PubMed

Metab Brain Dis. 2024 Jul 9. doi: 10.1007/s11011-024-01376-x. Online ahead of print.ABSTRACTIn this paper we investigated lipid and metabolite changes in diabetic neuropathy, using untargeted lipidomics and metabolomics analyses of the spinal cords from streptozotocin-treated diabetic rats.170 metabolites and 45 lipids were dysregulated in the painful diabetic neuropathy (PDN) phase. Pathway enrichment analysis revealed perturbations in starch and sucrose, tryptophan, pyrimidine, cysteine and methionine, thiamine, tyrosine, and nucleotides. The disturbance of tyrosine, tryptophan, methionine, triacylglycerol, and phosphatidylethanolamine metabolism indicated that pathological mechanisms in the PDN involved energy metabolism, oxidative stress, and neural reparative regeneration. These revelations offered potential biomarkers for PDN and enriched the comprehension of the complex molecular mechanisms characterizing PDN, establishing a solid foundation for subsequent inquiries into neural convalescence and recovery after PDN.PMID:38980579 | DOI:10.1007/s11011-024-01376-x

Metabolomics. 2024 Jul 9;20(4):75. doi: 10.1007/s11306-024-02138-7.ABSTRACTINTRODUCTION: Microbial communities affect several aspects of the earth's ecosystem through their metabolic interaction. The dynamics of this interaction emerge from complex multilevel networks of crosstalk. Elucidation of this interaction could help us to maintain the balance for a sustainable future.OBJECTIVES: To investigate the chemical language among highly abundant microbial genera in the rhizospheres of medicinal plants based on the metabolomic analysis at the interaction level.METHODS: Coculturing experiments involving three microbial species: Aspergillus (A), Trichoderma (T), and Bacillus (B), representing fungi (A, T) and bacteria (B), respectively. These experiments encompassed various interaction levels, including dual cultures (AB, AT, TB) and triple cultures (ATB). Metabolic profiling by LC-QTOFMS revealed the effect of interaction level on the productivity and diversity of microbial specialized metabolites.RESULTS: The ATB interaction had the richest profile, while the bacterial profile in the monoculture condition had the lowest. Two native compounds of the Aspergillus genus, aspergillic acid and the dipeptide asperopiperazine B, exhibited decreased levels in the presence of the AT interaction and were undetectable in the presence of bacteria during the interaction. Trichodermarin N and Trichodermatide D isolated from Trichoderma species exclusively detected during coexistence with bacteria (TB and ATB). These findings indicate that the presence of Bacillus activates cryptic biosynthetic gene clusters in Trichoderma. The antibacterial activity of mixed culture extracts was stronger than that of the monoculture extracts. The TB extract exhibited strong antifungal activity compared to the monoculture extract and other mixed culture treatments.CONCLUSION: The elucidation of medicinal plant microbiome interaction chemistry and its effect on the environment will also be of great interest in the context of medicinal plant health Additionally, it sheds light on the content of bioactive constituents, and facilitating the discovery of novel antimicrobials.PMID:38980562 | DOI:10.1007/s11306-024-02138-7

Metabolomics. 2024 Jul 9;20(4):74. doi: 10.1007/s11306-024-02137-8.ABSTRACTBACKGROUND AND AIMS: Biopterins, including tetrahydrobiopterin (BH4), dihydrobiopterin (BH2), and biopterin (B), were crucial enzyme cofactors in vivo. Despite their recognized clinical significance, there remain notable research gaps and controversies surrounding experimental outcomes. This study aims to clarify the biopterins-related issues, including analytical art, physiological intervals, and pathophysiological implications.MATERIALS AND METHODS: A novel LC-MS/MS method was developed to comprehensively profile biopterins in plasma, utilizing chemical derivatization and cold-induced phase separation. Subsequently, apparently healthy individuals were enrolled to investigate the physiological ranges. And the relationships between biopterins and biochemical indicators were analyzed to explore the pathophysiological implications.RESULTS: The developed method was validated as reliable for detecting biopterins across the entire physiological range. Timely anti-oxidation was found to be essential for accurate assessment of biopterins. The observed overall mean ± SDs levels were 3.51 ± 0.94, 1.54 ± 0.48, 2.45 ± 0.84 and 5.05 ± 1.14 ng/mL for BH4, BH2, BH4/BH2 and total biopterins. The status of biopterins showed interesting correlations with age, gender, hyperuricemia and overweight.CONCLUSION: In conjunction with proper anti-oxidation, the newly developed method enables accurate determination of biopterins status in plasma. The observed physiological intervals and pathophysiological implications provide fundamental yet inspiring support for further clinical researches.PMID:38980520 | DOI:10.1007/s11306-024-02137-8

