Proteomics-based identification of biomarkers reflecting endogenous and exogenous exposure to the advanced glycation end product precursor methylglyoxal in SH-SY5Y human neuroblastoma cells.

Methylglyoxal (MGO), a highly reactive precursor of advanced glycation end products, is endogenously produced and prevalent in various food products. This study aimed to characterize protein modifications in SH-SY5Y human neuroblastoma cells induced by MGO and identify potential biomarkers for its exposure and toxicity. A shot-gun proteomic analysis was applied to characterize protein modifications in cells incubated with and without exogenous MGO. Seventy-seven proteins were identified as highly susceptible to MGO modification, among which eight, including vimentin and histone H2B type 2-F, showing concentration-dependent modifications by externally added MGO, were defined as biomarkers for exogenous MGO exposure. Remarkably, up to 10 modification sites were identified on vimentin. Myosin light polypeptide 6 emerged as a biomarker for MGO toxicity, with modifications exclusively observed under cytotoxic MGO levels. Additionally, proteins like serine/threonine-protein kinase SIK2 and calcyphosin, exhibiting comparable or even higher modification levels in control compared to exogenous MGO-treated cells, were defined as biomarkers for endogenous exposure. Bioinformatics analysis revealed that motor proteins, cytoskeleton components, and glycolysis proteins were overrepresented among those highly susceptible to MGO modification. These results identify biomarkers for both endogenous and exogenous MGO exposure and provide insights into the cellular effects of endogenously formed versus externally added MGO.

Tetrahydrofolate Attenuates Cognitive Impairment after Hemorrhagic Stroke by Promoting Hippocampal Neurogenesis via PTEN Signaling.

Intracerebral hemorrhage (ICH), the most common subtype of hemorrhagic stroke, leads to cognitive impairment and imposes significant psychological burdens on patients. Hippocampal neurogenesis has been shown to play an essential role in cognitive function. Our previous study has shown that tetrahydrofolate (THF) promotes the proliferation of neural stem cells (NSCs). However, the effect of THF on cognition after ICH and the underlying mechanisms remain unclear. Here, we demonstrated that administration of THF could restore cognition after ICH. Using Nestin-GFP mice, we further revealed that THF enhanced the proliferation of hippocampal NSCs and neurogenesis after ICH. Mechanistically, we found that THF could prevent ICH-induced elevated level of PTEN and decreased expressions of phosphorylated AKT and mTOR. Furthermore, conditional deletion of PTEN in NSCs of the hippocampus attenuated the inhibitory effect of ICH on the proliferation of NSCs and abnormal neurogenesis. Taken together, these results provide molecular insights into ICH-induced cognitive impairment and suggest translational clinical therapeutic strategy for hemorrhagic stroke.

Coupling Relationships between the Brain and the Central Pattern Generator Based on a Fractional-Order Extended Hindmarsh-Rose Model.

BACKGROUND: The states of the central nervous system (CNS) can be classified into subcritical, critical, and supercritical states that endow the system with information capacity, transmission capabilities, and dynamic range. A further investigation of the relationship between the CNS and the central pattern generators (CPG) is warranted to provide insight into the mechanisms that govern the locomotion system. METHODS: In this study, we established a fractional-order CPG model based on an extended Hindmarsh-Rose model with time delay. A CNS model was further established using a recurrent excitation-inhibition neuronal network. Coupling between these CNS and CPG models was then explored, demonstrating a potential means by which oscillations generated by a neural network respond to periodic stimuli. RESULTS AND CONCLUSIONS: These simulations yielded two key sets of findings. First, frequency sliding was observed when the CPG was sent to the CNS in the subcritical, critical, and supercritical states with different external stimulus and fractional-order index values, indicating that frequency sliding regulates brain function on multiple spatiotemporal scales when the CPG and CNS are coupled together. The main frequency range for these simulations was observed in the gamma band. Second, with increasing external inputs the coherence index for the CNS decreases, demonstrating that strong external inputs introduce neuronal stochasticity. Neural network synchronization is then reduced, triggering irregular neuronal firing. Together these results provide novel insight into the potential mechanisms that may underlie the locomotion system.

