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An imbalance in the differentiation potential of bone marrow mesenchymal stem cells (BMSCs) is an important pathogenic mechanism underlying osteoporosis (OP). N6-methyladenosine (m 6 A) is the most common post-transcriptional modification in eukaryotic cells. The role of the Wilms’ tumor 1-associated protein (WTAP), a member of the m 6 A functional protein family, in regulating BMSCs differentiation remains unknown. We used patient-derived and mouse model-derived samples, qRT-PCR, western blot assays, ALP activity assay, ALP, and Alizarin Red staining to determine the changes in mRNA and protein levels of genes and proteins associated with BMSCs differentiation. Histological analysis and micro-CT were used to evaluate developmental changes in the bone. The results determined that WTAP promoted osteogenic differentiation and inhibited adipogenic differentiation of BMSCs. We used co-immunoprecipitation (co-IP), RNA immunoprecipitation (RIP), methylated RNA immunoprecipitation (MeRIP), RNA pulldown, and dual-luciferase assay to explore the direct mechanism. Mechanistically, the expression of WTAP increased during osteogenic differentiation and significantly promoted pri-miR-181a and pri-miR-181c methylation, which was recognized by YTHDC1, and increased the maturation to miR-181a and miR-181c. MiR-181a and miR-181c inhibited the mRNA expression of SFRP1, promoting the osteogenic differentiation of BMSCs. Our results demonstrated that the WTAP/YTHDC1/miR-181a and miR-181c/SFRP1 axis regulated the differentiation fate of BMSCs, suggesting that it might be a potential therapeutic target for osteoporosis.

This study investigated the acute effects of various doses of nitrate-rich beetroot juice on the responses to high-intensity interval exercise in women. A double-blinded, randomized, placebo-controlled, crossover trial was conducted with 13 recreationally active young women (age = 23 ± 2 years). All participants performed interval exercise (8 × 1-min bouts of cycling at 85% of peak power output [PPO] interspersed with 1-min active recovery at 20% of PPO) 2.5 h after consumption of the randomly assigned beetroot juice containing 0 mmol (placebo), 6.45 mmol (single-dose), or 12.9 mmol (double-dose) . The heart rate (HR), blood pressure, blood lactate, blood glucose, oxygen saturation, rating of perceived exertion (RPE), and emotional arousal were assessed. Nitrate supplementation significantly altered the HR and RPE responses across the three trials. The mean HR was lower in the single- and double-dose groups than in the placebo control group during both work intervals and recovery periods, as well as across the overall protocol (all  < .05). The mean RPE was lower in the single- and double-dose groups than in the control group during recovery periods and across the overall protocol (all  < .001). However, there was no significant difference in either HR or RPE between the single- and double-dose groups at any time point. Acute nitrate ingestion led to significant decreases in the mean HR and RPE during high-intensity interval exercise, but no additional benefit was observed with higher nitrate content. These findings may assist practitioners in implementing more effective nitrate supplementation strategies during high-intensity interval exercise.

Intervertebral disc degeneration (IVDD) is a chronic age-related degenerative disease accompanied by complex pathophysiological mechanisms. Increasing evidence indicates that NLRP3 inflammasome mediated pyroptosis of nucleus pulposus (NP) cells displays an important role in the pathological progression of IVDD. Milk fat globule-EGF factor-8 (MFG-E8) is an endogenously secreted glycoprotein with beneficial effects of anti-inflammatory, antioxidant, and modulation of NLRP3 inflammasome. However, the effect of MFG-E8 on IVDD remains unclear. In this study, our purpose is to clarify the expression changes of MFG-E8 in the IVDD process and explore the role and mechanism of MFG-E8. We found that MFG-E8’s expression was reduced in degraded nucleus pulposus tissues of humans and rats as well as hydrogen peroxide (H 2 O 2 )-treated NP cells. Exogenous supplementation of MFG-E8 could rescue H 2 O 2 -induced oxidative stress, mitochondrial dysfunction, and NLRP3 inflammasome activation and protect NP cells from pyroptosis and extracellular matrix (ECM) degradation. Mechanistically, Nrf2/TXNIP/NLRP3 axis plays a crucial role in MFG-E8-mediated suppression of the above-pathological events. In vivo, we established a rat intervertebral disc acupuncture model and found that MFG-E8 administration effectively alleviated IVDD development by imageological and histomorphological evaluation. Overall, our findings revealed the internal mechanisms underlying MFG-E8 regulation in NP cells and its intrinsic value for IVDD therapy.

