Serum Metabolomics Research Articles

Restorative mechanisms of Shugan Yiyang capsule on male infertility through 'pharmaco-metabo-net' tripartite correlation analysis.

Restorative mechanisms of Shugan Yiyang capsule on male infertility through 'pharmaco-metabo-net' tripartite correlation analysis.

Exploring the mechanism of action of Bailemian capsule in the treatment of insomnia based on metabolomics, 16S rRNA with UPLC-QE-Orbitrap-MS/MS.

Exploring the mechanism of action of Bailemian capsule in the treatment of insomnia based on metabolomics, 16S rRNA with UPLC-QE-Orbitrap-MS/MS.

Comparison of plasma metabolic profiling between children with hypertrophic obstructive cardiomyopathy and healthy controls.

The diagnostic value of serum metabolomics in congenital heart disease has been proven. The difference of serum metabolomics between children with hypertrophic obstructive cardiomyopathy (HOCM) and normal children is unknown. Fasting blood samples of 24 symptomatic children with HOCM, 11 children with left ventricular outflow tract obstruction because of other cardiac anomalies (non-HOCM group) and 41 normal controls were obtained. The targeted metabolomic approach was performed using a Vanquish ultra-performance liquid chromatography system coupled to a Q-Exactive HF mass spectrometer. The plasma level of 79 out of 224 metabolites were significantly changed (|log2FC| > 1 and P adj. < 0.05) between the HOCM and the normal group. There was no significant difference between the HOCM and non-HOCM groups. A total of 79 significantly changed metabolites between the HOCM and the normal group were significantly enriched in two pathways, including purine metabolism (P < 0.001) and thiamine metabolism (P = 0.034). Our results identified the significant changes of plasma metabolite between children with HOCM and healthy children, which is helpful for understanding the pathogenesis of HOCM and early diagnosis.

D-Psicose mitigates NAFLD mice induced by a high-fat diet by reducing lipid accumulation, inflammation, and oxidative stress

D-Psicose (DPS) serves as an optimal sucrose substitute, providing only 0.3% of sucrose’s energy content, while exhibiting anti-inflammatory properties and inhibiting lipid synthesis. However, its efficacy in managing non-alcoholic fatty liver disease (NAFLD) remains unclear. This study employed network pharmacology and molecular docking to identify potential DPS targets for NAFLD treatment. A high-fat diet was used to induce a NAFLD mouse model, with DPS administered in drinking water at 5% (high dose DPS group, DPSH group) and 2.5% (low dose DPS group, DPSL group) concentrations. After 12 weeks, blood lipid levels, liver lipid deposition, and inflammation were evaluated to assess the therapeutic effects of DPS. To explore its underlying mechanisms, colon contents 16S rRNA sequencing and serum untargeted metabolomics were performed. Results indicated that DPS significantly reduced lipid accumulation and inflammatory damage in the livers of NAFLD mice, improving both blood lipid profiles and oxidative stress. Network pharmacology analysis revealed that DPS primarily targets pathways associated with inflammation and oxidative stress, while molecular docking suggested its potential to inhibit the NF-κB pathway activation and the expression of the receptor for advanced glycation end-products (RAGE), findings corroborated by Western blotting. Additionally, gut microbiota and serum metabolomics analyses demonstrated that DPS improved microbiota composition by increasing the abundance of beneficial bacteria, such as Akkermansia, and restored serum metabolomic balance, enhancing anti-inflammatory and antioxidant metabolites like Tretinoin and Pyridoxamine. The non-targeted metabolomics results suggest that DPS is mediated by glutathione metabolism, arginine and proline metabolism, unsaturated fatty acid biosynthesis, and linoleic acid metabolism interferes with NAFLD progression. In conclusion, DPS may alleviate oxidative stress and lipid accumulation in NAFLD mice through the AGEs/RAGE/NF-κB pathway, while also ameliorating gut microbiota dysbiosis and serum metabolomic disturbances, fostering the production of anti-inflammatory and antioxidant metabolites.

