Highly sensitive near-infrared fluorescent probe for monitoring peroxynitrite in nonalcoholic fatty liver disease: Toward early diagnosis and therapeutic evaluation.

Nonalcoholic fatty liver disease (NAFLD) poses a significant global health concern, necessitating precise diagnostic tools and effective treatment strategies. Peroxynitrite (ONOO-), a reactive oxygen species, plays a pivotal role in NAFLD pathogenesis, highlighting its potential as a biomarker for disease diagnosis and therapeutic evaluation. This study reports on the development of a near-infrared (NIR) fluorescent probe, designated DRP-O, for the selective detection of ONOO- with high sensitivity and photostability. DRP-O exhibits rapid response kinetics (within 2 min) and an impressive detection limit of 2.3 nM, enabling real-time monitoring of ONOO- dynamics in living cells. Notably, DRP-O demonstrates excellent photostability under continuous laser irradiation, ensuring reliable long-term monitoring in complex biological systems. We apply DRP-O to visualize endogenous ONOO- in living cells, demonstrating its potential for diagnosing and monitoring NAFLD-related oxidative stress. Furthermore, DRP-O effectively evaluates the efficacy of therapeutic drugs in NAFLD cell models, underscoring its potential utility in drug screening studies. Moreover, we confirm DRP-O to enable selective identification of fatty liver tissues in a mouse model of NAFLD, indicating its potential for the early diagnosis of NAFLD. Collectively, DRP-O represents a valuable tool for studying ONOO- dynamics, evaluating drug efficacy, and diagnosing NAFLD, offering insights into novel therapeutic strategies for this prevalent liver disorder.

Glucosamine sulfate-loaded nanofiber reinforced carboxymethyl chitosan sponge for articular cartilage restoration.

Cartilage is severely limited in self-repair after damage, and tissue engineering scaffold transplantation is considered the most promising strategy for cartilage regeneration. However, scaffolds without cells and growth factors, which can effectively avoid long cell culture times, high risk of infection, and susceptibility to contamination, remain scarce. Hence, we developed a cell- and growth factor-dual free hierarchically structured nanofibrous sponge to mimic the extracellular matrix, in which the encapsulated core-shell nanofibers served both as mechanical supports and as long-lasting carriers for bioactive biomass molecules (glucosamine sulfate). Under the protection of the nanofibers in this designed sponge, glucosamine sulfate could be released continuously for at least 30 days, which significantly accelerated the repair of cartilage tissue in a rat cartilage defect model. Moreover, the nanofibrous sponge based on carboxymethyl chitosan as the framework could effectively fill irregular cartilage defects, adapt to the dynamic changes during cartilage movement, and maintain almost 100 % elasticity even after multiple compression cycles. This strategy, which combines fiber freeze-shaping technology with a controlled-release method for encapsulating bioactivity, allows for the assembly of porous bionic scaffolds with hierarchical nanofiber structure, providing a novel and safe approach to tissue repair.

Differential distribution of PINK1 and Parkin in the primate brain implies distinct roles.

JOURNAL/nrgr/04.03/01300535-202504000-00028/figure1/v/2024-07-06T104127Z/r/image-tiff The vast majority of in vitro studies have demonstrated that PINK1 phosphorylates Parkin to work together in mitophagy to protect against neuronal degeneration. However, it remains largely unclear how PINK1 and Parkin are expressed in mammalian brains. This has been difficult to address because of the intrinsically low levels of PINK1 and undetectable levels of phosphorylated Parkin in small animals. Understanding this issue is critical for elucidating the in vivo roles of PINK1 and Parkin. Recently, we showed that the PINK1 kinase is selectively expressed as a truncated form (PINK1-55) in the primate brain. In the present study, we used multiple antibodies, including our recently developed monoclonal anti-PINK1, to validate the selective expression of PINK1 in the primate brain. We found that PINK1 was stably expressed in the monkey brain at postnatal and adulthood stages, which is consistent with the findings that depleting PINK1 can cause neuronal loss in developing and adult monkey brains. PINK1 was enriched in the membrane-bound fractionations, whereas Parkin was soluble with a distinguishable distribution. Immunofluorescent double staining experiments showed that PINK1 and Parkin did not colocalize under physiological conditions in cultured monkey astrocytes, though they did colocalize on mitochondria when the cells were exposed to mitochondrial stress. These findings suggest that PINK1 and Parkin may have distinct roles beyond their well-known function in mitophagy during mitochondrial damage.