An underwater vest containing an antioxidant MXene hydrogel for sensitive recognition of fish locomotion.

The perception of fish locomotion is important for understanding their adaptive behaviors and ethological characteristics. However, the main strategy used for extracting fish attitudes involves the use of a vision-based monitoring system, which is limited in its range of observation and cannot perform tracking for long times. Here, we report the use of a wearable tagging electronic device, referred to as an underwater vest, to capture the surrounding flow field disturbances triggered by swimming or momentary postural changes. All of these goals were achieved by integrating a pair of pseudocapacitive pressure-sensing units and a flexible circuit board. Notably, additional conditions, such as variable hydraulic pressures and minimal changes in fish posture, require high stability and sensitivity of the sensing units. Thus, hybrid hydrogel electrodes were developed through cross-linking MXene with holey-reduced graphene oxide nanosheets and further modification with 1-ethyl-3-methylimidazolium dicyanamide ionic liquids, which increased the interfacial capacitance and long-term interfacial activity of the MXene. Consequently, the sensing unit exhibited ultrahigh sensitivity (Smax~136,207 kPa-1) in an aquatic environment for 60 days and superior high-pressure resolution (10 Pa) within a wide working range of 1 MPa. Ultimately, an underwater vest integrated with such sensing units clearly distinguished and recorded fish locomotion. We believe that the designed device may open avenues in flow field monitoring and ocean current detection and provide new insights into the development of sensitive underwater tagging.

Iron/ROS/Itga3 mediated accelerated depletion of hippocampal neural stem cell pool contributes to cognitive impairment after hemorrhagic stroke.

Hemorrhagic stroke, specifically intracerebral hemorrhage (ICH), has been implicated in the development of persistent cognitive impairment, significantly compromising the quality of life for affected individuals. Nevertheless, the precise underlying mechanism remains elusive. Here, we report for the first time that the accumulation of iron within the hippocampus, distal to the site of ICH in the striatum, is causally linked to the observed cognitive impairment with both clinical patient data and animal model. Both susceptibility-weighted imaging (SWI) and quantitative susceptibility mapping (QSM) demonstrated significant iron accumulation in the hippocampus of ICH patients, which is far from the actual hematoma. Logistical regression analysis and multiple linear regression analysis identified iron level as an independent risk factor with a negative correlation with post-ICH cognitive impairment. Using a mouse model of ICH, we demonstrated that iron accumulation triggers an excessive activation of neural stem cells (NSCs). This overactivation subsequently leads to the depletion of the NSC pool, diminished neurogenesis, and the onset of progressive cognitive dysfunction. Mechanistically, iron accumulation elevated the levels of reactive oxygen species (ROS), which downregulated the expression of Itga3. Notably, pharmacological chelation of iron accumulation or scavenger of aberrant ROS levels, as well as conditionally overexpressed Itga3 in NSCs, remarkably attenuated the exhaustion of NSC pool, abnormal neurogenesis and cognitive decline in the mouse model of ICH. Together, these results provide molecular insights into ICH-induced cognitive impairment, shedding light on the value of maintaining NSC pool in preventing cognitive dysfunction in patients with hemorrhagic stroke or related conditions.

Efficient production of protocatechuic acid using systems engineering of Escherichia coli.