Fish Physiol Biochem. 2024 Jul 9. doi: 10.1007/s10695-024-01377-8. Online ahead of print.ABSTRACTSturgeons are ancient fish, with 27 species distributed in the Northern Hemisphere. This review first touches upon the significance of sturgeons in the context of their biological, ecological, and economic importance, highlighting their status as "living fossils" and the challenges they face in genomic research due to their diverse chromosome numbers. This review then discusses how omics technologies (genomics, transcriptomics, proteomics, and metabolomics) have been used in sturgeon research, which so far has only been done on Acipenser species. It focuses on metabolomics as a way to better understand how sturgeons work and how they react to their environment. Specific studies in sturgeon metabolomics are cited, showing how metabolomics has been used to investigate various aspects of sturgeon biology, such as growth, reproduction, stress responses, and nutrition. These studies demonstrate the potential of metabolomics in improving sturgeon aquaculture practices and conservation efforts. Overall, the review suggests that metabolomics, as a relatively new scientific tool, has the potential to enhance our understanding of sturgeon biology and aid in their conservation and sustainable aquaculture, contributing to global food security efforts.PMID:38980504 | DOI:10.1007/s10695-024-01377-8

Metabolomics. 2024 Jul 9;20(4):73. doi: 10.1007/s11306-024-02135-w.ABSTRACTINTRODUCTION: During the Metabolomics 2023 conference, the Metabolomics Quality Assurance and Quality Control Consortium (mQACC) presented a QA/QC workshop for LC-MS-based untargeted metabolomics.OBJECTIVES: The Best Practices Working Group disseminated recent findings from community forums and discussed aspects to include in a living guidance document.METHODS: Presentations focused on reference materials, data quality review, metabolite identification/annotation and quality assurance.RESULTS: Live polling results and follow-up discussions offered a broad international perspective on QA/QC practices.CONCLUSIONS: Community input gathered from this workshop series is being used to shape the living guidance document, a continually evolving QA/QC best practices resource for metabolomics researchers.PMID:38980450 | DOI:10.1007/s11306-024-02135-w

J Cell Biol. 2024 Sep 2;223(9):e202310049. doi: 10.1083/jcb.202310049. Epub 2024 Jul 9.ABSTRACTAutophagy is essential for maintaining glucose homeostasis. However, the mechanism by which cells sense and respond to glucose starvation to induce autophagy remains incomplete. Here, we show that calcium serves as a fundamental triggering signal that connects environmental sensing to the formation of the autophagy initiation complex during glucose starvation. Mechanistically, glucose starvation instigates the release of vacuolar calcium into the cytoplasm, thus triggering the activation of Rck2 kinase. In turn, Rck2-mediated Atg11 phosphorylation enhances Atg11 interactions with Bmh1/2 bound to the Snf1-Sip1-Snf4 complex, leading to recruitment of vacuolar membrane-localized Snf1 to the PAS and subsequent Atg1 activation, thereby initiating autophagy. We also identified Glc7, a protein phosphatase-1, as a critical regulator of the association between Bmh1/2 and the Snf1 complex. We thus propose that calcium-triggered Atg11-Bmh1/2-Snf1 complex assembly initiates autophagy by controlling Snf1-mediated Atg1 activation in response to glucose starvation.PMID:38980288 | DOI:10.1083/jcb.202310049

