Metabolic Pathways Research Articles

Identification of a multi-modal mechanism for Se(VI) reduction and Se(0) allotropic transition by Stenotrophomonas bentonitica.

Microorganisms can play a key role in selenium (Se) bioremediation and the fabrication of Se-based nanomaterials by reducing toxic forms (Se(VI) and Se(IV)) into Se(0). In recent years, omics have become a useful tool in understanding the metabolic pathways involved in the reduction process. This paper aims to elucidate the specific molecular mechanisms involved in Se(VI) reduction by the bacterium Stenotrophomonas bentonitica. Both cytoplasmic and membrane fractions were able to reduce Se(VI) to Se(0) nanoparticles (NPs) with different morphologies (nanospheres and nanorods) and allotropes (amorphous, monoclinic, and trigonal). Proteomic analyses indicated an adaptive response against Se(VI) through the alteration of several metabolic pathways including those related to energy acquisition, synthesis of proteins and nucleic acids, and transport systems. Whilst the thioredoxin system and the Painter reactions were identified to play a crucial role in Se reduction, flagellin may also be involved in the allotropic transformation of Se. These findings suggest a multi-modal reduction mechanism is involved, providing new insights for developing novel strategies in bioremediation and nanoparticle synthesis for the recovery of critical materials within the concept of circular economy.

Metabolomics study on fermentation of Lactiplantibacillus plantarum ST-III with food grade proliferators in milk

Milk is a naturally complex medium that is suitable for the growth of most lactic acid bacteria. Unfortunately, Lactiplantibacillus plantarum ST-III grow poorly in milk without supplementation. To solve this problem, we use fresh pineapple and mung beans juice to develop an edible proliferator for L. plantarum ST-III. Our comparative analysis of metabolomics changes before and after fermentation reveals that amino acids and dipeptides are the most consumed compounds, with other substances including nucleotides and vitamins, implying the mechanism of proliferation. Combining the KEGG metabolic pathway analysis, substances that may promote the growth of L. plantarum ST-III in milk were screened. To explore which component of the proliferator is required for L. plantarum ST-III cultivate, we supplemented with several combinations of molecules aforementioned in milk. The simulation addition experiment results of L. plantarum ST-III in milk show that if any additions are missing, the concentration of viable bacteria is lower. Only when it contains all additives can the highest concentration of viable bacteria be obtained. Compared with the control, the fold change of the viable bacteria is about 32. Thus, it proves that milk primarily lacked available amino acids, dipeptides, uracil, xanthine, nicotinamide, and manganese for the growth of L. plantarum ST-III.

Modulation of adipogenesis and lipogenesis by indomethacin and pantoprazole

Endocrine disruptors are suggested to act as potential “obesogens” by interacting with various metabolic processes in adipose tissue. Besides industrial chemicals that are blamed to act as endocrine disruptors as well as obesogens, pharmaceuticals can also cause obesogenic effects as unintended adverse effects. However, limited studies evaluated the obesogenic adverse effects of pharmaceuticals. Based on this information, the present study aimed to investigate possible in vitro adipogenic/lipogenic potential of indomethacin and pantoprazole that are prescribed during pregnancy. Their effects on lipid accumulation, adiponectin level, glycerol-3-phosphate dehydrogenase (G3PDH) activity, and expression of adipogenic genes and proteins were investigated in 3 T3-L1 cell line. Range of concentrations of the pharmaceuticals were selected according to their Cmax values. Lipid accumulation was increased with indomethacin dose dependently and with pantoprazole at its highest concentration. Both pharmaceuticals also increased adiponectin levels, and this was thought to play a role in the stimulation of the adipogenesis pathway. Moreover, both pharmaceuticals altered the gene and/or protein expression of some adipogenic/lipogenic transcriptional factors, which may lead to disruption of metabolic pathways during fetal period. In conclusion, indomethacin and pantoprazole may have obesogenic effects through different mechanisms and their potential to cause obesity should be investigated by further in vivo and epidemiological studies.