Protocatechuic acid (3, 4-dihydroxybenzoic acid, PCA) is widely used in the pharmaceuticals, health food, and cosmetics industries owing to its diverse biological activities. However, the inhibition of 3-dehydroshikimate dehydratase (AroZ) by PCA and its toxicity to cells limit the efficient production of PCA in Escherichia coli. In this study, a high-level strain of 3-dehydroshikimate, E. coli DHS01, was developed by blocking the carbon flow from the shikimate-overproducing strain E. coli SA09. Additionally, the PCA biosynthetic pathway was established in DHS01 by introducing the high-activity ApAroZ. Subsequently, the protein structure and catalytic mechanism of 3-dehydroshikimate dehydratase from Acinetobacter pittii PHEA-2 (ApAroZ) were clarified. The variant ApAroZR363A, achieved by modulating the conformational dynamics of ApAroZ, effectively relieved product inhibition. Additionally, the tolerance of the strain E. coli PCA04 to PCA was enhanced by adaptive laboratory evolution, and a biosensor-assisted high-throughput screening method was designed and implemented to expedite the identification of high-performance PCA-producing strains. Finally, in a 5 L bioreactor, the final strain PCA05 achieved the highest PCA titer of 46.65 g/L, a yield of 0.23 g/g, and a productivity of 1.46 g/L/h for PCA synthesis from glucose using normal fed-batch fermentation. The strategies described herein serve as valuable guidelines for the production of other high-value and toxic products.

Normal-Direction Graded Hemispheres for Ionic Flexible Sensors with a Record-High Linearity in a Wide Working Range.

Flexible pressure sensors developed rapidly with increased sensitivity, a fast response time, high stability, and excellent deformability. These progresses have expanded the application of wearable electronics under high-pressure backgrounds while also bringing new challenges. In particular, the nonlinearity and narrow working range lead to a gradually insensitive response, principally because the microstructure deforms inconsistently on the device interfaces in the whole working range. Herein, we report an ionic flexible sensor with a record-high linearity (R2 = 0.99994) in a wide working range (up to 600 kPa). The linearity response comes from the normal-direction graded hemisphere (GH) microstructure. It is prepared from poly(dimethylsiloxane) (PDMS)/carbon nanotubes (CNTs)/Au into flexible and deformable electrodes, and its geometry is precisely designed from the linear elastic theory and optimized through finite element simulation. The sensor can achieve a high sensitivity of S = 165.5 kPa-1, a response-relaxation time of <30 ms, and superb consistency, allowing the device to detect vibration signals. Our sensor has been assembled with circuits and capsulation in order to monitor the function state of players in underwater sports in the frequency domain. This work deepens the theory of linearized design of microstructures and provides a strategy to make flexible pressure sensors that have combined the performances of ultrahigh linearity, high sensitivity, and a wide working range.

Advances in sequencing and key character analysis of mango (Mangifera indica L.).

Mango (Mangifera indica L.) is an important fruit crop in tropical and subtropical countries associated with many agronomic and horticultural problems, such as susceptibility to pathogens, including powdery mildew and anthracnose, poor yield and quality, and short shelf life. Conventional breeding techniques exhibit significant limitations in improving mango quality due to the characteristics of long ripening, self-incompatibility, and high genetic heterozygosity. In recent years, much emphasis has been placed on identification of key genes controlling a certain trait through genomic association analysis and directly breeding new varieties through transgene or genotype selection of offspring. This paper reviews the latest research progress on the genome and transcriptome sequencing of mango fruit. The rapid development of genome sequencing and bioinformatics provides effective strategies for identifying, labeling, cloning, and manipulating many genes related to economically important traits. Preliminary verification of the functions of mango genes has been conducted, including genes related to flowering regulation, fruit development, and polyphenol biosynthesis. Importantly, modern biotechnology can refine existing mango varieties to meet the market demand with high economic benefits.

Explanations as a New Metric for Feature Selection: A Systematic Approach.