Tryptophan metabolites exert potential therapeutic activity in graves' orbitopathy by ameliorating orbital fibroblasts inflammation and proliferation.

Graves' orbitopathy (GO) is a sight-threatening organ-specific autoimmune disease with complicated pathogenesis. Gut microbiota-derived tryptophan (Trp) metabolites play important roles in immune-related diseases, but their role in GO remains unknown. Trp metabolism-associated gut flora was analyzed by 16S sequencing in GO patients and controls. Serum metabolomics profiling was performed to assess Trp metabolic pathway. Trp metabolites levels were measured by ELISA in 401 serum samples from a case-control study, and their effects on inflammation and proliferation in orbital fibroblasts were evaluated in vitro. Trp metabolism-associated gut flora, including phylum Firmicutes and genus Anaerostipes, were significantly down-regulated in GO patients. Serum metabolomics revealed significant enrichment of Trp metabolic pathway in both GO and Graves' disease (GD) groups. Serum levels of indolepropionic acid (IPA), indole-3-lactate (ILA), and indoleacetic acid (IAA) were significantly decreased in both GD and GO patients compared to controls, with IAA levels further reduced in GO compared to GD patients. Notably, active GO patients had significantly lower IAA levels compared to inactive ones. Moreover, the levels of IAA were negatively correlated with clinical activity score and serum thyrotropin receptor antibody (TRAb) in GO patients. In vitro, IPA, ILA, and IAA mitigated TNFα-induced inflammation and proliferation in orbital fibroblasts by suppressing the Akt signaling pathway. Trp metabolites IAA maybe a novel biomarker for GO progression. And IPA, ILA and IAA may play a protective role in GO by regulating inflammation and proliferation in orbital fibroblasts, suggesting their potential as therapeutic targets for GO treatment.

Clostridium butyricum Ameliorates Atherosclerosis by Regulating Host Linoleic Acid Metabolism

Dysbiosis of the gut microbiota is strongly implicated in atherosclerosis (AS), thus prompting microbial modulation to be explored as a therapeutic strategy. However, limited evidence exists for probiotic interventions capable of alleviating AS. Here, we focused on Clostridium butyricum (C. butyricum; CB), a probiotic known for its production of short-chain fatty acids (SCFAs). We found that administration of C. butyricum to high-fat diet (HFD)-fed Apoe deficient (Apoe−/−) mice reduced plaque area by improving blood lipid profiles, decreasing macrophage infiltration in the aortic roots, and lowering the levels of circulating pro-inflammatory monocytes and macrophages. By non-targeted serum metabolomics analysis, C. butyricum treatment significantly reduced the levels of both linoleic acid and its downstream metabolites. Collectively, these findings establish C. butyricum-mediated amelioration of AS through modulation of linoleic acid metabolism.

Identification of serum metabolic markers in non-obese hypertensive patients using non-targeted metabolomics

The future of hypertension management lies in distinguishing disease subtypes for precise control. The underlying drivers and pathology of non-obese hypertension (J-HTN) remain unclear. There is a lack of biomarkers for the early identification of J-HTN. The aim of this study was to identify circulating metabolomic profiles that facilitate the early detection of J-HTN patients, thereby providing valuable insights for more targeted and precision-based therapies. A non-targeted metabolomics approach was used to quantify serum metabolites in 120 patients with newly diagnosed hypertension, and to determine the metabolomic characteristics of J-HTN and two types of obese hypertension (fat-dominant and muscle-dominant). 4 metabolites unique to J-HTN were identified, with lysophosphatidylcholine 22:6 (LysoPC(22:6/0:0)) standing out as the marker showing the most pronounced difference. Using the serum metabolome alone, we were able to distinguish J-HTN from other hypertensive patients. In a secondary validation with an independent cohort of 60 medically treated J-HTN patients, 3 metabolites, including LysoPC(22:6/0:0), remained significantly altered. The serum metabolic profiles identified in this study enable the early detection of J-HTN, with LysoPC(22:6/0:0) emerging as a highly promising biomarker. This metabolite may also correlate with the clinical efficacy of J-HTN treatments.