Identification and functional analysis of long non-coding RNA (lncRNA) and metabolites response to mowing in hulless barley (Hordeum vulgare L. var. nudum hook. f.)

BackgroundHulless barley (Hordeum vulgare L. var. nudum Hook. f.) is a significant cereal crop and a substantial source of forage for livestock. Long non-coding RNAs (lncRNAs) and metabolites play crucial roles in the nutrient accumulation and regeneration of hulless barley plants following mowing. The study aimed to identify differentially expressed lncRNAs and metabolites in hulless barley plants by analyzing transcriptomic and metabolomic datasets at 2 h, 24 h, and 72 h following mowing.ResultsThe study revealed that 190, 90, and 438 lncRNA genes were differentially expressed at the 2 h, 24 h, and 72 h time points compared to the non-mowing control. We identified 14 lncRNA genes—11 downregulated and 3 upregulated—showing consistently significant differential expression across all time points after mowing. These differentially expressed lncRNAs target genes involved in critical processes such as cytokinin signaling, cell wall degradation, storage protein accumulation, and biomass increase. In addition, we identified ten differentially expressed metabolites targeting diverse metabolic pathways, including plant hormones, alkaloids, and flavonoids, before and after mowing at various time points. Endogenous hormone analysis revealed that cytokinin most likely played a crucial role in the regeneration of hulless barley after mowing.ConclusionsThis study created a comprehensive dataset of lncRNAs, metabolites, and hormones in hulless barley after mowing, revealing valuable insights into the functional characteristics of lncRNAs, metabolites, and hormones in regulating plant regeneration. The results indicated that cytokinin plays a significant role in facilitating the regeneration process of hulless barley after mowing. This comprehensive dataset is an invaluable resource for better understanding the complex mechanisms that underlie plant regeneration, with significant implications for crop improvement.

Citrin deficiency-The East-side story.

Citrin deficiency (CD) is a complex metabolic condition due to defects in SLC25A13 encoding citrin, an aspartate/glutamate carrier located in the mitochondrial inner membrane. The condition was first described in Japan and other East Asian countries in patients who were thought to suffer from classical citrullinemia type 1, and was therefore classified as a urea cycle disorder. With an improved understanding of its molecular basis, it became apparent that a defect of citrin is primarily affecting the malate-aspartate shuttle with however multiple secondary effects on many central metabolic pathways including glycolysis, gluconeogenesis, de novo lipogenesis and ureagenesis. In the meantime, it became also clear that CD must be considered as a global disease with patients identified in many parts of the world and affected by SLC25A13 genotypes different from those known in East Asian populations. The present short review summarizes the (hi)story of this complex metabolic condition and tries to explain the relevance of including CD as a differential diagnosis in neonates and infants with cholestasis and in (not only adult) patients with hyperammonemia of unknown origin with subsequent impact on the emergency management.

Genome-wide identification of PAR domain protein 1 (PDP1) targets through ChIP-seq reveals the regulation of diapause-specific characteristics in Culex pipiens.

Insects use seasonal diapause as an alternative strategy to endure adverse seasons. This developmental trajectory is induced by environmental cues like short-day lengths in late summer and early fall, but how insects measure day length is unknown. The circadian clock has been implicated in regulating photoperiodic or seasonal responses in many insects, including the Northern house mosquito, Culex pipiens, which enters adult diapause. To investigate the potential control of diapause by circadian control, we employed ChIP-sequencing to identify the downstream targets of a circadian transcription factor, PAR domain protein 1 (PDP1), that contribute to the hallmark features of diapause. We identified the nearest genes in a 10 kb region of the anticipated PDP1 binding sites, listed prospective targets and searched for PDP1-specific binding sites. By examining the functional relevance to diapause-specific behaviours and modifications such as metabolic pathways, lifespan extension, cell cycle regulation and stress tolerance, eight genes were selected as targets and validated using ChIP-qPCR. In addition, qRT-PCR demonstrated that the mRNA abundance of PDP1 targets increased in the heads of diapausing females during the middle of the scotophase (ZT17) compared with the early photophase (ZT1), in agreement with the peak and trough of PDP1 abundance. Thus, our investigation uncovered the mechanism by which PDP1 might generate a diapause phenotype in insects.