With the extensive use of Machine Learning (ML) in the biomedical field, there was an increasing need for Explainable Artificial Intelligence (XAI) to improve transparency and reveal complex hidden relationships between variables for medical practitioners, while meeting regulatory requirements. Feature Selection (FS) is widely used as a part of a biomedical ML pipeline to significantly reduce the number of variables while preserving as much information as possible. However, the choice of FS methods affects the entire pipeline including the final prediction explanations, whereas very few works investigate the relationship between FS and model explanations. Through a systematic workflow performed on 145 datasets and an illustration on medical data, the present work demonstrated the promising complementarity of two metrics based on explanations (using ranking and influence changes) in addition to accuracy and retention rate to select the most appropriate FS/ML models. Measuring how much explanations differ with/without FS are particularly promising for FS methods recommendation. While reliefF generally performs the best on average, the optimal choice may vary for each dataset. Positioning FS methods in a tridimensional space, integrating explanations-based metrics, accuracy and retention rate, would allow the user to choose the priorities to be given on each of the dimensions. In biomedical applications, where each medical condition may have its own preferences, this framework will make it possible to offer the healthcare professional the appropriate FS technique, to select the variables that have an important explainable impact, even if this comes at the expense of a limited drop of accuracy.

An Ultrahighly Pressure Sensitive Electronic Fish Skin for Underwater Wave Sensing.

Underwater flexible sensors have a future for wide application, which is promising for attaching them to underwater creatures to monitor vital signals and biomechanical analysis of their motion and perceive tiny environmental disturbances. However, the pressure waves induced by biological swimming are extremely weak and susceptible to undercurrents, making them difficult to sense. Here, we report an ultrahighly sensitive biomimetic electronic fish skin designed by embedding an artificial pseudocapacitive-based hair cell into a simulated canal neuromast encapsulation structure, in which the artificial hair cell, as the key sensitive unit, is assembled from hybrid film electrodes and polyurethane-acidic electrolyte foam. Such a film is prepared by inter-cross-linking MXene and holey reduced graphene oxide with the assistance of l-cysteine, effectively increasing the interfacial capacitance and alleviating the oxidation issues of MXene. Meanwhile, the acidic foam with high porosity shows great compressibility to adapt to a high-pressure underwater environment. Consequently, the device exhibits ultrahighly sensitivity (maximum sensitivity ∼173688 kPa-1) over a wide range of depths (0-100 m) and remains stable after 10000 repeated tests. As an example case, the device is integrated as a motion monitoring system to identify the minor disturbances triggered by instantaneous postural changes of fish. The electronic fish skin is expected to demonstrate enormous potentials in flow field monitoring, ocean current detecting, and even seismic waves warning.

Exosomes from young healthy human plasma promote functional recovery from intracerebral hemorrhage via counteracting ferroptotic injury.

Intracerebral hemorrhage (ICH), as a type of life-threatening and highly disabled disease, has limited therapeutic approaches. Here, we show that exosomes derived from young healthy human plasma exhibiting typical exosomes features could facilitate functional recovery of ICH mice. When these exosomes are intraventricularly delivered into the brain after ICH, they mainly distribute around the hematoma and could be internalized by neuronal cells. Strikingly, exosomes administration markedly enhanced the behavioral recovery of ICH mice through reducing brain injury and cell ferroptosis. MiRNA sequencing revealed that microRNA-25-3p (miR-25-3p) was differentially expressed miRNA in the exosomes from young healthy human plasma, compared with exosomes from the old control. Importantly, miR-25-3p mimicked the treatment effect of exosomes on behavioral improvement, and mediated the neuroprotective effect of exosomes against ferroptosis in ICH. Furthermore, luciferase assay and western blotting data illustrated that P53 as assumed the role of a downstream effector of miR-25-3p, thereby regulating SLC7A11/GPX4 pathway to counteract ferroptosis. Taken together, these findings firstly reveal that exosomes from young healthy human plasma improve functional recovery through counteracting ferroptotic injury by regulating P53/SLC7A11/GPX4 axis after ICH. Given the easy availability of plasma exosomes, our study provides a potent therapeutic strategy for ICH patients with quick clinical translation in the near future.

Identification and characterization of auxin response factor (ARF) family members involved in fig (Ficus carica L.) fruit development.