Melittin promotes the proliferation of Schwann cells in hyperglycemic environment by up­regulating the Crabp2/Wnt/ß­catenin signaling pathway.

The present study aimed to explore the effect of melittin (MLT) on the growth of Schwann cells (SCs) in high glucose conditions and to understand the mechanisms involved. The goal was to provide a theoretical basis for using MLT in the treatment of diabetic peripheral neuropathy (DPN). The CCK­8 assay was used to measure cell activity at different concentrations of glucose and MLT. Flow cytometry was employed to analyze the effect of MLT on cell cycle phases and apoptosis in SCs under high glucose conditions. To identify differentially expressed proteins, 4D label­free quantitative proteomics with liquid chromatography­mass spectrometry was used, followed by biological analysis to explore potential mechanisms. PCR, western blotting and immunofluorescence were conducted to confirm these mechanisms. Melittin (0.2 µg/ml) increased the proliferation of SCs in a high glucose environment. Flow cytometry showed that after MLT treatment, the proportion of cells in the G2/M+S phase increased and the combined ratio of early and late apoptosis decreased under high glucose conditions. Proteomics identified 1,784 proteins with significant changes in expression; 725 were upregulated, and 1,059 were downregulated. Kyoto Encyclopedia of Genes and Genomes analysis indicated that the differentially expressed proteins were mainly involved in metabolic pathways and neurodegenerative disease pathways. PCR, western blotting and immunofluorescence confirmed the increase in Crabp2, Wnt3a, C­Jun, CDK4, CyclinD1 and proliferating cell nuclear antigen. In high glucose conditions, MLT protects SCs from glucose toxicity by upregulating the Crabp2/Wnt/ß­catenin signaling pathway, potentially providing a new treatment for DPN.

Release characteristics of arsenic from sediments and its source or sink competition with phosphorus: A case of a great lake with grass-algae alternation.

The arsenic (As) release from sediments in great lakes is affected by various factors. In this study, the characteristics of As release from sediments was investigated, and the As sources and sinks with the strengths in sediments from different areas (grass-type, algae-type, and grass-algae alternation areas) in great shallow lakes (Taihu Lake, China) were analyzed, and the influence of P competition in the process of As release was also studied. The results showed that changing trend of the values of equilibrium As concentration in sediments were consistent with the regional changes (0 to 28.12 µg/L), and the sediments from algae-type areas had the higher values. The sediments from western lake and northwest lake bay were a strong As and a weak P source, and the north lake bay had the opposite trend of these two regions. Intense P source competition with As from the sediments occurred in algae-type areas. The grass-type areas had strong As and P retention capacities, indicating a sink role of sediment with high As and P sorption capacities. The degree of As and P saturation had similar trend in sediments, and the grass-type areas had the higher values, 18.3%-21.4% and 15.31%-20.34%, respectively. Contribution analysis results showed that most of As release contribution was from the bottom (30-50 cm) sediments, and the surface (0-10 cm) sediments from algae-type areas contributed more to the overlying water than other region.

Impacts of distorted local chemical coordination on electrochemical performance in hydrated vanadium pentoxide.

Modulating and elevating the operating voltage of a given cathode is a significant challenge to enhance the energy density of secondary batteries without sacrificing power output. The chemical coordination strongly influences the energy levels of d-orbitals of redox cations in cathode materials, which tie to their operating voltage. In contrast to concentrated studies on enhancing the specific capacity, in this study, we choose bi-layered hydrated vanadium pentoxide as the model to modulate the d-orbital energy levels through local chemical coordination manipulation, achieving a higher operating voltage in rechargeable aqueous zinc ion batteries. Here we show that, by employing X-ray absorption spectroscopy (XAS) and pair distribution function (PDF) techniques, we can analyze the distortion of [VO6] octahedra and extract chemical bond information, deciphering the correlation between the chemical coordination and operating voltage in cathode materials. The fundamentals could guide the designing and developing RAZIBs with higher energy and power density.