Characterizing the metabolome of children with growth hormone deficiency.

Growth hormone deficiency (GHD) diagnosis requires inadequate GH responses to two provocative tests, which are time-consuming and may cause side effects. Recent advancements in serum metabolomics offer potential novel biomarkers for medical conditions. This study investigated serum metabolomics in children with GHD to explore new diagnostic approaches and identify altered biological pathways. We conducted a prospective study of 68 children (aged 3-18 years) undergoing growth hormone stimulation tests (GHST). Children with genetic syndromes, systemic illnesses, or end-stage renal disease were excluded. Untargeted metabolomics analysis using liquid chromatography-mass spectrometry (LC-MS) identified 951 circulating metabolites (280 polar and 671 lipids). From the 68 children evaluated, 25 children were diagnosed with GHD, and 41 children served as controls. Two children exhibited a suboptimal GH peak during the first GHST but did not undergo a second confirmatorytest. Significant differences were observed in 7 polar metabolites and 50 lipids between groups, but only phosphatidylserine (PS) (40:3) remained significant after false discovery rate correction. Cluster analysis revealed two lipid clusters significantly associated with GHD. Greater separation in metabolomic profiles was observed when a lower GH threshold was applied for diagnosis. This study provides proof of concept for a unique lipidomics profile in children with GHD, highlighting its potential as a diagnostic tool. Larger-scale studies are required to validate these findings.

Effects of Exercise on Gut Microbiome and Serum Metabolomics in Post-Traumatic Osteoarthritis Rats.

Objective: The aim of this work is to investigate the impact of exercise on gut microbiome composition, serum metabolites, and their correlation with osteoarthritis (OA) severity. Methods: Thirty-six Sprague-Dawley (SD) rats were randomly divided into four groups: Sham rats without treadmill walking (Sham/Sed group, n = 9), Sham rats with treadmill walking 2 months (Sham/TW2M group, n = 9), PTOA rats without treadmill walking (PTOA/Sed group, n = 9), and PTOA rats with treadmill walking 2 months (PTOA/TW2M group, n = 9). The PTOA model was induced by transection of the anterior cruciate ligament (ACLT) and destabilization of the medial meniscus (DMM). Histological evaluation and micro-CT analysis were performed to observe the pathological changes in cartilage and subchondral bone, respectively. Additionally, we conducted 16S rDNA sequencing of fecal samples and untargeted metabolomic analysis using liquid chromatography-mass spectrometry (LC-MS) of serum samples to detect the alteration of gut microbiota composition and metabolites. Results: Exercise effectively mitigated OA-related pathological changes, including articular cartilage degeneration and subchondral bone loss. Moreover, 16S rDNA sequencing analysis of gut microbiome revealed a decreased abundance of Bacteroidetes (p < 0.01), Bacteroidia (p < 0.01), Rikenellaceae (p < 0.01), [Paraprevotellaceae] (p < 0.01), and Paraprevotella (p < 0.01) but an increase in Firmicutes (p < 0.01) in PTOA/TW2M group rats compared with PTOA/Sed group as a response to exercise. In addition, the results of metabolomics analysis showed that exercise treatment contributed to the upregulation of Daidzein and Anthranilic acid and downregulation of 1-Palmitoyllysophosphatidylcholine. Moreover, the correlation analysis showed that Rikenellaceae significantly positively correlated with both OARSI (r = 0.81, p < 0.01) and Mankin score (r = 0.83, p < 0.01) and negatively correlated with the serum level of Anthranilic acid (r = -0.56, p < 0.01) and Daidzein (r = -0.46, p < 0.01). Conclusions: Exercise can effectively mitigate OA through slowing down articular cartilage degeneration and subchondral bone loss, modulating gut microbiota composition, and increasing beneficial metabolites.

Sarcopenia and Skeletal Muscle Loss after CAR T-cell Therapy in Diffuse Large B cell Lymphoma.

