RESUMEN

Background: Randomized trials have shown a survival benefit for fruquintinib over placebo in patients with metastatic colorectal cancer (mCRC) that progressed after standard therapies, but real-world prognostic analyses have been seldom reported. We evaluated survival, safety outcomes, and predictive and prognostic factors in patients treated with fruquintinib in a real-life setting. Methods: We conducted a multi-center study by collecting relevant data on patients with advanced colorectal cancer (CRC) who received fruquintinib, focusing on progression-free survival (PFS), overall survival (OS), and L3 skeletal muscle index (SMI), including safety follow-up. Results: From January 2020 to January 2022, a total of 140 patients were selected and included in this study. The cut-off date was 30 July 2022. The median follow-up time was 18.3 months (range, 6-29.3 months) and the median age of included cases was 63 years (range, 32-81 years). The median PFS and OS for the 140 patients was 6.3 and 12.6 months, respectively. The median PFS and OS for the 76 patients who were included in SMI analysis was 6.0 and 12.0 months, respectively. Multivariate analysis suggested brain metastasis {hazard ratio (HR) [95% confidence interval (CI)]: 2.779 (1.162-6.646), P=0.02}, decrease in SMI of >5% [HR (95% CI): 9.732 (2.201-43.028), P=0.003], and baseline carcinoembryonic antigen (CEA) level [HR (95% CI): 4.061 (1.391-11.858), P=0.01] as independent predictors of OS. The most common treatment-related adverse events (TRAEs) were hypertension (24, 17.1%), fatigue (21, 15%), and hand-foot syndrome (20, 14.3%); 9 (13.6%) and 15 (10.7%) patients had dose reduction and treatment discontinuation due to TRAEs respectively. Conclusions: The real-world efficacy and safety of fruquintinib in advanced CRC patients are numerically superior to that in the previous phase III studies. SMI, brain metastasis and CEA could serve as potential markers for patient selection.

RESUMEN

The "Returning Farmland to Lakes" (RFTL) project began in China following the catastrophic 1998 floods. It aims to recover flood storage capacity and mitigate flood risk to agriculture and people. This flood adaptation strategy divides the floodplain into three types of restoration polders with different flood control levels (double restoration polders, single restoration polders, and storage polders) and polders for intensive production and living (nonrestoration polders). During the substantial flooding in the Poyang Lake Basin in 2020, the double and single restoration polders were operated for flood diversion for the first time since 1999. This event provided an opportunity to assess the effectiveness of the RFTL project. Using satellite observations of rice planting and flooding areas, we found that 86% of paddy rice areas (3,400 km2) in the basin were successfully protected due to the timely flood diversion into different levels of polders. Compared to 1998, the flooded rice areas decreased overall by 58% (18 to 92% in different types of polders). Thus, the RFTL project has enhanced regional agricultural resistance to floods. A more comprehensive assessment of the RFTL project, including other ecosystem services and functions, is necessary in the future for regional sustainable development.

RESUMEN

Bile acids are microbial metabolites that can impact infection of enteric and hepatitis viruses, but their functions during systemic viral infection remain unclear. Here we show that elevated levels of the secondary bile acid taurolithocholic acid (TLCA) are associated with reduced fatality rates and suppressed viraemia in patients infected with severe fever with thrombocytopenia syndrome virus (SFTSV), an emerging tick-borne haemorrhagic fever virus. TLCA inhibits viral replication and mitigates host inflammation during SFTSV infection in vitro, and indirectly suppresses SFTSV-mediated induction of ferroptosis by upregulating fatty acid desaturase 2 via the TGR5-PI3K/AKT-SREBP2 axis. High iron and ferritin serum levels during early infection were correlated with decreased TLCA levels and fatal outcomes in SFTSV-infected patients, indicating potential biomarkers. Furthermore, treatment with either ferroptosis inhibitors or TLCA protected mice from lethal SFTSV infection. Our findings highlight the therapeutic potential of bile acids to treat haemorrhagic fever viral infection.