Regulation and mechanism of enzyme metabolism in germinated hemp seeds by ultrasound combined with exogenous calcium chloride treatment

γ-aminobutyric acid (GABA) plays an important role in anti-anxiety by inhibiting neurotransmitter in the central nervous system (CNS) of mammals, which is generated in the germinating seeds. The key enzymes activity of GABA metabolism pathway and nutrients content in hemp seeds during germination were studied after treated with ultrasound and CaCl2. The mechanism of exogenous stress on key enzymes in GABA metabolism pathway was investigated by molecular dynamics simulation. The results showed that ultrasonic combined with 1.5 mmol·L−1CaCl2 significantly increased the activities of glutamate decarboxylase (GAD) and GABA transaminase (GABA-T) in seeds, and promoted the conversion of glutamate to GABA, resulting in the decrease of glutamate content and the accumulation of GABA. Molecular dynamics simulations revealed that Ca2+ environment enhanced the activity of GAD and GABA-T enzymes by altering their secondary structure, exposing their hydrophobic residues. Ultrasound, germination and CaCl2 stress improved the nutritional value of hemp seeds.

Metabolic Responses to Redox Stress in Vascular Cells.

Significance: Redox stress underlies numerous vascular disease mechanisms. Metabolic adaptability is essential for vascular cells to preserve energy and redox homeostasis. Recent Advances: Single-cell technologies and multiomic studies demonstrate significant metabolic heterogeneity among vascular cells in health and disease. Increasing evidence shows that reductive or oxidative stress can induce metabolic reprogramming of vascular cells. A recent example is intracellular L-2-hydroxyglutarate accumulation in response to hypoxic reductive stress, which attenuates the glucose flux through glycolysis and mitochondrial respiration in pulmonary vascular cells and provides protection against further reductive stress. Critical Issues: Regulation of cellular redox homeostasis is highly compartmentalized and complex. Vascular cells rely on multiple metabolic pathways, but the precise connectivity among these pathways and their regulatory mechanisms is only partially defined. There is also a critical need to understand better the cross-regulatory mechanisms between the redox system and metabolic pathways as perturbations in either systems or their cross talk can be detrimental. Future Directions: Future studies are needed to define further how multiple metabolic pathways are wired in vascular cells individually and as a network of closely intertwined processes given that a perturbation in one metabolic compartment often affects others. There also needs to be a comprehensive understanding of how different types of redox perturbations are sensed by and regulate different cellular metabolic pathways with specific attention to subcellular compartmentalization. Lastly, integration of dynamic changes occurring in multiple metabolic pathways and their cross talk with the redox system is an important goal in this multiomics era.

Transcriptome profiling reveals the impact of various levels of biochar application on the growth of flue-cured tobacco plants

BackgroundBiochar, a carbon-rich source and natural growth stimulant, is usually produced by the pyrolysis of agricultural biomass. It is widely used to enhance plant growth, enzyme activity, and crop productivity. However, there are no conclusive studies on how different levels of biochar application influence these systems.Methods and resultsThe present study elucidated the dose-dependent effects of biochar application on the physiological performance, enzyme activity, and dry matter accumulation of tobacco plants via field experiments. In addition, transcriptome analysis was performed on 60-day-old (early growth stage) and 100-day-old (late growth stage) tobacco leaves to determine the changes in transcript levels at the molecular level under various biochar application levels (0, 600, and 1800 kg/ha). The results demonstrated that optimum biochar application enhances plant growth, regulates enzymatic activity, and promotes biomass accumulation in tobacco plants, while higher biochar doses had adverse effects. Furthermore, transcriptome analysis revealed a total of 6561 differentially expressed genes (DEGs) that were up- or down-regulated in the groupwise comparison under different treatments. KEGG pathways analysis demonstrated that carbon fixation in photosynthetic organisms (ko00710), photosynthesis (ko00195), and starch and sucrose metabolism (ko00500) pathways were significantly up-regulated under the optimal biochar dosage (600 kg/ha) and down-regulated under the higher biochar dosage (1800 kg/ha).ConclusionCollectively, these results indicate that biochar application at an optimal rate (600 kg/ha) could positively affect photosynthesis and carbon fixation, which in turn increased the synthesis and accumulation of sucrose and starch, thus promoting the growth and dry matter accumulation of tobacco plants. However, a higher biochar dosage (1800 kg/ha) disturbs the crucial source-sink balance of organic compounds and inhibits the growth of tobacco plants.