Sarcopenia is a hallmark of cancer cachexia. Chimeric antigen receptor (CAR) T-cell therapy is associated with an inflammatory state that may exacerbate sarcopenia. The relationship between CAR T-cell therapy, sarcopenia, and metabolism is poorly understood. In 83 large B-cell lymphoma patients, the skeletal muscle index (SMI) was measured from clinical images obtained at baseline and days 30 and 90 post-therapy. Serum metabolomics (n=57 patients) was performed in the first 4 weeks. Baseline sarcopenia was present in over half of patients and associated with shorter median overall survival (OS) than for non-sarcopenic patients (10.5 versus 34.3 months; P=0.006). This reduction was due to increased non-relapse mortality (NRM) with all six NRM events occurring in patients with baseline sarcopenia. In the first 30 days after CAR T-cell therapy, 1/3 of patients experienced skeletal muscle loss greater than 10%. Muscle loss was associated with higher tumor burden and neurotoxicity but was not significantly associated with long term survival. Serum metabolomics revealed an early (weeks 1-2) increase in purine metabolites, followed by a later (weeks 3-4) increase in triglyceride levels. The serum metabolite with the highest fold-increase from baseline was adipic acid, attributed to the inpatient hospital menu of Jello and other tart beverages. Skeletal muscle loss after CAR T-cell therapy is common and is associated with fatty acid catabolism. Patients with baseline sarcopenia have poor tolerance and reduced survival. Future studies of dietary and exercise interventions may improve CAR T-cell therapy outcomes.

Lipid Subclasses Differentiate Insulin Resistance by Triglyceride-Glucose Index.

Insulin resistance is a key driver of metabolic syndrome and related disorders, yet its underlying metabolic alterations remain incompletely understood. The Triglyceride-Glucose (TyG) index is an emerging, accessible marker for insulin resistance, with growing evidence supporting its clinical utility. This study aimed to characterize the metabolic profiles associated with insulin resistance using the TyG index in a large, population-based cohort, and to identify metabolic pathways potentially implicated in insulin resistance. Here, we conducted a cross-sectional study using data from the Qatar Biobank, including 1255 participants without diabetes classified as insulin-sensitive or insulin-resistant based on TyG index tertiles. Untargeted serum metabolomics profiling was performed using high-resolution mass spectrometry. Our statistical analyses included orthogonal partial least squares discriminate analysis and linear models. Distinct metabolic signatures differentiated insulin-resistant from insulin-sensitive participants. Phosphatidylethanolamines, phosphatidylinositols, and phosphatidylcholines, were strongly associated with insulin resistance, while plasmalogens and sphingomyelins were consistently linked to insulin sensitivity. Lipid-centric pathways emerge as potential biomarkers and therapeutic targets for the early detection and personalized management of insulin resistance and related metabolic disorders. Longitudinal studies are warranted to validate causal relationships.

Serum Metabolomic Profiles Predict Sensitivity and Toxicity to Platinum-Fluorouracil Chemotherapy in a Gastric Cancer Xenograft Model.

The mechanisms of chemotherapy sensitivity and toxicity are complex. Metabolomics can better reflect the status of anticancer drugs, tumors, and hosts simultaneously. To identify metabolites and metabolic pathways linked to varying sensitivity and toxicity to chemotherapy in gastric cancer. Mice were implanted with human gastric cancer cells through subcutaneous xenografting, and then treated with the PF (platinum-fluorouracil) regimen, with saline serving as the control. Tumor growth was monitored by measuring tumor volume, and body weight was recorded on Days 0, 2, 4, 6, and 8. Kidney damage was assessed using H&E staining. To analyze differential responses, PF-treated mice were grouped separately according to chemotherapy sensitivity (high/medium/low via tumor response) and toxicity (high/medium/low via body weight changes). Serum metabolomics was evaluated using Mass Spectrometry. Platinum-Fluorouracil (PF) chemotherapy significantly reduced tumor weight in mice (164.7 ± 73.5 mg vs. 334.0 ± 107.5 mg; 54.4% inhibition rate), although it also induced notable body weight loss and renal toxicity compared to controls. Serum metabolomic analysis revealed significant differences between PF and control groups, involving metabolites like deoxymethacin and dehydrocorticosterone, associated with AMPK and cortisol synthesis/secretion pathways. Further comparisons highlighted: (1) High- vs. low-sensitivity subgroups differed significantly in metabolites, such as palmitoyl-CoA and indoleacetic acid (linked to AGE-RAGE, insulin resistance, and AMPK pathways). (2) High- vs. low-toxicity subgroups displayed significant metabolic differences, including methylguanosine and methylcytidine (implicated in ferroptosis, ether lipid, and fatty acid metabolism pathways). The PF regimen effectively inhibits the growth of subcutaneous tumors in nude mice, while causing varying levels of sensitivity and toxicity in tumor chemotherapy. These observed effects of sensitivity and toxicity are linked to underlying metabolic mechanisms.