Chloramines are often used as a secondary disinfectant when free chlorine residuals are difficult to maintain. However, chloramination is often associated with the undesirable effect of nitrification, which results in operational problems for many drinking water utilities. The introduction of ammonia during chloramination provides a potential source of nitrogen either through the addition of excess ammonia or through chloramine decay. This promotes the growth of nitrifying microorganisms and provides a nitrogen source (i.e., nitrate) for the growth for other organisms. While the roles of canonical ammonia-oxidizing and nitrite-oxidizing bacteria in chloraminated drinking water systems have been extensively investigated, those studies have largely adopted a targeted gene-centered approach. Further, little is known about the potential long-term cooccurrence of complete-ammonia-oxidizing (i.e., comammox) bacteria and the potential metabolic synergies of nitrifying organisms with their heterotrophic counterparts that are capable of denitrification and nitrogen assimilation. This study leveraged data obtained for genome-resolved metagenomics over a time series to show that while nitrifying bacteria are dominant and likely to play a major role in nitrification, their cooccurrence with heterotrophic organisms suggests that nitric oxide production and nitrate reduction to ammonia may also occur in chloraminated drinking water systems. Ammonia availability due to chloramination can promote the growth of nitrifying organisms, which can deplete chloramine residuals and result in operational problems for drinking water utilities. In this study, we used a metagenomic approach to determine the identity and functional potential of microorganisms involved in nitrogen biotransformation within chloraminated drinking water reservoirs. Spatial changes in the nitrogen species included an increase in nitrate concentrations accompanied by a decrease in ammonium concentrations with increasing distance from the site of chloramination. This nitrifying activity was likely driven by canonical ammonia-oxidizing bacteria (i.e., Nitrosomonas ) and nitrite-oxidizing bacteria (i.e., Nitrospira ) as well as by complete-ammonia-oxidizing (i.e., comammox) Nitrospira -like bacteria. Functional annotation was used to evaluate genes associated with nitrogen metabolism, and the community gene catalogue contained mostly genes involved in nitrification, nitrate and nitrite reduction, and nitric oxide reduction. Furthermore, we assembled 47 high-quality metagenome-assembled genomes (MAGs) representing a highly diverse assemblage of bacteria. Of these, five MAGs showed high coverage across all samples, which included two Nitrosomonas, Nitrospira, Sphingomonas , and Rhizobiales -like MAGs. Systematic genome-level analyses of these MAGs in relation to nitrogen metabolism suggest that under ammonia-limited conditions, nitrate may be also reduced back to ammonia for assimilation. Alternatively, nitrate may be reduced to nitric oxide and may potentially play a role in regulating biofilm formation. Overall, this study provides insight into the microbial communities and their nitrogen metabolism and, together with the water chemistry data, improves our understanding of nitrogen biotransformation in chloraminated drinking water distribution systems. IMPORTANCE Chloramines are often used as a secondary disinfectant when free chlorine residuals are difficult to maintain. However, chloramination is often associated with the undesirable effect of nitrification, which results in operational problems for many drinking water utilities. The introduction of ammonia during chloramination provides a potential source of nitrogen either through the addition of excess ammonia or through chloramine decay. This promotes the growth of nitrifying microorganisms and provides a nitrogen source (i.e., nitrate) for the growth for other organisms. While the roles of canonical ammonia-oxidizing and nitrite-oxidizing bacteria in chloraminated drinking water systems have been extensively investigated, those studies have largely adopted a targeted gene-centered approach. Further, little is known about the potential long-term cooccurrence of complete-ammonia-oxidizing (i.e., comammox) bacteria and the potential metabolic synergies of nitrifying organisms with their heterotrophic counterparts that are capable of denitrification and nitrogen assimilation. This study leveraged data obtained for genome-resolved metagenomics over a time series to show that while nitrifying bacteria are dominant and likely to play a major role in nitrification, their cooccurrence with heterotrophic organisms suggests that nitric oxide production and nitrate reduction to ammonia may also occur in chloraminated drinking water systems.