The auxin response factor (ARF) combines with AuxREs cis-acting elements in response to auxin to regulate plant development. To date, no comprehensive analysis of ARF genes expressed during fruit development has been conducted for common fig (Ficus carica L.). In this study, members of the FcARF gene family were screened, identified in the fig genome database and their features characterized using bioinformatics. Twenty FcARF genes were clustered into three classes, with almost similar highly conserved DBD (B3-like DNA binding domain), AUX/IAA (auxin/indole-3-acetic acid gene family) and MR domain structure among class members. Analysis of amino acid species in MR domain revealed 10 potential transcription activators and 10 transcription inhibitors, and 17 FcARF members were predicted to be located in the nucleus. DNA sequence analysis showed that the ARF gene family consisted of 4-25 exons, and the promoter region contained 16 cis-acting elements involved in stress response, hormone response and flavonoid biosynthesis. ARF genes were expressed in most tissues of fig, especially flower and peel. Transcriptomics analysis results showed that FcARF2, FcARF11 and FcARF12, belonging to class-Ia, were stably and highly expressed in the early development stage of flower and peel of 'Purple peel' fig. However, their expression levels decreased after maturity. Expression of class-Ic member FcARF3 conformed to the regularity of fig fruit development. These four potential transcription inhibitors may regulate fruit growth and development of 'Purple Peel' fig. This study provides comprehensive information on the fig ARF gene family, including gene structure, chromosome position, phylogenetic relationship and expression pattern. Our work provides a foundation for further research on auxin-mediated fig fruit development.

A single-cell transcriptomic atlas characterizes the silk-producing organ in the silkworm.

The silk gland of the domesticated silkworm Bombyx mori, is a remarkable organ that produces vast amounts of silk with exceptional properties. Little is known about which silk gland cells execute silk protein synthesis and its precise spatiotemporal control. Here, we use single-cell RNA sequencing to build a comprehensive cell atlas of the silkworm silk gland, consisting of 14,972 high-quality cells representing 10 distinct cell types, in three early developmental stages. We annotate all 10 cell types and determine their distributions in each region of the silk gland. Additionally, we decode the developmental trajectory and gene expression status of silk gland cells. Finally, we discover marker genes involved in the regulation of silk gland development and silk protein synthesis. Altogether, this work reveals the heterogeneity of silkworm silk gland cells and their gene expression dynamics, affording a deeper understanding of silk-producing organs at the single-cell level.

Genome-wide analysis of JAZ family genes expression patterns during fig (Ficus carica L.) fruit development and in response to hormone treatment.

BACKGROUND: Jasmonate-ZIM domain (JAZ) repressors negatively regulate signal transduction of jasmonates, which regulate plant development and immunity. However, no comprehensive analysis of the JAZ gene family members has been done in the common fig (Ficus carica L.) during fruit development and hormonal treatment. RESULTS: In this study, 10 non-redundant fig JAZ family genes (FcJAZs) distributed on 7 chromosomes were identified in the fig genome. Phylogenetic and structural analysis showed that FcJAZ genes can be grouped into 5 classes. All the classes contained relatively complete TIFY and Jas domains. Yeast two hybrid (Y2H) results showed that all FcJAZs proteins may interact with the identified transcription factor, FcMYC2. Tissue-specific expression analysis showed that FcJAZs were highly expressed in the female flowers and roots. Expression patterns of FcJAZs during the fruit development were analyzed by RNA-Seq and qRT-PCR. The findings showed that, most FcJAZs were significantly downregulated from stage 3 to 5 in the female flower, whereas downregulation of these genes was observed in the fruit peel from stage 4 to 5. Weighted-gene co-expression network analysis (WGCNA) showed the expression pattern of FcJAZs was correlated with hormone signal transduction and plant-pathogen interaction. Putative cis-elements analysis of FcJAZs and expression patterns of FcJAZs which respond to hormone treatments revealed that FcJAZs may regulate fig fruit development by modulating the effect of ethylene or gibberellin. CONCLUSIONS: This study provides a comprehensive analysis of the FcJAZ family members and provides information on FcJAZs contributions and their role in regulating the common fig fruit development.