Glycogenolysis-Induced Astrocytic Serping1 Expression Regulates Neuroinflammatory Effects on Hippocampal neuron.

The bacterial pathogen, lipopolysaccharide (LPS), elicits microglial response and induces cytokine secretion that subsequently activates astrocytes. Recent findings have indicated that LPS-induced activation of postnatal glial cells has led to alterations in synapse formation in hippocampal and cortical neurons, thereby resulting in a prolonged increased risk for seizure or depression. Nevertheless, its mechanisms remain to be fully elucidated. Cellular metabolism has recently gained recognition as a critical regulatory mechanism for the activation of peripheral immune cells, as it supplies the requisite energy and metabolite for their activation. In the present study, we report that LPS did not change the expression of reported astrocyte-derived synaptogenic genes in the postnatal hippocampus; however, it induced upregulation of astrocytic complement component regulator Serping1 within the postnatal hippocampus. As a regulatory mechanism, activation of glycogen degradation (glycogenolysis) governs the expression of a subset of inflammatory-responsive genes including Serping1 through reactive oxygen species (ROS)-NF-κB axis. Our study further demonstrated that glycogenolysis is implicated in neurotoxic phenotypes of astrocytes, such as impaired neuronal synaptogenesis or cellular toxicity. These findings suggested that activation of glycogenolysis in postnatal astrocytes is an essential metabolic pathway for inducing responses in inflammatory astrocytes.

Itaconate is a metabolic regulator of bone formation in homeostasis and arthritis

ObjectivesBone remodelling is a highly dynamic process dependent on the precise coordination of osteoblasts and haematopoietic-cell derived osteoclasts. Changes in core metabolic pathways during osteoclastogenesis, however, are largely unexplored and...

6-Phosphogluconolactonase is critical for the efficient functioning of the pentose phosphate pathway.

The metabolic networks of microorganisms are remarkably robust to genetic and environmental perturbations. This robustness stems from redundancies such as gene duplications, isoenzymes, alternative metabolic pathways, and also from non-enzymatic reactions. In the oxidative branch of the pentose phosphate pathway (oxPPP), 6-phosphogluconolactone hydrolysis into 6-phosphogluconate is catalysed by 6-phosphogluconolactonase (Pgl) but in the absence of the latter, the oxPPP flux is thought to be maintained by spontaneous hydrolysis. However, in Δpgl Escherichia coli, an extracellular pathway can also contribute to pentose phosphate synthesis. This raises question as to whether the intracellular non-enzymatic reaction can compensate for the absence of 6-phosphogluconolactonase and, ultimately, on the role of 6-phosphogluconolactonase in central metabolism. Our results validate that the bypass pathway is active in the absence of Pgl, specifically involving the extracellular spontaneous hydrolysis of gluconolactones to gluconate. Underthese conditions, metabolic flux analysis reveals that this bypass pathway accounts for the entire flux into the oxPPP. This alternative metabolic route-partially extracellular-sustains the flux through the oxPPP necessary for cell growth, albeit at a reduced rate in the absence of Pgl. Importantly, these findings imply that intracellular non-enzymatic hydrolysis of 6-phosphogluconolactone does not compensate for the absence of Pgl. This underscores the crucial role of Pgl in ensuring the efficient functioning of the oxPPP.