Fermented Wheat Germ Ameliorates High-Fat Diet-Induced Maternal Obesity in Rats: Insights from Microbiome and Metabolomics.

Maternal obesity significantly increases the risk of adverse outcomes for the mother and fetus. Fermented wheat germ (FWG) has demonstrated the potential to improve metabolic disorders, yet its effects have not been explored in maternal obesity models. This study investigated the ameliorating impact of FWG in rats with maternal obesity, focusing on its mechanisms through biochemical, gut microbiome, and serum metabolomics analysis. The results demonstrated that FWG was more effective than wheat germ in reducing body weight gain and fat accumulation, improving glycolipid metabolism disorders, and alleviating inflammation. Specifically, FWG modulated the composition of gut microbiota by fostering the growth of beneficial bacteria (e.g., Corynebacterium) while suppressing genera associated with maternal obesity (e.g., Blautia, Akkermansia, Dorea_A, and Faecousia). Furthermore, FWG modified high-fat diet-induced metabolites, primarily affecting pyrimidine metabolism and amino acid metabolism. These findings suggest that FWG may serve as a promising dietary intervention for mitigating maternal obesity and improving pregnancy outcomes.

Serum Metabolite Profile in Progressive Versus Nonprogressive Alcohol-Related Liver Disease: A Cross-Sectional Metabolomics Study.

Alcohol-related liver disease (ALD) is a major cause of mortality and disability-adjusted life years. It is not fully understood why a small proportion of patients develop progressive forms of ALD (e.g., fibrosis and cirrhosis). Differences in the metabolic processes could be behind the individual progression of ALD. Our aim was to examine differences in serum metabolome between patients with nonprogressive ALD and patients with an early form of progressive ALD. The study had three study groups: progressive ALD (alcohol-related steatohepatitis or early-stage fibrosis, n = 50), nonprogressive ALD (simple steatosis, n = 50) and healthy controls (n = 32). Both ALD groups took part in a voluntary alcohol rehabilitation programme. A nontargeted metabolomics analysis and targeted analysis of short-chain fatty acids were done to the serum samples taken on the day of admission. We found 111 significantly (p < 0.0005) altered identified metabolites between the study groups. Our main finding was that levels of glycine-conjugated bile acids (Cohen's d = 0.90-0.91), glutamic acid (d = 1.01), 7-methylguanine (d = 0.77) and several phosphatidylcholines (d = 0.61-0.85) were elevated in the progressive ALD group in comparison to the nonprogressive ALD group. Glycine-conjugated bile acids, glutamic acid and 7-methylguanine also positively correlated with increased levels of aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, cell death biomarker M65 and liver stiffness. Our results indicate that the enterohepatic cycle of glycine-conjugated bile acids, as well as lipid and energy metabolism, is altered in early forms of progressive ALD. These metabolic processes could be a target for preventing the progression of ALD.

Effects and mechanisms of acupuncture for PIGD-subtype Parkinson's disease via integration of fMRI and gut microbiota-metabolomics analysis: protocol for a prospective randomized controlled trial.