Carbapenem-resistant Klebsiella oxytoca transmission linked to preoperative shaving in emergency neurosurgery, tracked by rapid detection via chromogenic medium and whole genome sequencing.

Objectives: This study describes the detection and tracking of emergency neurosurgical cross-transmission infections with carbapenem-resistant Klebsiella oxytoca (CRKO). Methods: We conducted an epidemiological investigation and a rapid screening of 66 surveillance samples using the chromogenic selective medium. Two CRKO isolates from infected patients and three from the preoperative shaving razors had similar resistance profiles identified by the clinical laboratory. Results: The whole genome sequencing (WGS) results identified all isolates as Klebsiella michiganensis (a species in the K. oxytoca complex) with sequence type 29 (ST29) and carrying resistance genes bla KPC-2 and bla OXY-5, as well as IncF plasmids. The pairwise average nucleotide identity values of 5 isolates ranged from 99.993% to 99.999%. Moreover, these isolates displayed a maximum genetic difference of 3 among 5,229 targets in the core genome multilocus sequence typing scheme, and the razors were confirmed as the contamination source. After the implementation of controls and standardized shaving procedures, no new CRKO infections occurred. Conclusion: Contaminated razors can be sources of neurosurgical site infections with CRKO, and standard shaving procedures need to be established. Chromogenic selective medium can help rapidly identify targeted pathogens, and WGS technologies are effective mean in tracking the transmission source in an epidemic or outbreak investigation. Our findings increase the understanding of microbial transmission in surgery to improve patient care quality.

Combined HDAC8 and checkpoint kinase inhibition induces tumor-selective synthetic lethality in preclinical models.

The elevated level of replication stress is an intrinsic characteristic of cancer cells. Targeting the mechanisms that maintain genome stability to further increase replication stress and thus induce severe genome instability has become a promising approach for cancer treatment. Here, we identify histone deacetylase 8 (HDAC8) as a drug target whose inactivation synergizes with the inhibition of checkpoint kinases to elicit substantial replication stress and compromise genome integrity selectively in cancer cells. We showed that simultaneous inhibition of HDAC8 and checkpoint kinases led to extensive replication fork collapse, irreversible cell-cycle arrest, and synergistic vulnerability in various cancer cells. The efficacy of the combination treatment was further validated in patient tumor-derived organoid (PDO) and xenograft mouse (PDX) models, providing important insights into patient-specific drug responses. Our data revealed that HDAC8 activity was essential for reducing the acetylation level of structural maintenance of chromosomes protein 3 (SMC3) ahead of replication forks and preventing R loop formation. HDAC8 inactivation resulted in slowed fork progression and checkpoint kinase activation. Our findings indicate that HDAC8 guards the integrity of the replicating genome, and the cancer-specific synthetic lethality between HDAC8 and checkpoint kinases provides a promising replication stress-targeting strategy for treating a broad range of cancers.

The increased tendency for anemia in traditional Chinese medicine deficient body constitution is associated with the gut microbiome.

Background: Constitution is a valuable part of traditional Chinese medicine theory; it is defined as the internal foundation for the occurrence, development, transformation and outcome of diseases, and has its characteristic gut microbiota. Previous study showed that deficiency constitution was related to lower Hb counts. However, no research has examined how alterations in the gut microbiome induced by deficiency constitution may increase the tendency for anemia. Methods: We used a multiomics strategy to identify and quantify taxonomies and compounds found under deficient constitution individuals and further explore the possible pathological factors that affect red blood cell indices. Results: ① People with deficient constitution showed lower hemoglobin (Hb), more Firmicutes, less Bacteroidetes, and higher α diversity. ② We identified Escherichia coli, Clostridium bolteae, Ruminococcus gnavus, Streptococcus parasanguinis and Flavonifractor plautii as potential biomarkers of deficient constitution. ③ Slackia piriformis, Clostridium_sp_L2_50 and Bacteroides plebeius were enriched in balanced-constitution individuals, and Parabacteroides goldsteinii was the key bacterial marker of balanced constitution. ④ Flavonifractor plautii may be a protective factor against the tendency for anemia among deficient individuals. ⑤ Ruminococcus gnavus may be the shared microbe base of deficiency constitution-related the tendency for anemia. ⑥ The microorganism abundance of the anaerobic phenotype was lower in deficient constitution group. ⑦ Alterations in the microbiome of deficient-constitution individuals were associated with worse health status and a greater risk of anemia, involving intestinal barrier function, metabolism and immune responses, regulated by short-chain fatty acids and bile acid production. Conclusion: The composition of the gut microbiome was altered in people with deficient constitution, which may explain their poor health status and tendency toward anemia.