Microbiol Spectr. 2024 Jul 9:e0005224. doi: 10.1128/spectrum.00052-24. Online ahead of print.ABSTRACTThis study aims to explore the link between retinal vein occlusion (RVO), a blinding ocular condition, and alterations in gut microbiota composition, to offer insights into the pathogenesis of RVO. Fecal samples from 25 RVO patients and 11 non-RVO individuals were analyzed using 16S rRNA sequencing and liquid chromatography-mass spectrometry (LC-MS). Significant differences in the abundance of gut microbial species were noted between RVO and non-RVO groups. At the phylum level, the RVO group showed an elevation in the ratio of Firmicutes to Bacteroidetes. At the genus level, the RVO group showed higher abundance in Escherichia_Shigella (P < 0.05) and less abundance in Parabacteroides (P < 0.01) than the non-RVO group. Functional predictions indicated reduced folate synthesis, biotin metabolism, and oxidative phosphorylation, with an increase in butyric acid metabolism in the RVO group. LC-MS analysis showed significant differences in purine metabolism, ABC transporters, and naphthalene degradation pathways, especially purine metabolism. Pearson correlation analysis revealed significant associations between bacterial genera and fecal metabolites. Enrichment analysis highlighted connections between specific metabolites and bacterial genera. The findings showed that the dysregulation of gut microbiota was observed in RVO patients, suggesting the gut microbiota as a potential therapeutic target. Modulating the gut microbiota could be a novel strategy for managing RVO and improving patient outcomes. Furthermore, the study findings suggest the involvement of gut microbial dysbiosis in RVO development, underscoring the significance of understanding its pathogenesis for effective treatment development.IMPORTANCE: Retinal vein occlusion (RVO) is a blinding ocular condition, and understanding its pathogenesis is crucial for developing effective treatments. This study demonstrates significant differences in gut microbiota composition between RVO patients and non-RVO individuals, implicating the involvement of gut microbial dysbiosis in RVO development. Functional predictions and metabolic profiling provide insights into the underlying mechanisms, highlighting potential pathways for therapeutic intervention. These findings suggest that modulating the gut microbiota might be a promising strategy for managing RVO and improving patient outcomes.PMID:38980030 | DOI:10.1128/spectrum.00052-24

Pest Manag Sci. 2024 Jul 9. doi: 10.1002/ps.8282. Online ahead of print.ABSTRACTBACKGROUND: Monochamus saltuarius is a destructive trunk-borer of pine forest and an effective dispersal vector for pinewood nematode (PWN), a causative agent of pine wilt disease (PWD), which leads to major ecological disasters. Cold winter temperatures determine insect survival and distribution. However, little is known about the cold tolerance and potential physiological mechanisms of M. saltuarius.RESULTS: We demonstrated that dead Pinus koraiensis trunks do not provide larvae with insulation. The M. saltuarius larvae are freeze-tolerant species. Unlike most other freeze-tolerant insects, they can actively freeze extracellular fluid at higher subzero temperatures by increasing their supercooling points. The main energy sources for larvae overwintering are glycogen and the mid-late switch to lipid. The water balance showed a decrease in free and an increase in bound water of small magnitude. Cold stress promoted lipid peroxidation, thus activating the antioxidant system to prevent cold-induced oxidative damage. We found eight main pathways linked to cold stress and 39 important metabolites, ten of which are cryoprotectants, including maltose, UDP-glucose, d-fructose 6P, galactinol, dulcitol, inositol, sorbitol, l-methionine, sarcosine, and d-proline. The M. saltuarius larvae engage in a dual respiration process involving both anaerobic and aerobic pathways when their bodily fluids freeze. Cysteine and methionine metabolism, as well as alanine, aspartate, and glutamate metabolism, are the most important pathways linked to antioxidation and energy production.CONCLUSIONS: The implications of our findings may help strengthen and supplement the management strategies for monitoring, quarantine, and control of this pest, thereby contributing to controlling the further spread of PWD. © 2024 Society of Chemical Industry.PMID:38979967 | DOI:10.1002/ps.8282