Parkinson's disease (PD) can be categorized into various subtypes based on the primary symptoms associated with motor dysfunction. One subtype, known as postural instability and gait difficulty (PIGD), is characterized by severe clinical symptoms, an increased risk of walking difficulties and falls, and a poorer prognosis compared to other subtypes. This condition imposes a significant burden on patients, their families, and the healthcare system. Recently, acupuncture, a practice rooted in traditional Chinese medicine, has gained attention for its potential to influence neurophysiological pathways and enhance the overall brain function in individuals with PD. This randomized controlled study aimed to evaluate the clinical effectiveness of acupuncture in patients with the PIGD subtype of PD and to investigate the preliminary exploration of mechanisms of acupuncture by analyzing intestinal microbiota and metabolomics, thereby providing deeper insights into its impact on patients. This randomized controlled trial will involve 64 patients diagnosed with the PIGD subtype of PD. Participants in both groups will undergo three acupuncture sessions weekly for a duration of 4 weeks, followed by an 8-week follow-up period. The primary outcome measure will be the Unified Parkinson's Disease Rating Scale III. Secondary outcomes will include the Berg Balance Scale (BBS), wearable gait analysis, and functional magnetic resonance imaging (fMRI). Additionally, serum and stool samples will be collected for 16S ribosomal RNA sequencing, and liquid chromatography coupled with tandem mass spectrometry analysis (LC-MS/MS) will be employed to elucidate theunderlying mechanisms. This trial has been reviewed and approved by the Medical Ethics Committee of Zhejiang Hospital (Approval no. 2023-15 K). Participation in this study will require written informed consent from all patients. The findings of this study will be published in a peer-reviewed journal, and there will be no restrictions on publication. In this study, we integrate traditional assessment scales with fMRI to demonstrate the therapeutic effects of acupuncture. We will also analyze the modulation of gut microbiota and serum metabolome to explore the underlying neural mechanisms. Our results will provide a foundation for future studies in this area. https://www.chictr.org.cn, identifier ChiCTR2300071703.

Effects of combining yeast products with antimicrobials in grain adaptation diets for feedlot Nellore bulls on performance, behavior, and metabolome

This study evaluated the effects of different combinations of yeast products and antimicrobials during adaptation to high-grain feedlot diets on performance, feeding behavior, carcass traits, and the serum metabolome of feedlot Nellore bulls. One hundred twenty Nellore bulls were divided into two body weight groups and assigned within groups to 24 pens. The following dietary treatments were applied: MVY: monensin at 18 mg/kg of dry matter (DM) + virginiamycin at 15 mg/kg of DM + live yeast at 2 g/animal/day; NLY: narasin at 13 mg/kg of DM + live yeast at 2 g/animal/day; NYC: narasin at 13 mg/kg of DM + yeast culture at 7 g/animal/day; NDY: narasin at 13 mg/kg of DM + active dry yeast at 1 g/animal/day. Treatments were administered during the grain adaptation period (d1–d21). Blood samples were collected at the end of the grain adaptation period for serum metabolome profiling. During the 21-day grain adaptation period, bulls fed NYC tended (P = 0.09) to have a greater average daily gain than bulls fed MVY. Dry matter intake (DMI), final body weight, and feed efficiency were similar (P &amp;gt; 0.05) among treatments. During the finishing period, bulls fed NLY had a lower (P = 0.04) DMI as a percentage of body weight than bulls receiving MVY. There were no treatment effects (P &amp;gt; 0.05) on the carcass traits. Bulls fed NDY spent more time resting (P = 0.03) and tended (P ≤ 0.10) to have fewer meals per day and greater DMI per meal than animals fed MVY. Lactate was the most important serum metabolite for discriminating all treatment groups, with a higher concentration in the MVY group. The three most important metabolites for discriminating the MVY and NLY groups were lactate, creatine, and valine, whose concentrations were higher in the MVY group. The three most important metabolites for discriminating MVY and NYC were 3-phenylpropionate, hippurate, and betaine, whose concentrations were higher in the NYC group. Thus, narasin can replace the combination of monensin and virginiamycin in high-grain adaptation diets for Nellore bulls when administered together with yeast products, with the NYC combination showing great potential.