Genetic insights of blood lipid metabolites on polycystic ovary syndrome risk: a bidirectional two-sample Mendelian randomization study

BackgroundPathologically, metabolic disorder plays a crucial role in polycystic ovarian syndrome (PCOS). However, there is no conclusive evidence lipid metabolite levels to PCOS risk.MethodsIn this study, genome-wide association study (GWAS) genetic data for 122 lipid metabolites were used to assign instrumental variables (IVs). PCOS GWAS were derived from a large-scale meta-analysis of 10,074 PCOS cases and 103,164 controls. An inverse variance weighted (IVW) analysis was the primary methodology used for Mendelian randomization (MR). For sensitivity analyses, Cochran Q test, MR-Egger intercept, MR-PRESSO, leave-one-out analysis,and Steiger test were performed. Furthermore, we conducted replication analysis, meta-analysis, and metabolic pathway analysis. Lastly, reverse MR analysis was used to determine whether the onset of PCOS affected lipid metabolites.ResultsThis study detected the blood lipid metabolites and potential metabolic pathways that have a genetic association with PCOS onset. After IVW, sensitivity analyses, replication and meta-analysis, two pathogenic lipid metabolites of PCOS were finally identified: Hexadecanedioate (OR=1.85,95%CI=1.27–2.70, P=0.001) and Dihomo-linolenate (OR=2.45,95%CI=1.30–4.59, P=0.005). Besides, It was found that PCOS may be mediated by unsaturated fatty acid biosynthesis and primary bile acid biosynthesis metabolic pathways. Reverse MR analysis showed the causal association between PCOS and 2-tetradecenoyl carnitine at the genetic level (OR=1.025, 95% CI=1.003–1.048, P=0.026).ConclusionGenetic evidence suggests a causal relationship between hexadecanedioate and dihomo-linolenate and the risk of PCOS. These compounds could potentially serve as metabolic biomarkers for screening PCOS and selecting drug targets. The identification of these metabolic pathways is valuable in guiding the exploration of the pathological mechanisms of PCOS, although further studies are necessary for confirmation.

Genetic insights of blood lipid metabolites on polycystic ovary syndrome risk: a bidirectional two-sample Mendelian randomization study

BackgroundPathologically, metabolic disorder plays a crucial role in polycystic ovarian syndrome (PCOS). However, there is no conclusive evidence lipid metabolite levels to PCOS risk.MethodsIn this study, genome-wide association study (GWAS) genetic data for 122 lipid metabolites were used to assign instrumental variables (IVs). PCOS GWAS were derived from a large-scale meta-analysis of 10,074 PCOS cases and 103,164 controls. An inverse variance weighted (IVW) analysis was the primary methodology used for Mendelian randomization (MR). For sensitivity analyses, Cochran Q test, MR-Egger intercept, MR-PRESSO, leave-one-out analysis,and Steiger test were performed. Furthermore, we conducted replication analysis, meta-analysis, and metabolic pathway analysis. Lastly, reverse MR analysis was used to determine whether the onset of PCOS affected lipid metabolites.ResultsThis study detected the blood lipid metabolites and potential metabolic pathways that have a genetic association with PCOS onset. After IVW, sensitivity analyses, replication and meta-analysis, two pathogenic lipid metabolites of PCOS were finally identified: Hexadecanedioate (OR=1.85,95%CI=1.27–2.70, P=0.001) and Dihomo-linolenate (OR=2.45,95%CI=1.30–4.59, P=0.005). Besides, It was found that PCOS may be mediated by unsaturated fatty acid biosynthesis and primary bile acid biosynthesis metabolic pathways. Reverse MR analysis showed the causal association between PCOS and 2-tetradecenoyl carnitine at the genetic level (OR=1.025, 95% CI=1.003–1.048, P=0.026).ConclusionGenetic evidence suggests a causal relationship between hexadecanedioate and dihomo-linolenate and the risk of PCOS. These compounds could potentially serve as metabolic biomarkers for screening PCOS and selecting drug targets. The identification of these metabolic pathways is valuable in guiding the exploration of the pathological mechanisms of PCOS, although further studies are necessary for confirmation.