Anal Chem. 2024 Jul 9. doi: 10.1021/acs.analchem.4c01494. Online ahead of print.ABSTRACTAn effective tool to assess embryo quality in the assisted reproduction clinical practice will enhance successful implantation rates and mitigate high risks of multiple pregnancies. Potential biomarkers secreted into culture medium (CM) during embryo development enable rapid and noninvasive methods of assessing embryo quality. However, small volumes, low biomolecule concentrations, and impurity interference collectively preclude the identification of quality-related biomarkers in single blastocyst CM. Here, we developed a noninvasive trace multiomics approach to screen for potential markers in individual human blastocyst CM. We collected 84 CM samples and divided them into high-quality (HQ) and low-quality (LQ) groups. We evaluated the differentially expressed proteins (DEPs) and metabolites (DEMs) in HQ and LQ CM. A total of 504 proteins and 189 metabolites were detected in individual blastocyst CM. Moreover, 9 DEPs and 32 DEMs were identified in different quality embryo CM. We also categorized HQ embryos into positive implantation (PI) and negative implantation (NI) groups based on ultrasound findings on day 28. We identified 41 DEPs and 4 DEMs associated with clinical implantation outcomes in morphologically HQ embryos using a multiomics analysis approach. This study provides a noninvasive multiomics analysis technique and identifies potential biomarkers for clinical embryo developmental quality assessment.PMID:38979898 | DOI:10.1021/acs.analchem.4c01494

Andrology. 2024 Jul 9. doi: 10.1111/andr.13678. Online ahead of print.ABSTRACTBACKGROUND: Understanding the pathogenesis of unexplained recurrent pregnancy loss is paramount for advancing effective treatments. Various biological processes, including spermatogenesis and embryo development, are tightly regulated by N6-methyladenosine modifications. However, few studies have focused on the impact of sperm N6-methyladenosine modifications on embryonic development. Therefore, we aimed to study altered N6-methyladenosine-mediated messenger RNA methylation modifications in the spermatozoa of male partners from couples experiencing unexplained recurrent pregnancy loss, to identify potential diagnostic markers and explore their potential molecular mechanisms in pregnancy loss and embryogenesis.METHODS: Methylated RNA immunoprecipitation (MeRIP) sequencing and RNA sequencing were conducted on the spermatozoa of men from couples in the 'unexplained recurrent pregnancy loss' group (n = 6), and the fertility control group (n = 6). To identify the role of the detected key genes, zebrafish model embryos were studied, and multi-omics (transcriptomics, proteomics, and metabolomics) analyses helped to explore the molecular mechanism of abnormal embryogenesis.FINDINGS: Comparing unexplained recurrent pregnancy loss with the fertility control group, 217 N6-methyladenosine peaks were significantly upregulated, and 40 were downregulated in the spermatozoa. The combined analyses of spermatozoa-methylated RNA immunoprecipitation sequencing and RNA sequencing indicated that N6-methyladenosine methylation and the expression of SEMA5A, MT-ATP6, ZNF662, and KDM4C were significantly different. In zebrafish embryos, the altered expression of the four genes increased embryonic mortality and malformations by disturbing several key signaling pathways and zygotic genome activation.INTERPRETATION: This study highlights the paternal epigenome, which could be one of the reasons for faulty embryogenesis leading to pregnancy loss. The N6-methyladenosine modification, the most prevalent RNA modification, contributes to the exploration and understanding of the paternal epigenome in the maintenance of pregnancy and fetal growth and development. The four genes identified in this study may serve as potential diagnostic markers and elucidate novel molecular mechanisms of embryogenesis.PMID:38979761 | DOI:10.1111/andr.13678

OMICS. 2024 Jul 9. doi: 10.1089/omi.2024.0127. Online ahead of print.ABSTRACTThere is a pressing need for novel pharmacological interventions and drug delivery innovations to attenuate the cigarette smoke-associated oxidative stress and lung disease. We report here on the attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) and metabolomics of Wistar rats exposed to cigarette smoke for 28 days. The animals were treated for 15 days with plain cysteamine given orally or cysteamine as nanoemulsion given orally or via inhalation. The study design also included two control groups as follows: rats exposed to cigarette smoke but did not receive a treatment (diseased control group) and rats neither exposed to cigarette smoke nor a treatment (normal control group). The targeted metabolomics using Parallel Reaction Monitoring showed that in the diseased control group, ornithine, nicotinamide, xanthine, hypoxanthine, and caprolactam were increased compared with the normal control group. In addition, (±)8(9)-DiHET, which was initially downregulated in the diseased control group, exhibited a reversal of this trend with cysteamine nanoemulsion given via inhalation. The cysteamine nanoemulsion delivered by inhalation highlighted the importance of the route of drug administration for targeting the lungs. To the best of our knowledge, this is the first work to use ATR-FTIR and metabolomics in Wistar rat lung tissues, suggesting how cysteamine nanoemulsion can potentially reduce cigarette smoke-induced oxidative damage. The metabolites reported herein have potential implications for discovery of novel theranostics and, thus, to cultivate diagnostic and therapeutic innovation for early prevention and treatment of cigarette smoke-associated lung diseases.PMID:38979603 | DOI:10.1089/omi.2024.0127