Patients with periodontitis exhibit persistent dysbiosis of the gut microbiota and distinct serum metabolome

ABSTRACT Objectives Animal studies suggest that periodontopathic bacteria induce gut dysbiosis and related pathology, possibly connecting periodontitis to non-oral diseases. However, the effects on the gut ecosystem in periodontitis patients are not fully understood. Methods We conducted a comprehensive analysis of the salivary and gut microbiota using 16S rRNA sequencing in periodontitis patients before and after treatment, comparing them to healthy participants. Serum metabolites were also analyzed. Results Periodontitis patients showed high alpha diversity in both salivary and gut microbiota with a strong correlation. Significant differences were also observed in the gut microbiota composition between patients before treatment and healthy participants, irrespective of the ectopic colonization of periodontitis-associated bacteria in the gut. Co-abundance group analysis demonstrated that the gut microbiota of healthy participants was enriched with short-chain fatty acid producers. Changes in the gut microbiota coincided with alterations in the serum metabolite profile. While periodontal therapy improved salivary microbiota, it did not significantly affect gut microbiota. Conclusions Gut dysbiosis of periodontitis patients may impact systemic metabolite profiles. Given that periodontal therapy alone did not substantially improve the gut microbiota, adjunctive strategies targeting the gut microbiome may be effective in reducing the risk of periodontitis-associated diseases.

Unveiling the pharmacological mechanisms of Spirulina platensis in rheumatoid arthritis rats through the integration of serum metabolomics, pathways analysis, and experimental validation.

Rheumatoid arthritis (RA) is an autoimmune disease primarily manifested by insistent proliferative synovitis, joint degradation, and bone erosions with no targeted therapy yet. Spirulina platensis serves as a treasure house of bioactive compounds with potential significance against different inflammatory ailments. Inspired by the potentiating biological attributes of S. platensis, the current investigation is concerned with dissecting the mechanistic basis of S. platensis against rheumatoid arthritis (RA) through a series of biochemical and histopathological assessments integrated with a serum metabolomics strategy to explore more efficacious and safe alternative therapies to rectify RA. Firstly, a rat model of RA was established using complete Freund's adjuvant (CFA), and RA-related biochemical and histopathological scores were determined as monitoring indexes for control efficiency of S. platensis against RA. Serum metabolomics was adopted to profile the potential biomarkers and their corresponding metabolic pathways modulated by Spirulina through UPLC-MS/MS analysis integrated with chemometrics and MetaboAnalyst 5.0 pathway analysis. The results demonstrated that Spirulina exerted significantly modulatory effects in the CFA model by reducing systemic manifestations of oxidative stress, inflammation, and impaired liver and kidney functions typically exemplified by catalase (CAT), superoxide dismutase (SOD), reduced glutathione (GSH), rheumatoid factor (RF), monocyte chemotactic protein 1 (MCP-1), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6), as well as alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, and urea. Histopathological investigations have revealed that Spirulina intervention causes moderately lower inflammatory cells infiltrations, synovial hyperplasia, and cartilage destruction. Regarding serum metabolomics, Spirulina could remarkably reverse disordered RA-associated metabolites, namely glutamic acid, arachidonic acid, 5-hydroxyeicosatetraenoic acid, (20:4/18:0) phosphatidylcholine, and citric acid, to a normal-like state through modulating arachidonic acid metabolism, alanine, aspartate and glutamate metabolism, and citrate cycle pathways putatively implicated in inflammation and joint damage. Our findings provide compelling evidence that S. platensis possesses a broad spectrum of mechanisms to restore the disrupted homeostasis in RA by multi-targeted, synergistic actions.