RESUMEN

Dissolved organic matter (DOM) present in aquatic environments can significantly influence microalgal metabolism and the enrichment of heavy metals. However, the specific mechanism through which typical DOM affects the enrichment of the heavy metal chromium (Cr) in green algae remains unclear. This study investigates the impacts of varying concentrations of humic acid (HA), selected as a representative DOM in water, on the growth, metabolism, and Cr enrichment in Chlorella vulgaris, a typical green alga. The results indicated that low concentrations of HA were capable of enhancing Cr enrichment in C. vulgaris, with the highest Cr enrichment rate recorded at 41.50 % at TOC = 10 mg/L. The enrichment of Cr in algal cells primarily occurred through cell proliferation and complexation reduction of extracellular polymeric substances (EPS). In the presence of HA, C. vulgaris predominantly removed Cr through extracellular adsorption, accounting for 79.76-85.88 % of the total Cr removal. Furthermore, carboxyl complexation and hydroxyl reduction within EPS facilitated both the enrichment of Cr (18.72-21.49 %) and the reduction of Cr(VI) (63.93-74.10 %). These findings provide valuable insights into strategies for mitigating heavy metal pollution and managing associated risks in aquatic environments.

RESUMEN

Introduction. Recently, the incidence of Mycoplasma pneumoniae (M. pneumoniae) infection in children has been increasing annually. Early differential diagnosis of M. pneumoniae infection can not only avoid the abuse of antibiotics, but also is essential for early treatment and reduction of transmission.Gap statement. The change of routine blood parameters may have important clinical significance for the diagnosis of M. pneumoniae infection, but it has not been reported so far.Aim. This study aims to establish a predictive model for M. pneumoniae infection and explore the changes and clinical value of routine blood parameters in children with M. pneumoniae infection, serving as auxiliary indicators for the diagnosis and differentiation of clinical M. pneumoniae infection.Methodology. A total of 770 paediatric patients with respiratory tract infections were enrolled in this study, including 360 in the M. pneumoniae group, 40 in the SARS-CoV-2 group, 200 in the influenza A virus group, and 170 in the control group. The differences of routine blood parameters among all groups were compared, and risk factors were analysed using multivariate logistics analysis, and the diagnostic efficacy of differential indicators using ROC curves.Results. This study revealed that Mono% (OR: 3.411; 95% CI: 1.638-7.102; P=0.001) was independent risk factor associated with M. pneumoniae infection, and Mono% (AUC=0.786, the optimal cutoff at 7.8%) had a good discriminative ability between patients with M. pneumoniae infection and healthy individuals. Additionally, Mono% (OR: 0.424; 95% CI: 0.231-0.781; P=0.006) and Lymp% (OR: 0.430; 95% CI: 0.246-0.753; P=0.003) were independent risk factors for distinguishing M. pneumoniae infection from influenza A virus infection, and the Lymp% (AUC=0.786, the optimal cutoff at 22.1%) and Net% (AUC=0.761, the optimal cutoff at 65.2%) had good discriminative abilities between M. pneumoniae infection and influenza A infection. Furthermore, platelet distribution width (OR: 0.680; 95% CI: 0.538-0.858; P=0.001) was independent risk factor for distinguishing M. pneumoniae infection from SARS-CoV-2 infection. Meanwhile, the ROC curve demonstrated that PDW (AUC=0.786, the optimal cutoff at 15%) has a good ability to differentiate between M. pneumoniae infection and SARS-CoV-2 infection.Conclusion. This study demonstrates that routine blood parameters can be used as auxiliary diagnostic indicators for M. pneumoniae infection and provide reference for the diagnosis and differentiation of clinical M. pneumoniae infection.