Front Immunol. 2024 Jun 24;15:1405348. doi: 10.3389/fimmu.2024.1405348. eCollection 2024.ABSTRACTBACKGROUND: Antiretroviral therapy (ART) for HIV-1 treatment has improved lifespan but requires lifelong adherence for people living with HIV (PLWH), highlighting the need for a cure. Evaluation of potential cure strategies requires analytic treatment interruption (ATI) with close monitoring of viral rebound. Predictive biomarkers for HIV-1 rebound and/or duration of control during ATI will facilitate these HIV cure trials while minimizing risks. Available evidence suggests that host immune, glycomic, lipid, and metabolic markers of inflammation may be associated with HIV-1 persistence in PLWH who are treated during chronic HIV-1 infection.METHODS: We conducted post-hoc analysis of HIV controllers who could maintain low levels of plasma HIV-1 without ART in a phase 1b vesatolimod trial. Baseline and pre-ATI levels of immune, glycomic, lipidomic, and metabolomic markers were tested for association with ATI outcomes (time of HIV-1 rebound to 200 copies/mL and 1,000 copies/mL, duration of HIV-1 RNA ≤400 copies/mL and change in intact proviral HIV-1 DNA during ATI) using Spearman's correlation and Cox proportional hazards model.RESULTS: Higher levels of CD69+CD8+ T-cells were consistently associated with shorter time to HIV-1 rebound at baseline and pre-ATI. With few exceptions, baseline fucosylated, non-galactosylated, non-sialylated, bisecting IgG N-glycans were associated with shorter time to HIV rebound and duration of control as with previous studies. Baseline plasma MPA and HPA binding glycans and non-galactosylated/non-sialylated glycans were associated with longer time to HIV rebound, while baseline multiply-galactosylated glycans and sialylated glycans, GNA-binding glycans, NPA-binding glycans, WGA-binding glycans, and bisecting GlcNAc glycans were associated with shorter time to HIV rebound and duration of control. Fourteen bioactive lipids had significant baseline associations with longer time to rebound and duration of control, and larger intact proviral HIV-1 DNA changes; additionally, three baseline bioactive lipids were associated with shorter time to first rebound and duration of control.CONCLUSION: Consistent with studies in HIV non-controllers, proinflammatory glycans, lipids, and metabolites were generally associated with shorter duration of HIV-1 control. Notable differences were observed between HIV controllers vs. non-controllers in some specific markers. For the first time, exploratory biomarkers of ATI viral outcomes in HIV-controllers were investigated but require further validation.PMID:38979421 | PMC:PMC11229794 | DOI:10.3389/fimmu.2024.1405348

bioRxiv [Preprint]. 2024 Jun 25:2024.06.24.600521. doi: 10.1101/2024.06.24.600521.ABSTRACTPseudomonas aeruginosa (PA) is a gram-negative opportunistic pathogen that can infect the cornea as a result of trauma or contact lens wear. In addition to their known energy producing role, mitochondria are important mediators of immune signaling and host defense. While certain pathogens have developed strategies to evade host defenses by modulating host mitochondrial dynamics and metabolism, the ability of PA to harness host cell mitochondria during corneal infection is unknown. Using a combination of biochemical and imaging techniques, we show that PA infection of corneal epithelial cells induced mitochondrial fission in a DRP1-dependent manner that preceded PINK1/Parkin and FUNDC1-mediated mitophagy. PA also impaired NADH-linked respiration through a reduction in complex 1. This corresponded to a decrease in metabolic pathways related to glycolysis and the TCA cycle. Metabolomics analysis further demonstrated an upregulation of the pentose phosphate pathway, arginine, purine, and pyrimidine metabolism in PA infected cells. These pathways may provide a key source of nucleotides, amino acids, and nitrogen for both the host cell and PA, in addition to antioxidant functions. Following treatment with gentamicin to kill all extracellular bacteria, metabolic flux analysis showed that corneal epithelial cells were able to restore mitochondrial function despite the continued presence of intracellular PA. Taken together, these data demonstrate that mitochondrial dysfunction and metabolic rewiring in host cells is triggered by extracellular PA, but once inside, PA requires healthy mitochondria to ensure host cell survival.PMID:38979356 | PMC:PMC11230238 | DOI:10.1101/2024.06.24.600521