Engineered biochars for simultaneous immobilization of as and Cd in soil: Field evidence.

Agricultural soil contamination by potentially toxic elements (PTEs) such as arsenic (As) and cadmium (Cd) poses a serious threat to food security. Immobilization serves as a widely used approach for the remediation of PTEs contaminated soils, nevertheless, the long-term effectiveness for the simultaneous immobilization of both cations and oxyanions remains a challenge. In order to effectively enhance the synergistic immobilization effect of soil As and Cd contaminated by multiple elements and improve the ecological environment of farmland. In this study, a typical polluted tailings area farmland was selected for situ immobilization experiments, and biochar was prepared from cow manure (CMB), rice straw (RSB), and pine wood (PWB) as raw materials. On this basis, the pristine biochar was modified with ferric chloride (F), potassium permanganate (K), magnesium chloride (M), and aluminum chloride (A), respectively. Furthermore, the immobilization effect of modified biochar on As-Cd and the stress effect on soil respiration were investigated. The results showed that CMB and RSB reduced the bioavailability of heavy metals, potassium permanganate has strong oxidizing properties, and the strong oxidability of potassium permanganate stimulated the generation of more oxygen-containing functional groups on the surface of biochar, thereby enhancing the adsorption and complexation effect of modified materials on As and Cd. Among them, the extracted Cd concentration of Diethylenetriamine pentaacetic acid (DTPA) in KCMB and KRSB in 2020 decreased by 8.23-43.12% and 9.67-35.29% compared to other treatments, respectively. Meanwhile, the KCMB and KRSB treatments also reduced the enrichment of As and Cd in plant tissues. In addition, the dissolved organic carbon (DOC) content in KCMB treatment was relatively high, and the carbon stability of the material was weakened. Simultaneously, the soil respiration emission of KCMB treatment was increased by 5.63% and 11.93% compared to KRSB and KPWB treatments, respectively. In addition, the structural equation also shows that DOC has a large positive effect on soil respiration. In summary, the KRSB treatment effectively achieve synergistic immobilization of As-Cd and provide important guiding significance for green and low-carbon remediation of polluted farmland.

Ruscogenin attenuates osteoarthritis by modulating oxidative stress-mediated macrophage reprogramming via directly targeting Sirt3.

BACKGROUND: Synovial inflammation, Cartilage erosion, and subchondral osteosclerosis, which are collectively referred to as the triad of pathogenesis, contribute to osteoarthritis (OA) progression. Specifically, the M1 macrophage in the synovium worsens the development of the illness and is a significant factor in the deterioration and functioning of cartilage. OBJECTIVE: To investigate whether Ruscogenin attenuates progressive degeneration of articular cartilage in rats with anterior cruciate ligament transection (ACLT)-induced osteoarthritis (OA) by modulating macrophage reprogramming and to explore its specific mechanism of action. METHODS: In vitro, SW1353 cells and RAW264.7 cells were applied to elucidate the mechanisms by which Ruscogenin protects articular cartilage. Specifically, the expression levels of molecules related to cartilage ECM synthesis and degradation enzymes and macrophages were analysed. In vivo, a rat osteoarthritis model was established using ACLT. The protective effect of Ruscogenin on articular cartilage was observed. RESULTS: Ruscogenin significantly reversed LPS-induced macrophage inflammatory response and promoted cartilage regeneration-related factors. In addition, Ruscogenin had a significant protective effect on the knee joint of ACLT rats, effectively preventing cartilage degeneration. These positive therapeutic effects were achieved on the one hand by Ruscogenin regulating macrophage reprogramming by targeting Sirt3, and on the other hand Ruscogenin could attenuate the ROS level of chondrocytes thereby inhibiting chondrocyte ferroptosis. CONCLUSIONS: Ruscogenin exerts chondroprotective effects by regulating macrophage reprogramming and inhibiting chondrocyte ferroptosis.