Asunto(s)

RESUMEN

BACKGROUND: Medium-chain fatty acids (MCFAs) and docosahexaenoic acid (DHA) could affect the occurrence of mild cognitive impairment (MCI). ß-hydroxybutyrate (BHB), mitochondrial DNA copy number (mtDNAcn) and mitochondrial DNA (mtDNA) deletions might be their potential mechanisms. This study aimed to explore the relationship between MCFAs, DHA and MCI, and potential mechanisms. METHODS: This study used data from Tianjin Elderly Nutrition and Cognition (TENC) cohort study, 120 individuals were identified with new onset MCI during follow-up, 120 individuals without MCI were selected by 1:1 matching sex, age, and education levels as the control group from TENC. Conditional logistic regression analysis and mediation effect analysis were used to explore their relationship. RESULTS: Higher serum octanoic acid levels (OR: 0.633, 95% CI: 0.520, 0.769), higher serum DHA levels (OR: 0.962, 95% CI: 0.942, 0.981), and more mtDNAcn (OR: 0.436, 95% CI: 0.240, 0.794) were associated with lower MCI risk, while more mtDNA deletions was associated with higher MCI risk (OR: 8.833, 95% CI: 3.909, 19.960). Mediation analysis suggested that BHB and mtDNAcn, in series, have mediation roles in the association between octanoic acid and MCI risk, and mtDNA deletions have mediation roles in the association between DHA and MCI risk. CONCLUSION: Higher serum octanoic acid and DHA levels were associated with lower MCI risk. Octanoic acid could affect the incidence of MCI through BHB, then mitochondria function, or through mitochondria function, or directly. Serum DHA level could affect the incidence of MCI through mitochondria function, or directly.

RESUMEN

BACKGROUND: Charge heterogeneity is a critical quality attribute for therapeutic biologics including antibody-drug conjugates (ADCs). Developing an ion exchange chromatography (IEX) or an imaged capillary isoelectric focusing (icIEF) method for ADCs with high drug-to-antibody ratio (DAR) is challenging because of the increased hydrophobicity from the payload-linker, DAR heterogeneity, and payload-linker instability. A sub-optimal method can be poorly stability-indicating due to the inability to discern contributions from charge and size variants conjugated with different number of drugs/payloads. Systematic strategy and guidance on charge variant method development is highly desired for high DAR ADCs with various complex structures. RESULTS: This work encompasses the development and optimization of icIEF methods for high DAR ADCs of various DAR values (4-8) and payload linker chemistry. Method optimization focuses on improving resolution and stability indicating capabilities and differentiating contributions from the protein and payload-linker. Types, proportion, and combination of solubilizers and carrier ampholytes, as well as focusing parameters were interrogated. Our findings show that the structural units of the linker, the DAR, and the payload chemistry prescribe the selection of buffer, solubilizer, and ampholyte. We demonstrate that a stronger denaturant or solubilizer is needed for high DAR ADCs with polyethylene glycol (PEG)-containing linker structure compared to peptide linker. For unstable payload-linker, buffer system enhances sample stability which is vital to method robustness. In addition, a longer isoelectric focusing time is necessary for an ADC than its corresponding antibody to reach optimal focusing. SIGNIFICANCE: To the best of our knowledge, this is the first comprehensive study on icIEF method development for charge variant determination of high DAR ADCs with unique physicochemical properties.

Asunto(s)

RESUMEN

An important goal in the opioid field is to discover effective analgesic drugs with minimal side effects. MCRT demonstrated potent antinociceptive effects with limited side effects, making it a promising candidate. However, its pharmacological properties and how it minimizes side effects remain unknown. Various mouse pain and opioid side effect models were used to evaluate the antinociceptive properties and safety at the spinal level. The targets of MCRT were identified through cAMP measurement, isolated tissue assays, and pharmacological experiments. Immunofluorescence was employed to visualize protein expression. MCRT displayed distinct antinociceptive effects between acute and chronic inflammatory pain models due to its multifunctional properties at the µ opioid receptor (MOR), µ-δ heterodimer (MDOR), and neuropeptide FF receptor 2 (NPFFR2). Activation of NPFFR2 reduced MOR-mediated antinociception, leading to bell-shaped response curves in acute pain models. However, activation of MDOR produced more effective antinociception in chronic inflammatory pain models. MCRT showed limited tolerance and opioid-induced hyperalgesia in both acute and chronic pain models and did not develop cross-tolerance to morphine. Additionally, MCRT did not exhibit addictive properties, gastrointestinal inhibition, and effects on motor coordination. Mechanistically, peripheral chronic inflammation or repeated administration of morphine and MCRT induced an increase in MDOR in the spinal cord. Chronic administration of MCRT had no apparent effect on microglial activation in the spinal cord. These findings suggest that MCRT is a versatile compound that provides potent antinociception with minimal opioid-related side effects. MDOR could be a promising target for managing chronic inflammatory pain and addressing the opioid crisis.