bioRxiv [Preprint]. 2024 Jun 29:2024.06.25.600674. doi: 10.1101/2024.06.25.600674.ABSTRACTThe molecular underpinnings of H igh G rade E ndometrial C arcinoma (HGEC) metastatic growth and survival are poorly understood. Here we show that ascites-derived and primary tumor HGEC cell lines in 3D spheroid culture faithfully recapitulate key features of malignant peritoneal effusion and exhibit fundamentally distinct transcriptomic, proteomic and metabolomic landscapes when compared with conventional 2D monolayers. Using genetic screening platform we identify MAPK14 (which encodes the protein kinase p38α) as a specific requirement for HGEC in spheroid culture. MAPK14 /p38α has broad roles in programing the phosphoproteome, transcriptome and metabolome of HGEC spheroids, yet has negligible impact on monolayer cultures. MAPK14 promotes tumorigenicity in vivo and is specifically required to sustain a sub-population of spheroid cells that is enriched in cancer stemness markers. Therefore, spheroid growth of HGEC activates unique biological programs, including p38α signaling, that cannot be captured using 2D culture models and are highly relevant to malignant disease pathology.PMID:38979238 | PMC:PMC11230443 | DOI:10.1101/2024.06.25.600674

bioRxiv [Preprint]. 2024 Jun 28:2023.09.05.556135. doi: 10.1101/2023.09.05.556135.ABSTRACTLoss-of-function (LoF) variants in the lipid transporter ABCA7 significantly increase the risk of Alzheimer's disease (odds ratio ∼2), yet the pathogenic mechanisms and the neural cell types affected by these variants remain largely unknown. Here, we performed single-nuclear RNA sequencing of 36 human post-mortem samples from the prefrontal cortex of 12 ABCA7 LoF carriers and 24 matched non-carrier control individuals. ABCA7 LoF was associated with gene expression changes in all major cell types. Excitatory neurons, which expressed the highest levels of ABCA7, showed transcriptional changes related to lipid metabolism, mitochondrial function, cell cycle-related pathways, and synaptic signaling. ABCA7 LoF-associated transcriptional changes in neurons were similarly perturbed in carriers of the common AD missense variant ABCA7 p.Ala1527Gly (n = 240 controls, 135 carriers), indicating that findings from our study may extend to large portions of the at-risk population. Consistent with ABCA7's function as a lipid exporter, lipidomic analysis of isogenic iPSC-derived neurons (iNs) revealed profound intracellular triglyceride accumulation in ABCA7 LoF, which was accompanied by a relative decrease in phosphatidylcholine abundance. Metabolomic and biochemical analyses of iNs further indicated that ABCA7 LoF was associated with disrupted mitochondrial bioenergetics that suggested impaired lipid breakdown by uncoupled respiration. Treatment of ABCA7 LoF iNs with CDP-choline (a rate-limiting precursor of phosphatidylcholine synthesis) reduced triglyceride accumulation and restored mitochondrial function, indicating that ABCA7 LoF-induced phosphatidylcholine dyshomeostasis may directly disrupt mitochondrial metabolism of lipids. Treatment with CDP-choline also rescued intracellular amyloid β -42 levels in ABCA7 LoF iNs, further suggesting a link between ABCA7 LoF metabolic disruptions in neurons and AD pathology. This study provides a detailed transcriptomic atlas of ABCA7 LoF in the human brain and mechanistically links ABCA7 LoF-induced lipid perturbations to neuronal energy dyshomeostasis. In line with a growing body of evidence, our study highlights the central role of lipid metabolism in the etiology of Alzheimer's disease.PMID:38979214 | PMC:PMC11230156 | DOI:10.1101/2023.09.05.556135