New Flexible Tactile Sensor Based on Electrical Impedance Tomography.

In order to obtain external information and ensure the security of human-computer interaction, a double sensitive layer structured tactile sensor was proposed in this paper. Based on the EIT (Electrical Impedance Tomography) method, the sensor converts the information from external collisions or contact into local conductivity changes, and realizes the detection of one or more contact points. These changes can be processed into an image containing positional and force information. The experiments were conducted on the actual sensor sample. The OpenCV toolkit was used to process the positional information of contact points. The distributional regularities of errors in positional detection were analyzed, and the accuracy of the positional detection was evaluated. The effectiveness, sensitivity, and contact area of the force detection were analyzed based on the result of the EIT calculations. Furthermore, multi-object tests of pressure were conducted. The results of the experiment indicated that the proposed sensor performed well in detecting the position and force of contact. It is suitable for human-robot interaction.

Genome-Wide Characterization and Analysis of bHLH Transcription Factors Related to Anthocyanin Biosynthesis in Fig (Ficus carica L.).

The basic helix-loop-helix (bHLH) transcription factor family is the second largest transcription factor family in plants, and participates in various plant growth and development processes. A total of 118 bHLH genes were identified from fig (Ficus carica L.) by whole-genome database search. Phylogenetic analysis with Arabidopsis homologs divided them into 25 subfamilies. Most of the bHLHs in each subfamily shared a similar gene structure and conserved motifs. Seventy-two bHLHs were found expressed at fragments per kilobase per million mapped (FPKM) > 10 in the fig fruit; among them, 15 bHLHs from eight subfamilies had FPKM > 100 in at least one sample. bHLH subfamilies had different expression patterns in the female flower tissue and peel during fig fruit development. Comparing green and purple peel mutants, 13 bHLH genes had a significantly different (≥ 2-fold) expression. Light deprivation resulted in 68 significantly upregulated and 22 downregulated bHLH genes in the peel of the fruit. Sixteen bHLH genes in subfamily III were selected by three sets of transcriptomic data as candidate genes related to anthocyanin synthesis. Interaction network prediction and yeast two-hybrid screening verified the interaction between FcbHLH42 and anthocyanin synthesis-related genes. The transient expression of FcbHLH42 in tobacco led to an apparent anthocyanin accumulation. Our results confirm the first fig bHLH gene involved in fruit color development, laying the foundation for an in-depth functional study on other FcbHLH genes in fig fruit quality formation, and contributing to our understanding of the evolution of bHLH genes in other horticulturally important Ficus species.

Exosomes mediated the delivery of ochratoxin A-induced cytotoxicity in HEK293 cells.

Ochratoxin A (OTA) is one of the mycotoxins, which widely pollutes food systems and seriously threatens human health. OTA's target organ is the kidney. Exosome, as one of the extracellular vesicles, could be secreted by all kinds of cells. It contains different proteins, nucleic acid, and lipid, which are decided by their donor cells and could be uptake by the recipient cells, release their contents, and affect the recipient cell's life activity. In this study, a 24 h-treatment with 5 µM OTA was found to significantly reduce the cell viability of HEK293 cells and meanwhile to provide a sufficient quantity of exosomes, thus this concentration and time were selected for subsequent experiments. In addition, exosomes extracted by ultracentrifugation had higher purity, fewer impurities, and uniform morphology than that by the ExoQuick-TC kit. Furthermore, these exosomes increased ROS levels and decreased mitochondrial membrane potential in HEK293 cells. By RNA-seq, the cytotoxicity mechanisms induced by OTA-treated HEK293 cell-derived exosomes (EXO-OTA) and OTA were mainly the metabolism of proteins and the cell cycle respectively. Also, it proved that exosomes deliver partial OTA-induced cytotoxicity.