RESUMEN

Integrated diagnostic and therapeutic dressings are desirable to relieve diabetic patients who often suffer from diabetic foot ulcers (DFUs) and peripheral vascular diseases (PVDs). However, it is highly difficult to monitor the pulse waves with fidelity under wet environments and connect the waveforms to diseases through a small strain sensor. Additionally, immobilizing MXenzyme to regulate spatially heterogeneous levels of reactive oxygen species (ROS) and applying active intervention to enhance ulcer healing on a single structure remain a complex task. To address these issues, we designed a multiscale wearable dressing comprising a knitted all-textile sensing array for quantitatively investigating the pulse wave toward PVD diagnosis. MXenzyme was loaded onto the dressing to provide multiple enzyme mimics for anti-inflammatory activities and deliver electrical stimulation to promote wound growth. In mice, we demonstrate that high and uniform expression of the vascular endothelial growth factor (VEGF) is observed only in the group undergoing dual mediation with electrical stimulation and MXenzyme. This observation indicates that the engineered wound dressing has the capability to accelerate healing in DFU. In human patient evaluations, the engineered dressing distinguishes vascular compliance and pulse period, enabling the diagnosis of arteriosclerosis and return blockage, two typical PVDs. The designed and engineered multiscale dressing achieves the purpose of integrating diagnostic peripheral vessel health monitoring and ulcer healing therapeutics for satisfying the practical clinical requirements of geriatric patients.

Asunto(s)

RESUMEN

An innovative acidic hydrolysate fingerprinting workflow was proposed for the characterization of Lyophyllum Decastes polysaccharide (LDP) by ultra performance liquid chromatography-mass spectrometry (UPLC-MS). The crude polysaccharides were firstly separated and purified by using DE-52 column and the BRT GPC purification system, respectively. The molecular weight and monosaccharide content of homogeneous polysaccharides were ascertained by utilizing HPGPC and ion chromatography separately. Secondly, the linkage of LDP was identified by methylation analysis and 1D/2D NMR spectra. The UPLC-MS/MS was used to scan and identify the acidic hydrolysate products of LDP using the PGC column. The oligosaccharides were collected by chromatography and identified by mass spectrometry. Thirdly, the expression of IL-1ß, IL-6, iNOS, TNF-α and IFNAR-I was measured in order to assess the immunological activity of LDP. Besides, the targeted receptors identification of polysaccharides was performed by screening the expression of TLRs family protein. The results showed that oligosaccharide fragments with different molecular weights can be obtained by partial hydrolysis, which further verified that the structures of LDP polysaccharides was a 1-6-linked ß-glucan. Moreover, the LDP polysaccharide can up-regulate the content of IL-1ß, IL-6, iNOS, TNF-α and IFNAR-I and plays an important immunoregulation role through TLRs family.

Asunto(s)

RESUMEN

Oxidative stress and its impact on aging are critical areas of research. Natural anti-oxidants, such as saponins found in Polygonatum sibiricum, hold promise as potential clinical interventions against aging. In this study, we utilized the nematode model organism, Caenorhabditis elegans, to investigate the pharmacological effects of Polygonatum sibiricum saponins (PKS) on antioxidation and anti-aging. The results demonstrated a significant anti-aging biological activity associated with PKS. Through experiments involving lifespan and stress, lipofuscin, q-PCR, and ROS measurement, we found that PKS effectively mitigated aging-related processes. Furthermore, the mechanism underlying these anti-aging effects was linked to the SKN-1 signaling pathway. PKS increased the nuclear localization of the SKN-1 transcription factor, leading to the up-regulation of downstream anti-oxidant genes, such as gst-4 and sod-3, and a substantial reduction in intracellular ROS levels within the nematode. In conclusion, our study sheds light on the anti-oxidant and anti-aging properties of PKS in C. elegans. This research not only contributes to understanding the biological mechanisms involved but also highlights the potential therapeutic applications of these natural compounds in combating aging-related processes.