Cryo-EM structure of the human subcortical maternal complex and the associated discovery of infertility-associated variants.

The functionally conserved subcortical maternal complex (SCMC) is essential for early embryonic development in mammals. Reproductive disorders caused by pathogenic variants in NLRP5, TLE6 and OOEP, three core components of the SCMC, have attracted much attention over the past several years. Evaluating the pathogenicity of a missense variant in the SCMC is limited by the lack of information on its structure, although we recently solved the structure of the mouse SCMC and proposed that reproductive disorders caused by pathogenic variants are related to the destabilization of the SCMC core complex. Here we report the cryogenic electron microscopy structure of the human SCMC and uncover that the pyrin domain of NLRP5 is essential for the stability of SCMC. By combining prediction of SCMC stability and in vitro reconstitution, we provide a method for identifying deleterious variants, and we successfully identify a new pathogenic variant of TLE6 (p.A396T). Thus, on the basis of the structure of the human SCMC, we offer a strategy for the diagnosis of reproductive disorders and the discovery of new infertility-associated variants.

Single ambipolar OECT-based inverter with volatility and nonvolatility on demand.

Organic electrochemical transistor (OECT)-based inverter introduces new prospects for energy-efficient brain-inspired artificial intelligence devices. Here, we report single-component OECT-based inverters by incorporating ambipolar p(gDPP-V). Notably, p(gDPP-V) shows state-of-the-art ambipolar OECT performances in both conventional (p/n-type mode transconductance of 29/25 S cm-1) and vertical (transconductance of 297.2/292.4 µS µm-2 under p/n operation) device architectures. Especially, the resulting highly stable vertical OECT-based inverter shows a high voltage gain of 105 V V-1 under a low driving voltage of 0.8 V. The inverter exhibits undiscovered voltage-regulated dual mode: volatile receptor and nonvolatile synapse. Moreover, applications of physiology signal recording and demonstrations of NAND/NOR logic circuits are investigated within the volatile feature, while neuromorphic simulations with a convolutional neural network and image memorizing capabilities are explored under the nonvolatile behavior. The ambipolar OECT-based inverter, capable of both volatile and nonvolatile operations, provides possibilities for the applications of reconfigurable complementary logic circuits in novel neuromorphic computing paradigms.

Synthesis, anticancer activity, and mechanistic investigations of aryl-alkyl diorganotin arylformylhydrazone complexes.

Diorganotin acylhydrazone complexes with mitochondrial targeting demonstrate significant potential as replacements for platinum-based complexes due to their potent anticancer properties. Twelve methylphenyltin arylformylhydrazone complexes have been synthesized by microwave "one-pot" reaction. The complexes have been characterized by FT-IR, multinuclear NMR (1H, 13C, and 119Sn), TGA, and HRMS. Crystal structures were determined for 10 out of the 12 complexes under study. Structures 1 through 8, 10 and 12 possessed a central symmetric structure of a di-nuclear Sn2O2 tetrahedral ring. All complexes were tested for their inhibitory activity against human cell lines NCI-H460, MCF-7, and HepG2. Complex 8 exhibited the most effective inhibitory effect on HepG2 cells, with an IC50 value of 1.34 ± 0.04 µM. Preliminary studies on the anticancer mechanism suggest that complex 8 induces apoptosis in HepG2 cells via the mitochondrial pathway, accompanied by G2/M phase cell cycle arrest.

LRG1 promotes metastatic colorectal cancer growth through HER3 signaling.