bioRxiv [Preprint]. 2024 Jun 28:2024.06.23.598940. doi: 10.1101/2024.06.23.598940.ABSTRACTImpaired cerebral glucose metabolism is a pathologic feature of Alzheimer Disease (AD), and recent proteomic studies highlight a disruption of glial carbohydrate metabolism with disease progression. Here, we report that inhibition of indoleamine-2,3-dioxygenase 1 (IDO1), which metabolizes tryptophan to kynurenine (KYN) in the first step of the kynurenine pathway, rescues hippocampal memory function and plasticity in preclinical models of amyloid and tau pathology by restoring astrocytic metabolic support of neurons. Activation of IDO1 in astrocytes by amyloid-beta 42 and tau oligomers, two major pathological effectors in AD, increases KYN and suppresses glycolysis in an AhR-dependent manner. Conversely, pharmacological IDO1 inhibition restores glycolysis and lactate production. In amyloid-producing APP Swe -PS1 ΔE9 and 5XFAD mice and in tau-producing P301S mice, IDO1 inhibition restores spatial memory and improves hippocampal glucose metabolism by metabolomic and MALDI-MS analyses. IDO1 blockade also rescues hippocampal long-term potentiation (LTP) in a monocarboxylate transporter (MCT)-dependent manner, suggesting that IDO1 activity disrupts astrocytic metabolic support of neurons. Indeed, in vitro mass-labeling of human astrocytes demonstrates that IDO1 regulates astrocyte generation of lactate that is then taken up by human neurons. In co-cultures of astrocytes and neurons derived from AD subjects, deficient astrocyte lactate transfer to neurons was corrected by IDO1 inhibition, resulting in improved neuronal glucose metabolism. Thus, IDO1 activity disrupts astrocytic metabolic support of neurons across both amyloid and tau pathologies and in a model of AD iPSC-derived neurons. These findings also suggest that IDO1 inhibitors developed for adjunctive therapy in cancer could be repurposed for treatment of amyloid- and tau-mediated neurodegenerative diseases.PMID:38979192 | PMC:PMC11230169 | DOI:10.1101/2024.06.23.598940

bioRxiv [Preprint]. 2024 Jun 28:2024.06.24.600378. doi: 10.1101/2024.06.24.600378.ABSTRACTChronic diseases like ME/CFS and long COVID exhibit high heterogeneity with multifactorial etiology and progression, complicating diagnosis and treatment. To address this, we developed BioMapAI, an explainable Deep Learning framework using the richest longitudinal multi-'omics dataset for ME/CFS to date. This dataset includes gut metagenomics, plasma metabolome, immune profiling, blood labs, and clinical symptoms. By connecting multi-'omics to asymptom matrix, BioMapAI identified both disease- and symptom-specific biomarkers, reconstructed symptoms, and achieved state-of-the-art precision in disease classification. We also created the first connectivity map of these 'omics in both healthy and disease states and revealed how microbiome-immune-metabolome crosstalk shifted from healthy to ME/CFS. Thus, we proposed several innovative mechanistic hypotheses for ME/CFS: Disrupted microbial functions - SCFA (butyrate), BCAA (amino acid), tryptophan, benzoate - lost connection with plasma lipids and bile acids, and activated inflammatory and mucosal immune cells (MAIT, γδT cells) with INFγ and GzA secretion. These abnormal dynamics are linked to key disease symptoms, including gastrointestinal issues, fatigue, and sleep problems.PMID:38979186 | PMC:PMC11230215 | DOI:10.1101/2024.06.24.600378