RESUMEN

BACKGROUND: Photodynamic therapy (PDT) is a pioneering and effective anticancer modality with low adverse effects and high selectivity. Hypochlorous acid or hypochlorite (HClO/ClO-) is a type of inflammatory cytokine. The abnormal increase of ClO- in tumor cells is related to tumor pathogenesis and may be a "friend" for the design and synthesis of responsive phototherapy agents. However, preparing responsive phototherapy agents for all-in-one noninvasive diagnosis and simultaneous in situ therapy in a complex tumor environment is highly desirable but still remains an enormously demanding task. RESULTS: An acceptor-π bridge-donor-π bridge-acceptor (A-π-D-π-A) type photosensitizer TPTPy was designed and synthesized based on the phenothiazine structure which was used as the donor moiety as well as a ClO- responsive group. TPTPy was a multifunctional mitochondria targeted aggregation-induced emission (AIE) photosensitizer which could quickly and sensitively respond to ClO- with fluorescence "turn on" performance (19-fold fluorescence enhancement) and enhanced type I reactive oxygen species (ROS) generation to effectively ablate hypoxic tumor cells. The detection limit of TPTPy to ClO- was calculated to be 185.38 nM. The well-tailored TPTPy anchoring to mitochondria and producing ROS in situ could disrupt mitochondria and promote cell apoptosis. TPTPy was able to image inflammatory cells and tumor cells through ClO- response. In vivo results revealed that TPTPy was successfully utilized for PDT in tumor bearing nude mice and exhibited excellent biological safety for major organs. SIGNIFICANCE AND NOVELTY: A win-win integration strategy was proposed to design a tumor intracellular ClO- responsive photosensitizer TPTPy capable of both type I and type II ROS production to achieve photodynamic therapy of tumor. This work sheds light on the win-win integration design by taking full advantage of the characteristics of tumor microenvironment to build up responsive photosensitizer for in situ PDT of tumor.

Asunto(s)

RESUMEN

Feeding rate is an important factor influencing the carbon and nitrogen input and greenhouse gas emission from aquaculture systems. However, the quantitative relationship between feeding rates and GHG emissions is still poorly understood. In this study, we conducted a laboratory-scale experiment to examine the impact of feeding rate (0%, 2%, 4%, 6%, and 8%) on the CH4 and N2O emissions from a pond rice-fish co-culture system. The results showed that the total amount of CH4 emission did not significantly differ when the feeding rate was no more than 6%, but increased more than four times when the feeding rate reach to 8%. The amount of N2O emission showed a linearly increasing trend with the feeding rate. The emission factors of CH4 and N2O was significantly higher for 8% feeding rate than other feeding rates. The variation of CH4 emission was primarily attributed to the ratio of mcrA/pmoA in the sediment and the contents of biological oxygen demand (COD) and dissolved oxygen (DO) in the water; and the variation of N2O was primarily affected by the available nitrogen in the water and sediment and the content of DO in the water. The overall emission of CH4 and N2O showed an exponential relationship with feeding rate. The total yields of fish and rice did not continuously increase when the feeding rate exceeded 4%. The lowest emission intensity per unit yield was reached at the feeding rate of 2.99%. These results can provide a reference for the determination of low-carbon feeding strategy for pond rice-fish co-culture system.

Asunto(s)

RESUMEN

The advent of dual-atom nanozymes (DAzymes) featuring distinctive bimetallic active sites garnered significant attention, representing enhanced iterations of conventional single-atom nanozymes. The quest for an effective and universal strategy to modulate the catalytic activity of DAzymes posed a formidable challenge, yet few published reports addressed this. Herein, we designed and synthesized S-doped Fe/Co DAzymes (S-FeCo-NC) under theoretical guidance and revealed their excellent oxidase-like activity. Experimental and theoretical calculations indicated that the superior oxidase-like activity exhibited by S-FeCo-NC was attributed to the S-doping, which modulated the local electronic structure of the dual-atom active site. This modulation of the local electronic structure significantly optimizes oxygen adsorption energy, thereby accelerating the rate of enzyme-catalyzed reactions. As a proof-of-concept, this study integrated S-FeCo-NC with the cascade inhibition reaction of acetylcholinesterase (AChE) to devise a sensitive analytical platform for detecting organophosphorus pesticides. This study paved the way for elucidating the correlation between the local electronic structure of the active site and enzyme activity, offering novel methodologies and insights for the rational design of DAzymes.