Obesity poses a significant public health challenge among middle-aged women, driven by physiological changes associated with aging and menopause. This parallel-group, assessor-blinded, four-arm randomized controlled trial investigated the effects of 12-week 8-hour flexible time-restricted eating (flexTRE) and aerobic exercise (EX), alone or in combination (flexTRE+EX), on body composition and metabolic health in a free-living setting. Participant enrolment began on September 1 st 2023 and data collection was completed on July 1 st 2024. Conducted at a single research site in Hong Kong, the trial enrolled women aged 40–60 years with overweight/obesity. Participants were randomized in a 1:1:1:1 ratio to a flexTRE, EX, flexTRE+EX, or control (CON) group (n = 26 per group), with all 104 participants included in the final intention-to-treat analysis. Outcomes were assessed at baseline, and week 12. The primary outcome was fat mass. The flexTRE+EX group achieved the greatest fat mass reduction compared to the CON group (adjusted mean difference [99% Confidence Interval] −2.85 kg [−4.01 to −1.69]), and additional benefit over the flexTRE group alone (−1.56 kg [−2.74 to −0.38]), and the EX group alone (−2.01 kg [−3.21 to −0.81]). Secondary outcomes were reported in the main text. No serious adverse events were reported, and adherence was high (83%-87%) across intervention groups. These findings suggest that the combined approach effectively reduces fat mass and enhances related metabolic parameters, providing a feasible and effective strategy in middle-aged women facing overweight/obesity. Trial registration: ChiCTR2300074846. Obesity poses a health challenge among middle-aged women in part driven by physiological changes associated with aging and menopause. Here the authors report a randomized controlled trial showing that a combination intervention of flexible time-restricted eating and exercise leads to greater reduction in fat mass than single interventions in women aged 40-60 years.

BackgroundThe imbalance between osteoblasts and osteoclasts may lead to osteoporosis. Osteoblasts and osteoclasts have different energy requirements, with aerobic glycolysis being the prominent metabolic feature of osteoblasts, while osteoclast differentiation and fusion are driven by oxidative phosphorylation.MethodsBy polymerase chain reaction as well as Western blotting, we assayed coactivator-associated arginine methyltransferase 1 (CARM1) expression in bone tissue, the mouse precranial osteoblast cell line MC3T3-E1 and the mouse monocyte macrophage leukaemia cell line RAW264.7, and expression of related genes during osteogenic differentiation and osteoclast differentiation. Using gene overexpression (lentivirus) and loss-of-function approach (CRISPR/Cas9-mediated knockout) in vitro, we examined whether CARM1 regulates osteogenic differentiation and osteoblast differentiation by metabolic regulation. Transcriptomic assays and metabolomic assays were used to find the mechanism of action of CARM1. Furthermore, in vitro methylation assays were applied to clarify the arginine methylation site of PPP1CA by CARM1.ResultsWe discovered that CARM1 reprogrammed glucose metabolism in osteoblasts and osteoclasts from oxidative phosphorylation to aerobic glycolysis, thereby promoting osteogenic differentiation and inhibiting osteoclastic differentiation. In vivo experiments revealed that CARM1 significantly decreased bone loss in osteoporosis model mice. Mechanistically, CARM1 methylated R23 of PPP1CA, affected the dephosphorylation of AKT-T450 and AMPK-T172, and increased the activities of phosphofructokinase-1 and pructose-2,6-biphosphatase3, causing an up-regulation of glycolytic flux. At the same time, as a transcriptional coactivator, CARM1 regulated the expression of pyruvate dehydrogenase kinase 3, which resulted in the inhibition of pyruvate dehydrogenase activity and inhibition of the tricarboxylic acid cycle, leading to a subsequent decrease in the flux of oxidative phosphorylation.ConclusionsThese findings reveal for the first time the mechanism by which CARM1 affects both osteogenesis and osteoclast differentiation through metabolic regulation, which may represent a new feasible treatment strategy for osteoporosis.