Structural constraints limit the regime of optimal flux in autocatalytic reaction networks

Autocatalytic chemical networks play a predominant role in a large number of natural systems such as in metabolic pathways and in ecological networks. Despite recent efforts, the precise impact of thermodynamic constraints on these networks remains elusive. In this work, we present a theoretical framework that allows specific bounds on the thermodynamic affinity and on the concentrations of autocatalysts in mass-action autocatalytic networks. These bounds can be obtained solely from the stoichiometry of the underlying chemical reaction network, and are independent from the numerical values of kinetic parameters. This property holds in the specific regime where all the fluxes of the network are tightly coupled and maximal. Our method is applicable to large networks, and can be used to complement constraints-based modeling methods of metabolic networks, which typically do not provide predictions about thermodynamic properties or concentration ranges of metabolites.

Identification of Parkinson’s disease PACE subtypes and repurposing treatments through integrative analyses of multimodal data

Parkinson’s disease (PD) is a serious neurodegenerative disorder marked by significant clinical and progression heterogeneity. This study aimed at addressing heterogeneity of PD through integrative analysis of various data modalities. We analyzed clinical progression data (≥5 years) of individuals with de novo PD using machine learning and deep learning, to characterize individuals’ phenotypic progression trajectories for PD subtyping. We discovered three pace subtypes of PD exhibiting distinct progression patterns: the Inching Pace subtype (PD-I) with mild baseline severity and mild progression speed; the Moderate Pace subtype (PD-M) with mild baseline severity but advancing at a moderate progression rate; and the Rapid Pace subtype (PD-R) with the most rapid symptom progression rate. We found cerebrospinal fluid P-tau/α-synuclein ratio and atrophy in certain brain regions as potential markers of these subtypes. Analyses of genetic and transcriptomic profiles with network-based approaches identified molecular modules associated with each subtype. For instance, the PD-R-specific module suggested STAT3, FYN, BECN1, APOA1, NEDD4, and GATA2 as potential driver genes of PD-R. It also suggested neuroinflammation, oxidative stress, metabolism, PI3K/AKT, and angiogenesis pathways as potential drivers for rapid PD progression (i.e., PD-R). Moreover, we identified repurposable drug candidates by targeting these subtype-specific molecular modules using network-based approach and cell line drug-gene signature data. We further estimated their treatment effects using two large-scale real-world patient databases; the real-world evidence we gained highlighted the potential of metformin in ameliorating PD progression. In conclusion, this work helps better understand clinical and pathophysiological complexity of PD progression and accelerate precision medicine.

Cardiac Manifestations in Inherited Metabolic Diseases.

Inherited metabolic diseases (IMDs) stem from genetic defects affecting enzyme function within specific metabolic pathways, collectively constituting rare conditions with an incidence of less than 1/100,000 births. While IMDs typically manifest with multisystemic symptoms, cardiac manifestations are common, notably hypertrophic cardiomyopathy. Additionally, they can lead to dilated or restrictive cardiomyopathy, as well as noncompacted left ventricular cardiomyopathy. Rhythm disturbances such as atrioventricular conduction abnormalities, Wolff-Parkinson-White syndrome, and ventricular arrhythmias, along with valvular pathologies and ischemic coronary issues, are also prevalent. This study aims to provide a narrative review of IMDs associated with cardiac involvement, delineating the specific cardiac manifestations of each disorder alongside systemic symptoms pivotal for diagnosis.

Lingguizhugan Decoction Improved Obesity by Modulating the Gut Microbiota and its Metabolites in Mice.