Gut microbiota dysbiosis orchestrates vitiligo-related oxidative stress through the metabolite hippuric acid

BackgroundVitiligo, a depigmenting autoimmune skin disease characterized by melanocyte dysfunction or death, is known to be associated with an imbalance in gut microbiota. Oxidative stress plays a critical role in the pathogenesis of vitiligo. However, the complex promising interaction between abnormal accumulation of reactive oxygen species (ROS) in the skin and gut microbiota has remained unclear.ResultsHere, we compared transcriptome data of vitiligo lesions and normal skin and identified a high expression of oxidative stress-related genes in vitiligo lesions. We also established a vitiligo mouse model and found that the presence of gut microbiota influenced the expression of ROS-related genes. Depletion of gut microbiota reduced abnormal ROS accumulation and mitochondrial abnormalities in melanocytes, significantly improving depigmentation. Our findings from manipulating gut microbiota through cohousing, fecal microbiota transplantation (FMT), and probiotic supplementation showed that transferring gut microbiota from mice with severe vitiligo-like phenotypes exacerbated skin depigmentation while probiotics inhibited its progression. Targeted metabolomics of fecal, serum, and skin tissues revealed gut microbiota-dependent accumulation of hippuric acid, mediating excessive ROS in the skin. Elevated serum hippuric acid levels were also confirmed in vitiligo patients. Additionally, a microbiota-dependent increase in intestinal permeability in vitiligo mice mediated elevated hippuric acid levels, and we found that hippuric acid could directly bind to ROS-related proteins (NOS2 and MAPK14).ConclusionsOur results suggested the important role of gut microbiota in regulating vitiligo phenotypes and oxidative stress. We identified hippuric acid, a gut microbiota-host co-metabolite, as a critical mediator of oxidative stress in vitiligo skin and its binding targets (NOS2 and MAPK14), resulting in oxidative stress. Validation in a small human cohort suggested that hippuric acid could serve as a novel diagnostic biomarker and therapeutic target for vitiligo. These findings provided new insights into how gut microbiota regulates skin oxidative stress in vitiligo and suggested potential treatment strategies for the disease.8-83LeDu4YFos1a_9ZYpcdVideo

Traditional Chinese medicine Youguiyin decoction ameliorate glucocorticoid-induced osteonecrosis in rat by modulating ROS/PHD2/HIF-1α oxidative stress signaling pathway in bone marrow mesenchymal stem cells

BackgroundThe incidence of osteonecrosis is increasing annually due to the widespread use of glucocorticoids. Recent evidence suggests a significant association between glucocorticoid-induced osteonecrosis and oxidative stress. Youguiyin (YGY) decoction, a classic formula of traditional Chinese medicine, has been widely used for the prevention of glucocorticoid-induced osteonecrosis. However, its underlying pharmacological mechanisms are still not fully understood.MethodsUPLC-Q-TOF–MS and network pharmacology were used to elucidate the material basis of YGY decoction and its mechanism for the treatment of glucocorticoid-induced osteonecrosis. The anti-oxidative stress and bone-enhancing effects in vivo were detected by hematoxylin–eosin (HE) staining, serum metabolomics, enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC), and Western Blot (WB). Rat bone marrow mesenchymal stem cells (BMSCs) were induced with dexamethasone (DXMS) for 24 h, followed by YGY medicated serum for 24 h. Significantly up- and down-regulated genes were detected by RNA sequencing. Oxidative stress levels were detected by ROS fluorescence. Alizarin red S staining was used to detect osteogenic effects. WB and ELISA were used to detect the expression of proteins related to the ROS/PHD2/HIF-1a pathway.ResultsThe application of YGY decoction significantly promoted bone repair and antagonized excess reactive oxygen species (ROS) generation in glucocorticoid-associated osteonecrosis of the femoral head (GA-ONFH) rats. In addition, YGY medicated serum antagonized DXMS-induced ROS production and promoted osteogenic differentiation in BMSCs. We also found that YGY medicated serum attenuated excess ROS generation while PHD2 expression was significantly increased, HIF-1α expression was significantly decreased and RUNX2 expression was significantly increased.ConclusionThese results provide compelling in vivo and in vitro evidence that YGY decoction may play a role in promoting glucocorticoid-induced osteonecrosis bone repair by targeting the mediation of the ROS/PHD2/HIF-1α oxidative stress signaling pathway, thus providing a new theoretical basis for the clinical application of YGY decoction to glucocorticoid-induced osteonecrosis.Graphical