Limiting microbial growth during drinking water distribution is achieved either by maintaining a disinfectant residual or through nutrient limitation without using a disinfectant. The impact of these contrasting approaches on the drinking water microbiome is not systematically understood. We use genome-resolved metagenomics to compare the structure, metabolic traits, and population genomes of drinking water microbiome samples from bulk drinking water across multiple full-scale disinfected and non-disinfected drinking water systems. Microbial communities cluster at the structural- and functional potential-level based on the presence/absence of a disinfectant residual. Disinfectant residual alone explained 17 and 6.5% of the variance in structure and functional potential of the drinking water microbiome, respectively, despite including multiple drinking water systems with variable source waters and source water communities and treatment strategies. The drinking water microbiome is structurally and functionally less diverse and variable across disinfected compared to non-disinfected systems. While bacteria were the most abundant domain, archaea and eukaryota were more abundant in non-disinfected and disinfected systems, respectively. Community-level differences in functional potential were driven by enrichment of genes associated with carbon and nitrogen fixation in non-disinfected systems and γ-aminobutyrate metabolism in disinfected systems likely associated with the recycling of amino acids. Genome-level analyses for a subset of phylogenetically-related microorganisms suggests that disinfection selects for microorganisms capable of using fatty acids, presumably from microbial decay products, via the glyoxylate cycle. Overall, we find that disinfection exhibits systematic selective pressures on the drinking water microbiome and may select for microorganisms able to utilize microbial decay products originating from disinfection-inactivated microorganisms. 7T6A_iTC8wqejGvHmCotW6 Video abstract

BackgroundAnxiety disorders are persistent, functionally impairing conditions with high societal burden. In contrast, anxiety symptoms are elevated anxiety meeting scale thresholds (not formal diagnoses). While exercise is recognised as a complementary intervention for anxiety, the most effective mode of exercise for anxiety disorders remains unclear.ObjectiveTo evaluate the effectiveness and acceptability of exercise treatments for adults with anxiety disorders via network meta-analysis.MethodsSystematic review and frequentist network meta-analysis were conducted, searching five databases (MEDLINE, EMBASE, PsycINFO, CENTRAL, SPORTDiscus) up to 1 March 2025. Treatments assessed included aerobic exercise, mind-body exercise (MBE), resistance training (RT), stretching, multicomponent exercise, cognitive-behavioral therapy, psychoeducation, waitlist control, usual care and placebo. Risk of bias was assessed using the Cochrane Risk of Bias Tool 2.0 (RoB 2.0). Outcomes included anxiety severity reduction (for effectiveness) and all-cause discontinuation rates (for acceptability).Results30 RCTs (1421 participants) were included: four had low risk, 19 some concerns and seven high risk. For combined anxiety conditions (anxiety disorders and symptoms), RT was most effective (standardised mean difference (SMD) −0.80, 95% CI −1.24 to −0.36, SUCRA 78.7%), followed by MBE (SMD −0.78, 95% CI −1.12 to −0.44, SUCRA 77.8%). For anxiety disorders, RT was most effective (SMD −0.79, 95% CI −1.18 to −0.40, SUCRA 78.5%) and MBE for anxiety symptoms (SMD −0.84, 95% CI −1.48 to −0.20, SUCRA 77.9%). No acceptability differences across treatments; network meta-regression showed diagnosis status did not alter effects.ConclusionsBoth resistance exercise and MBE may be effective for anxiety disorders, with moderate certainty evidence. Acceptability remains unclear.Prospero registration numberCRD42024561238.