BACKGROUND AND AIMS: Therapy failure in patients with metastatic colorectal cancer (mCRC, ∼80% occur in the liver) remains an overarching challenge. Preclinical studies demonstrated that HER3 promotes CRC cell survival, but therapies blocking the neuregulin-induced canonical HER3 signaling have made little impact in the clinic. Recent studies suggest that the liver microenvironment promotes CRC growth by activating HER3 in a neuregulin-independent fashion, thus elucidation of these mechanisms may reveal new strategies for treating patients with mCRC. METHODS: Patient-derived primary liver endothelial cells (ECs) were used to interrogate EC-CRC crosstalk. We conducted proteomic analysis to identify EC-secreted factor(s) that triggers non-canonical HER3 activation in CRC, and determined the subsequent effects on mCRC using diverse murine mCRC models. In vitro studies with genetic and pharmacological interventions were used to map the non-canonical HER3 pathway. RESULTS: We demonstrated that EC-secreted leucine-rich alpha-2-glycoprotein 1 (LRG1) directly binds and activates HER3 and promotes CRC growth distinct from neuregulin, the canonical HER3 ligand. Blocking host-derived LRG1 by gene knockout or a neutralizing antibody impaired mCRC outgrowth in the liver and prolonged mouse survival. We identified protein synthesis activated by the PI3K-PDK1-RSK-eIF4B axis as the biologically relevant signaling cascade downstream of the LRG1-HER3 interaction, which was not blocked by conventional HER3-specific antibodies that failed in prior clinical trials. CONCLUSIONS: LRG1 is a novel HER3 ligand and mediates liver-mCRC crosstalk. The LRG1-HER3 signaling axis is distinct from canonical HER3 signaling and represents a new therapeutic opportunity to treat patients with mCRC, and potentially other types of liver metastases.

Phosphorus modifies the association between body mass index and uric acid: Results from NHANES 2007-2018.

INTRODUCTION: Studies in recent years have shown that high uric acid causes harm to the human body, which has become a serious public health problem. Elevated serum uric acid has been shown to be associated with obesity, but the relationship between BMI and uric acid (UA) remains controversial. Although the association between BMI and UA has been well studied, the effect of phosphorus levels in vivo on this association remains unclear. This study aimed to determine the relationship between BMI and serum uric acid and the effect of phosphorus on the relationship between the two. RESEARCH DESIGN AND METHODS: The present study analyzed data from the National Health and Nutrition Examination Survey (NHANES) continuous 2007-2018 cycle. We included 10786 participants aged 20 years and over. Multivariable linear regression was performed to assess the association between BMI and serum uric acid. phosphorus was stratified into low phosphorus (<3.3 mg/dl), middle phosphorus (3.3-3.9 mg/dl) and high phosphorus (>3.9 mg/dl). Correction of the effect of phosphorus was assessed by testing the interaction between BMI and UA in multivariate linear regression. RESULTS: In this cross-sectional study, we found that BMI was positively associated with UA in the female population but not significantly in the male population or in the total population. In multiple regression analysis, UA was 0.51 higher in the highest female BMI group than in the lowest group (p = 0.0001). The relationship between BMI and UA differed significantly by gender under the influence of phosphorus, with men and women in Model II having a greater elevation of UA in men than in women within most groups. (BMI >30, phosphorus >3.9 mg/dl, ß:0.83 95% CI: 0.43, 1.23 vs ß: 0.79 95% CI: 0.30, 1.29). In addition, phosphorus significantly altered the positive association between BMI and UA in most models. CONCLUSION: Our results indicate significant associations between BMI and uric acid in women, with higher BMI values likely to be associated with a higher risk of hyperuricemia, suggesting that uric acid levels in obese people should be closely monitored in clinical practice. Phosphorus and BMI have an interactive effect in elevating UA and should be noted as indicators of phosphorus in clinical practice.

Insights into the Differences in Polysaccharide and Alkaloid Biosynthesis in the Medicinal Orchids Dendrobium nobile and D. officinale.

Both Dendrobium nobile and D. officinale are widely used medicinal plants in China and their major medicinal components are alkaloids and polysaccharides, respectively. It is still unclear why these two closely related orchids synthesize and accumulate different chemical components. Here, we investigated the molecular mechanisms underlying polysaccharide and alkaloid biosynthesis in D. nobile and D. officinale through transcriptome and metabolomic analysis at different growth stages. A total of 1267 metabolites were identified in the juvenile and mature stages of the two species. D. nobile accumulated a large number of alkaloids, benzenoids/phenylpropanoids, flavonoids, and terpenoids during the transition from juvenile to mature plants. In contrast, D. officinale accumulated a small number of those metabolites and an absence of flavonoids. The correlation analysis of polysaccharide contents with the differentially expressed genes suggested that the differential expression of GH1, GH3, and GH9 might be related to the difference in polysaccharide contents between the two Dendrobium species. Meanwhile, the difference in the biosynthesis of dendrobine, the main component of alkaloids in D. nobile, was involved in the differential expression of HMGCR, DXR, DXS, ISPH and eight CYP450s. These findings provided new insights into understanding the biosynthetic mechanisms of the main medicinal components in Dendrobium species.