RESUMEN

Agonistic antibodies against CD137 have been demonstrated to completely regress established tumors through activating T cell immunity. Unfortunately, current CD137 antibodies failed to benefit patients with cancer. Moreover, their antitumor mechanisms in vivo remain to be determined. Here, we report the development of a small molecular CD137 agonist, JNU-0921. JNU-0921 effectively activates both human and mouse CD137 through direct binding their extracellular domains to induce oligomerization and signaling and effectively shrinks tumors in vivo. Mechanistically, JNU-0921 enhances effector and memory function of cytotoxic CD8+ T cells (CTLs) and alleviates their exhaustion. JNU-0921 also skews polarization of helper T cells toward T helper 1 type and enhances their activity to boost CTL function. Meanwhile, JNU-0921 attenuates the inhibitory function of regulatory T cells on CTLs. Our current work shows that JNU-0921 shrinks tumors by enhancing the cytotoxicity of CTLs in cis and in trans and sheds light on strategy for developing CD137 small molecular agonists.

Asunto(s)

RESUMEN

Acute leukaemia is a group of aggressive malignancies with a high mortality rate. The reduction in functional immune cells due to the disease itself and radiotherapy/chemotherapy makes the patients susceptible to co-infections, of which pulmonary infection is a major cause of death. Early accurate diagnosis and appropriate treatment may prevent the spread of infection in patients with acute leukaemia complicated with pulmonary infection, thus reduce serious complications such as sepsis, respiratory failure and multi-organ failure. However, there are still clinical difficulties in the diagnosis and treatment of pulmonary infections in acute leukemia patients. Therefore, the current research advances in the diagnosis and treatment of bacterial, fungal and viral infections in the lungs of patients with acute leukemia were briefly summarized in this review.

Asunto(s)

RESUMEN

The recovery of rare earth elements (REEs) from acidic wastewater is crucial to sustainable development, industrial processes, and human health. In this research, ß-cyclodextrin-based nanosponges (ß-CD/PVA-SA NSs) have been proposed as potential adsorbents for europium (Eu), dysprosium (Dy), and gadolinium (Gd) recovery. The nanosponges are synthesized by cross-linking ß-cyclodextrin (ß-CD) functionalized polyvinyl alcohol (PVA) and sodium alginate (SA). Experimental results indicate that ß-CD/PVA-SA NSs exhibit favorable selectivity for Eu, Dy, and Gd, with the maximum adsorption capacity of 222, 217, and 204 mg/g, respectively, in addition to stability and cyclicity. ß-CD/PVA-SA NSs maintain selective adsorption effects towards RE ions that are present in acidic mine drainage (AMD), thereby highlighting their potential for practical applications. Furthermore, density functional theory (DFT) simulations have unveiled the fundamental interactions between the functional groups anchored in ß-CD/PVA-SA NSs and the REEs, providing vital insights into their adsorption mechanism. Hence, the utilization of ß-CD/PVA-SA NSs has the potential to advance initiatives in remediating acidic water pollution and facilitating the sustainable recycling of RE resources.

RESUMEN

BACKGROUND: Neutral Lipid Storage Disease with Myopathy (NLSDM) is a rare lipid metabolism disorder caused by PNPLA2 gene mutations. Clinical manifestations are heterogeneous, and diagnosis is often delayed, usually gaining patients' attention due to the increased risk of cardiomyopathy. CASE PRESENTATION: We herein report a 36-year-old Asian male presenting with progressive limb weakness, muscle atrophy of limbs and trunk, dysarthria, and heart failure. Electromyography indicated myogenic changes, and muscle biopsy results revealed characteristics of lipid storage myopathy. Genetic analysis of PNPLA2 revealed two heterozygous mutations: c.757 + 1G > T (chr11-823588, splice-5) on intron 6 and c.919delG (chr11-823854, p.A307Pfs*13) on exon 7. The patient improved limb strength, and dysarthria disappeared after the Medium Chain Fatty Acids diet. CONCLUSIONS: In conclusion, we report for the first time that the two heterozygous mutations PNPLA2 c.919delG and c.757 + 1G > T together induced NLSDM, which was confirmed by muscle biopsy.