New insights into the proteins interacting with the promoters of silkworm fibroin genes.

The silkworm, Bombyx mori, is a silk-producing insect that has contributed greatly to human society. The silk gland of B. mori is a specialized organ responsible for synthesizing silk fibroin and sericin proteins under control of numerous factors. However, which factors are involved in direct silk protein synthesis regulation remains largely unknown. We report the identification of promoter-interacting proteins (PIPs) necessary for the regulation of genes encoding fibroin proteins, including the fibroin heavy chain (fibH), fibroin light chain (fibL), and a 25-kD polypeptide protein (P25). In the fourth larval molting stage (M4) or day 5 fifth-instar larvae (L5D5), a total of 198, 292, and 247 or 330, 305, and 460 proteins interacting with the promoter region of fibH, fibL and P25, respectively, were identified from the posterior silk gland by DNA pull-down combined with mass spectrometry. Many PIPs were particularly involved in ribosome- and metabolism-related pathways. Additionally, 135 and 212 proteins were identified as common PIPs of fibH, fibL and P25 in M4 and L5D5, respectively. Among all PIPs, we identified 31 potential transcription factors, such as Y-box and poly A-binding proteins, which play roles in nucleotide binding, ATP binding, or protein folding. This study provides the first in-depth profile of proteins interacting with fibroin gene promoters and contributes to a better understanding of silk protein synthesis regulation.

[IgG4-related diseases: A comprehensive review].

IgG4-related disease (IgG4-RD) is an inflammatory disorder with slow progression in multiple organs, characterized by abundant infiltration of IgG4-positive plasmacytes and fibrosis in the involved organs. The precise pathogenic mechanism of IgG4-RD still remains unclear. Currently, the abnormal regulation of acquired immunity and adaptive immunity is considered as the main pathogenesis of IgG4-RD, and its clinical manifestations are diverse. IgG4-RD can affect any tissue and organ. Inflammatory pseudotumor and diffuse enlargement are the common manifestations, which are easily misdiagnosed as tumor or inflammation. The treatment of glucocorticoid-based drugs is effective. However, the symptoms of IgG4-RD are variable and the prognosis is poor. We mainly summarized the research progress in the pathogenesis, clinical features, diagnosis and treatment of IgG4-RD.

Precision toxicology shows that troxerutin alleviates ochratoxin A-induced renal lipotoxicity.

Lipotoxicity is the most common cause of severe kidney disease, with few treatment options available today. Precision toxicology can improve detection of subtle intracellular changes in response to exogenous substrates; thus, it facilitates in-depth research on bioactive molecules that may interfere with the onset of certain diseases. In the current study, troxerutin significantly relieved nephrotoxicity, increased endurance, and improved systemic energy metabolism and renal inflammation in OTA-induced nephrotic mice. Lipidomics showed that troxerutin effectively reduced the levels of triglycerides, phosphatidylcholines, and phosphatidylethanolamines in nephropathy. The mechanism was partly attributable to troxerutin in alleviating the aberrantly up-regulated expression of sphingomyelinase, the cystic fibrosis transmembrane conductance regulator, and chloride channel 2. Renal tubular epithelial cells, the main site of toxin-induced accumulation of lipids in the kidney, were subjected to transcriptomic profiling, which uncovered several metabolic factors relevant to aberrant lipid and lipoprotein metabolism. Our work provides new insights into the molecular features of toxin-induced lipotoxicity in renal tubular epithelial cells in vivo and demonstrates the function of troxerutin in alleviating OTA-induced nephrosis and associated systemic energy metabolism disorders.-Yang, X., Xu, W., Huang, K., Zhang, B., Wang, H., Zhang, X., Gong, L., Luo, Y., He, X. Precision toxicology shows that troxerutin alleviates ochratoxin A-induced renal lipotoxicity.