Association between the duration of smoking cessation and α-Klotho levels in the US middle-aged and elderly population.

Background: α-Klotho is a molecule associated with aging and several diseases. Previous studies have reported decreased levels of serum α-Klotho (SαKl) in smokers compared to never smokers. Interestingly, we also found the SαKl level could partly recover in those who quit smoking. The objective of this study was to investigate SαKl levels in the US population who quit smoking for a certain period. Methods: A total of 9268 participants, ranging in age from 40 to 79 years were enrolled in this cross-sectional study, 37.04 % were identified as former smoker. Data from the NHANES conducted between 2007 and 2016 were utilized for analysis. The association between the period of smoking cessation and SαKl levels was evaluated through multivariate linear regression models. Additionally, a detailed analysis stratified by key clinical factors was performed. Results: The mean level of SαKl among the former smoker was 827.41 pg/mL. After full adjustment, the SαKl level increased over time after smoking cessation, with an increase of 1.20 pg/ml per year of abstinence (P = 0.005). The linear correlation persists regardless of the duration of the smoking habit before quitting. In the stratified analysis, a positive correlation was observed between duration of smoking cessation and SαKl levels in individuals aged 60-79 years, females, normal weight individuals, those involved in moderate or vigorous physical activity, and those with a history of cancer (all P<0.05). Conclusion: This study showed a positive association between the duration of smoking cessation and SαKl levels in former smokers. Prolonged abstinence may contribute to increased SαKl levels which may protect people against aging-related diseases.

AIBP protects drug-induced liver injury by inhibiting MAPK-mediated NR4A1 expression.

Drug-induced liver injury (DILI) is an important adverse drug reaction that can lead to acute liver failure or even death in severe cases. AIBP is a binding protein of apolipoprotein AI involved in lipid metabolism and maintenance of oxidative respiration in mitochondria, but its role in DILI is unclear. By constructing AIBP knockout mice, overexpressing and knocking down AIBP in cell lines, we established animal and cell models of DILI. Using western blotting and real-time qPCR assay, we explored the influence of AIBP in activation of mitogen-activated protein kinases (MAPK) signal pathways and possible targets. AIBP was downregulated during hepatocyte injury. AIBP deficient mice develop severe liver injury and more sensitive to drug-induced cell death. Overexpression of AIBP protects cells under APAP treatment. Furthermore, AIBP inhibits the activation of MAPK pathways, through which AIBP regulates NR4A1. These results suggest that AIBP is expected to become a valuable biomarker and therapeutic target in liver injury.

Development of an adipose-tropic AAV capsid ablating liver tropism.

AAV vectors are mainstream delivery platforms in gene therapy, yet AAV-mediated gene transfer to adipose tissue is underdeveloped due to low efficiency of natural AAVs. We previously demonstrated that an engineered capsid Rec2 displayed improved adipo-tropism but with the caveat of liver transduction. To generate highly adipo-tropic capsid, we modified Rec2 capsid by site-specific mutagenesis and found the variant V7 with F503Y, Y708D and K709I substitution to harbor highly selective adipo-tropism while diminishing liver transduction. Intraperitoneal injection favored transduction to visceral fat while intravenous administration favored subcutaneous fat. Intraperitoneal administration of V7 vector harboring human leptin and adiponectin as single transcript normalized the metabolic dysfunction of ob/ob mice at a low dose. Moreover, introducing the same mutagenesis to AAV8 capsid diminished liver transduction suggesting F503, Y708 and K709 critical for liver transduction. The Rec2.V7 vector may provide a powerful tool for basic research and potent vehicle for adipose-targeting gene therapy.