated STAT3 accompanied with autophagy was observed in HS treatment. In turn, the inactivation of STAT3 as well as enhanced expression of caspase 3 was observed in HASP treatment. We generated Thr242APro and Thr282Pro on ZIPK using CRISPR-Cas9 in β-TC3 cells and found the weakened interaction with STAT3 as well as the reduced phosphorylation of STAT3 even under HS stimulation. Finally, we observed that ankyrin repeat domain containing 11 (ANKRD11) could interact with ZIPK and play an inhibitory role in the phosphorylation of Thr242APro and Thr282Pro of ZIPK. However, HASP can induce the retention of ANKRD11 in the cytoplasm by phenylpyruvic acid (the metabolite of ASP). Taken together, this study determined that ASP with high concentration and long-term exposure could lead to caspase-dependent apoptosis of pancreatic islet cells through ANKRD11/ZIPK/STAT3 inhibition. Our results give evidence of adverse effects of aspartame on islet cells in some extreme conditions, which might help people to reconsider the biosafety of non-nutritive sweeteners. (AU)

The effect of aspartame on accelerating caspase-dependent apoptosis of pancreatic islet via ZIPK/STAT3/caspase 3 signaling pathway

Aspartame (ASP) as an important sugar substitute is widely used in pharmaceutical and food processing. Here, we compared the effects of ASP and sucrose on mice pancreatic islet cells in vivo and observed that ASP with the condition of high concentration and long-term exposure (HASP) could cause insulin secretion (500 mg/kg for 1 month). Next, we conducted iTRAQ mass spectrometry to profile the global phosphoproteome and found that phosphorylation of zipper-interacting protein kinase (ZIPK) in murine pancreatic islet tissues were induced at Thr197, Thr242, Thr282, and Ser328 by high-sucrose (HS) treatment, but only induced at Thr197 and Ser328 by HASP treatment. Simultaneously, phosphorylation of STAT3 could be induced at Tyr705 and Ser727 by HS but not by HASP. Furthermore, presence of activated STAT3 accompanied with autophagy was observed in HS treatment. In turn, the inactivation of STAT3 as well as enhanced expression of caspase 3 was observed in HASP treatment. We generated Thr242APro and Thr282Pro on ZIPK using CRISPR-Cas9 in β-TC3 cells and found the weakened interaction with STAT3 as well as the reduced phosphorylation of STAT3 even under HS stimulation. Finally, we observed that ankyrin repeat domain containing 11 (ANKRD11) could interact with ZIPK and play an inhibitory role in the phosphorylation of Thr242APro and Thr282Pro of ZIPK. However, HASP can induce the retention of ANKRD11 in the cytoplasm by phenylpyruvic acid (the metabolite of ASP). Taken together, this study determined that ASP with high concentration and long-term exposure could lead to caspase-dependent apoptosis of pancreatic islet cells through ANKRD11/ZIPK/STAT3 inhibition. Our results give evidence of adverse effects of aspartame on islet cells in some extreme conditions, which might help people to reconsider the biosafety of non-nutritive sweeteners. (AU)