Asunto(s)

RESUMEN

The potential of circular RNAs (circRNAs) as biomarkers and therapeutic targets is becoming increasingly evident, yet their roles in cardiac regeneration and myocardial renewal remain largely unexplored. Here, we investigated the function of circIGF1R and related mechanisms in cardiac regeneration. Through analysis of circRNA sequencing data from neonatal and adult cardiomyocytes, circRNAs associated with regeneration were identified. Our data showed that circIGF1R expression was high in neonatal hearts, decreased with postnatal maturation, and up-regulated after cardiac injury. The elevation was validated in patients diagnosed with acute myocardial infarction (MI) within 1 week. In human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and myocardial tissue from mice after apical resection and MI, we observed that circIGF1R overexpression enhanced cardiomyocyte proliferation, reduced apoptosis, and mitigated cardiac dysfunction and fibrosis, while circIGF1R knockdown impeded endogenous cardiac renewal. Mechanistically, we identified circIGF1R binding proteins through circRNA precipitation followed by mass spectrometry. RNA pull-down Western blot and RNA immunoprecipitation demonstrated that circIGF1R directly interacted with DDX5 and augmented its protein level by suppressing ubiquitin-dependent degradation. This subsequently triggered the ß-catenin signaling pathway, leading to the transcriptional activation of cyclin D1 and c-Myc. The roles of circIGF1R and DDX5 in cardiac regeneration were further substantiated through site-directed mutagenesis and rescue experiments. In conclusion, our study highlights the pivotal role of circIGF1R in facilitating heart regeneration and repair after ischemic insults. The circIGF1R/DDX5/ß-catenin axis emerges as a novel therapeutic target for enhancing myocardial repair after MI, offering promising avenues for the development of regenerative therapies.

RESUMEN

INTRODUCTION: It is uncertain whether folic acid (FA) combined with docosahexaenoic acid (DHA) could improve cognitive performance. This study evaluated the effects of a 12-month FA and DHA supplementation, in combination or alone, on cognitive function, DNA oxidative damage, and mitochondrial function in participants with mild cognitive impairment (MCI). METHODS: This randomized, double-blind, placebo-controlled trial recruited MCI participants aged 60 years and older. Two hundred and eighty participants were randomly divided in equal proportion into four groups: FA + DHA (FA 800 µg/d + DHA 800 mg/d), FA (800 µg/d), DHA (800 mg/d), and placebo groups daily orally for 12 months. The primary outcome was cognitive function evaluated by the Wechsler Adult Intelligence Scale-Revised (WAIS-RC). Cognitive tests and blood mechanism-related biomarkers were determined at baseline and 12 months. RESULTS: During the 12-month follow-up, scores of full intelligence quotient (ßDHA: 1.302, 95% CI: 0.615, 1.990, p < 0.001; ßFA: 1.992, 95% CI: 1.304, 2.679, p < 0.001; ßFA+DHA: 2.777, 95% CI: 2.090, 3.465, p < 0.001), verbal intelligence quotient, and some subtests of the WAIS-RC were significantly improved in FA + DHA and single intervention groups compared to the placebo group. Moreover, the FA and DHA intervention combination was superior to either intervention alone (p < 0.001). Meanwhile, FA, DHA, and their combined use significantly decreased 8-OHdG level and increased mitochondrial DNA copy number compared to the placebo (p < 0.05). CONCLUSIONS: Supplementation of FA and DHA, alone or combined, for 12 months can improve cognitive function in MCI participants, possibly through mitigating DNA oxidative damage and enhancing mitochondrial function. Combined supplementation may provide more cognitive benefit than supplementation alone.

Asunto(s)