Background Human dental pulp stem cells (hDPSCs) have received widespread attention in the fields of tissue engineering and regenerative medicine. Although amphiregulin (AREG) has been shown to play a vital function in the biological processes of various cell types, its effects on DPSCs remain largely unknown. The aim of this study was to explore the specific role of AREG as a biologically active factor in the regeneration of dental pulp tissue. Methods The growth of hDPSCs, together with their proliferation and apoptosis, in response to AREG was examined by CCK-8 assay and flow cytometry. We explored the effects of AREG on osteo/odontogenic differentiation in vitro and investigated the regeneration and mineralization of hDPSCs in response to AREG in vivo. The effects of AREG gain- and loss-of-function on DPSC differentiation were investigated following transfection using overexpression plasmids and shRNA, respectively. The involvement of the mitogen-activated protein kinase (MAPK) or phosphatidylinositol 3-kinase (PI3K)/Akt pathways in the mineralization process and the expression of odontoblastic marker proteins after AREG induction were investigated by using Alizarin Red S staining and Western blotting, respectively. Results AREG (0.01–0.1 µg/mL) treatment of hDPSCs from 1 to 7 days increased hDPSCs growth and affected apoptosis minimally compared with negative controls. AREG exposure significantly promoted hDPSC differentiation, shown by increased mineralized nodule formation and the expression of odontoblastic marker protein expression. In vivo micro-CT imaging and quantitative analysis showed significantly greater formation of highly mineralized tissue in the 0.1 μg/mL AREG exposure group in DPSC/NF-gelatin-scaffold composites. AREG also promoted extracellular matrix production, with collagen fiber, mineralized matrix, and calcium salt deposition on the composites, as shown by H&E, Masson, and Von Kossa staining. Furthermore, AREG overexpression boosted hDPSC differentiation while AREG silencing inhibited it. During the differentiation of hDPSCs, AREG treatment led to phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and PI3K/Akt. Notably, a specific inhibitor of ERK, JNK, and PI3K/Akt signaling markedly reduced AREG-induced differentiation, as well as levels of phosphorylated ERK and JNK in hDPSCs. Conclusions The data indicated that AREG promoted odontoblastic differentiation and facilitated regeneration and mineralization processes in hDPSCs.

A persistently substantial energy demand and metabolic reprogramming endure throughout the entire course of osteoclastogenesis, accompanied by an intensified oxidative stress. Hence, balancing cellular energy metabolism and maintaining redox homeostasis offer potential for coordinating osteoclastogenesis and bone loss in pathological conditions. In the present study, we have discovered Visomitin, a novel antioxidant that specifically targets mitochondria, which efficiently decreases intracellular reactive oxygen species (ROS) levels, inhibits osteoclastogenesis, and impairs the function of bone resorption. Mechanistically, Visomitin directly targets signal transducer and activator of transcription 3 (STAT3), leading to the inhibition of its transcriptional activity and modulation of lactate dehydrogenase B (LDHB) expression levels, consequently triggering metabolic reprogramming and exerting antagonistic effects on osteoclasts. Furthermore, administration of Visomitin demonstrates marked protective effects against pathological bone loss in vivo. Given its established clinical safety profile in ophthalmologic applications, Visomitin emerges as a promising anti-resorptive agent for clinical translation. This study also unveils the STAT3/LDHB axis as a critical nexus linking mitochondrial redox regulation to osteoclast metabolism, providing a novel therapeutic strategy for osteoclast-driven bone diseases.