bioRxiv [Preprint]. 2024 Jul 3:2024.06.20.599846. doi: 10.1101/2024.06.20.599846.ABSTRACTThe liver, the largest internal organ and a metabolic hub, undergoes significant declines due to aging, affecting mitochondrial function and increasing the risk of systemic liver diseases. How the mitochondrial three-dimensional (3D) structure changes in the liver across aging, and the biological mechanisms regulating such changes confers remain unclear. In this study, we employed Serial Block Face-Scanning Electron Microscopy (SBF-SEM) to achieve high-resolution 3D reconstructions of murine liver mitochondria to observe diverse phenotypes and structural alterations that occur with age, marked by a reduction in size and complexity. We also show concomitant metabolomic and lipidomic changes in aged samples. Aged human samples reflected altered disease risk. To find potential regulators of this change, we examined the Mitochondrial Contact Site and Cristae Organizing System (MICOS) complex, which plays a crucial role in maintaining mitochondrial architecture. We observe that the MICOS complex is lost during aging, but not Sam50. Sam50 is a component of the sorting and assembly machinery (SAM) complex that acts in tandem with the MICOS complex to modulate cristae morphology. In murine models subjected to a high-fat diet, there is a marked depletion of the mitochondrial protein SAM50. This reduction in Sam50 expression may heighten the susceptibility to liver disease, as our human biobank studies corroborate that Sam50 plays a genetically regulated role in the predisposition to multiple liver diseases. We further show that changes in mitochondrial calcium dysregulation and oxidative stress accompany the disruption of the MICOS complex. Together, we establish that a decrease in mitochondrial complexity and dysregulated metabolism occur with murine liver aging. While these changes are partially be regulated by age-related loss of the MICOS complex, the confluence of a murine high-fat diet can also cause loss of Sam50, which contributes to liver diseases. In summary, our study reveals potential regulators that affect age-related changes in mitochondrial structure and metabolism, which can be targeted in future therapeutic techniques.PMID:38979162 | PMC:PMC11230271 | DOI:10.1101/2024.06.20.599846

Front Pharmacol. 2024 Jun 24;15:1412816. doi: 10.3389/fphar.2024.1412816. eCollection 2024.ABSTRACTBACKGROUND: Pueraria montana var. lobata (Willd.) Maesen & S.M.Almeida ex Sanjappa & Predeep (syn. Pueraria lobata (Willd.) Ohwi) and Schisandra sphenanthera Rehder & E.H. Wilson are traditional edible and medicinal hepatoprotective botanical drugs. Studies have shown that the combination of two botanical drugs enhanced the effects of treating acute liver injury (ALI), but the synergistic effect and its action mechanisms remain unclear. This study aimed to investigate the synergistic effect and its mechanism of the combination of Pueraria montana var. lobata (Willd.) Maesen & S.M.Almeida ex Sanjappa & Predeep (syn. Pueraria lobata (Willd.) Ohwi) (PM) and Schisandra sphenanthera Rehder & E.H. Wilson (SS) in the treatment of ALI.METHODS: High performance liquid chromatography (HPLC) were utilized to conduct the chemical interaction analysis. Then the synergistic effects of botanical hybrid preparation of PM-SS (BHP PM-SS) against ALI were comprehensively evaluated by the CCl4 induced ALI mice model. Afterwards, symptom-oriented network pharmacology, transcriptomics and metabolomics were applied to reveal the underlying mechanism of action. Finally, the key target genes were experimentally by RT-qPCR.RESULTS: Chemical analysis and pharmacodynamic experiments revealed that BHP PM-SS was superior to the single botanical drug, especially at 2:3 ratio, with a better dissolution rate of active ingredients and synergistic anti-ALI effect. Integrated symptom-oriented network pharmacology combined with transcriptomics and metabolomics analyses showed that the active ingredients of BHP PM-SS could regulate Glutathione metabolism, Pyrimidine metabolism, Arginine biosynthesis and Amino acid sugar and nucleotide sugar metabolism, by acting on the targets of AKT1, TNF, EGFR, JUN, HSP90AA1 and STAT3, which could be responsible for the PI3K-AKT signaling pathway, MAPK signaling pathway and Pathway in cancer to against ALI.CONCLUSION: Our study has provided compelling evidence for the synergistic effect and its mechanism of the combination of BHP PM-SS, and has contributed to the development and utilization of BHP PM-SS dietary supplements.PMID:38978983 | PMC:PMC11228302 | DOI:10.3389/fphar.2024.1412816

Food Chem X. 2024 Apr 21;22:101393. doi: 10.1016/j.fochx.2024.101393. eCollection 2024 Jun 30.ABSTRACT[This corrects the article DOI: 10.1016/j.fochx.2024.101239.].PMID:38978693 | PMC:PMC11228433 | DOI:10.1016/j.fochx.2024.101393