The global obese population is rapidly increasing, urgently requiring the development of effective and safe weight-loss medications. The classic Chinese medicine formulation Lingguizhugan De-coction has exerted a significant anti-obesity effect. However, the underlying mechanism is still unclear. This study aimed to explore the mechanism of LGZGD in the treatment of obesity based on the gut microbiota and its metabolites. Three different dosages of LGZGD were gavaged to ob/ob mice for 8 weeks. Body mass and visceral fat mass were evaluated. Additionally, the changes in gut microbiota, fecal and plasma metabolites in mice after LGZGD treatment were analyzed by metagenomics and non-targeted metabolomics. The results demonstrated a significant anti-obesity effect of LGZGD treatment in ob/ob mice. Fur-thermore, the metagenomic analysis revealed that LGZGD reduced the ratio of Firmicutes / Bacteroidetes (F to B) in the gut, restored gut microbiota diversity, and identified 3 enriched KEGG pathways, including energy metabolism, lipid metabolism, and energy production and conversion pathways. Based on non-targeted metab-olomics analysis, 20 key metabolites in the feces and 30 key metabolites in the plasma responding to LGZGD treatment were identified, and the levels of Eicosapentaenoic acid (EPA) and Myristoleic acid (MA) might be the metabolites related to gut microbiota after LGZGD treatment. Their biological functions were mainly re-lated to the metabolism pathway. These findings suggested that LGZGD had therapeutic potential for obesity. The mechanism of LGZGD alleviating obesity was associated with improving dysbiosis of the gut microbiota. LDZGD affected gut microbiota-derived metabolites of EPA and MA and may act on energy metabolism pathways.

Elucidating of the metabolic impact of risperidone on brain microvascular endothelial cells using untargeted metabolomics-based LC-MS

Risperidone is useful for the treatment of schizophrenia symptoms; however, it also has side effects, and an overdose can be harmful. The metabolic effects of risperidone at high therapeutic doses and its metabolites have not been elucidated. Endogenous cellular metabolites may be comprehensively analyzed using untargeted metabolomics-based liquid chromatography-mass spectrometry (LC-MS), which can reveal changes in cell regulation and metabolic pathways. By identifying the metabolites and pathway changes using a nontargeted metabolomics-based LC-MS approach, we aimed to shed light on the potential toxicological effects of high-dose risperidone on brain microvascular endothelial cells (MVECs) associated with the human blood brain barrier. A total of 42 metabolites were selected as significant putative metabolites of the toxicological response of high-dose risperidone in MVECs. Six highly correlated pathways were identified, including those involving diacylglycerol, fatty acid, ceramide, glycerophospholipid, amino acid, and tricarboxylic acid metabolism. We demonstrated that methods focused on metabolomics are useful for identifying metabolites that may be used to clarify the mechanism of drug-induced toxicity.

Urolithiasis Causes Osteoporosis in Asians: Genetic Evidence from Mendelian Randomization and Pathway Analysis.

It is an indisputable fact that patients with urolithiasis are prone to osteoporosis (OP), but the specific mechanism of their association is unclear. Previous studies have focused on the mediation of environmental factors such as diet; however, the potential of urolithiasis itself to induce OP remains uncertain. In this study, we used data from the Japan BioBank (6,638 urolithiasis and 7,788 OP cases) to investigate the direct causal relationship and mechanism between urolithiasis and OP, applying Mendelian randomization (MR), genetic correlation analysis, colocalization, and pathway analysis. We selected ten genetic variants as instrumental variables (IVs) for urolithiasis. The results showed a positive association between genetically predicted urolithiasis and OP, with significant direct effects persisting after adjusting for OP-associated factors in four models. Reverse analysis revealed no significant causal effect of genetically predicted OP on urolithiasis. While genetic correlation analysis and colocalization did not find conclusive evidence, mediation analysis identified eGFR as a significant contributor. Co-risk factor analysis unveiled cardiovascular elements as common risks for both conditions. Bioanalysis implicates cytokine, metabolic, and calcium signaling pathways may bridge urolithiasis and OP, with BCAS3, DGKH, TBX2, and TBX2-AS1 identified as potential causal genes. In conclusion, the study establishes a direct causal link between urolithiasis and OP, independent of environmental factors. Regardless of lifestyle, urolithiasis patients should remain vigilant about the risk of OP and consider regular OP screening. The biological mechanism of urolithiasis combined with OP and related drugs still needs to be further explored.