PubMed

Sci Data. 2024 Oct 15;11(1):1129. doi: 10.1038/s41597-024-03947-0.ABSTRACTStudying the regulatory mechanisms in different tissues of pepper is crucial for understanding organ formation, growth, and development. However, relevant studies are far from sufficient. In the current study, the stipe, calyx, pericarp, placenta, and seed of ripe pepper were sampled, and metabolites were determined by the untargeted metabolomics method. Transcriptome sequencing was performed by Illumina NovaSeq 6000, and then a high-throughput data set was built. The results showed that a total of 4879 annotated metabolites were detected in 15 samples of the five tissues under positive and negative ion mode. A total of 110.66 Gb of clean data was obtained by transcriptome sequencing, the clean data of each sample reached 6.21 Gb, and a total of 35 336 annotated expression genes were obtained. Furthermore, validate the accuracy of the data by combining principal component analysis and other methods. In summary, this study provides valuable information for the genetic improvement and breeding of peppers, and it holds potential application value, particularly in enhancing the quality and nutritional value of pepper fruits.PMID:39406716 | DOI:10.1038/s41597-024-03947-0

Br J Pharmacol. 2024 Oct 15. doi: 10.1111/bph.17346. Online ahead of print.ABSTRACTBACKGROUND AND PURPOSE: Drug repurposing (DR) offers a compelling alternative to traditional drug discovery's lengthy, resource-intensive process. DR is the process of identifying alternative clinical applications for pre-approved drugs as a low-risk and low-cost strategy. Computational approaches are crucial during the early hypothesis-generating stage of DR. However, 'large-scale' data retrieval remains a significant challenge. A computational workflow addressing such limitations might improve hypothesis generation, ultimately benefit patients and advance DR research.EXPERIMENTAL APPROACH: We introduce a novel computational workflow (combining free-accessible computational platforms) to provide 'proof-of-concept' of the pre-approved drug's suitability for repurposing. Three key phases are included: target fishing (via reverse pharmacophore mapping), target identification (via disease- and drug-target pathway identification) and retrospective literature and drug-like analysis (via in silico ADMET properties determination). Istradefylline is a Parkinson's disease-approved drug with literature-attributed antidepressant properties remaining unclear. Practically applied, istradefylline's antidepressant activity was assessed in the context of major depressive disorder (MDD).KEY RESULTS: Data mining aided by target identification resulted in istradefylline potentially representing a novel antidepressant drug class. Retrieved drug targets (KYNU, MAO-B, ALOX12 and PLCB2) associated with selected MDD pathways (tryptophan metabolism and serotonergic synapse) generated a hypothesis that istradefylline increased extracellular 5-HT levels (MAO-B inhibition) and reduced inflammation (KYNU, ALOX12 and PLCB2 inhibition).CONCLUSION AND IMPLICATIONS: The practically applied workflow's generated hypothesis aligns with known experimental data, validating the effectiveness of this novel computational workflow. It is a low-risk and low-cost DR computational tool providing a bird's-eye view for exploring alternative clinical applications of pre-approved drugs.PMID:39406391 | DOI:10.1111/bph.17346

J Agric Food Chem. 2024 Oct 15. doi: 10.1021/acs.jafc.4c02671. Online ahead of print.ABSTRACTAlcoholic liver disease (ALD) is the predominant type of liver disease worldwide, resulting in significant mortality and a high disease burden. ALD damages multiple organs, including the liver, gut, and brain, causing inflammation, oxidative stress, and fat deposition. In this study, we investigated the effects of rice protein peptides (RPP) on ALD in mice with a primary focus on the gut microbiota and liver metabolites. The results showed that administration of RPP significantly alleviated the symptoms of ALD in mice including adiposity, oxidative stress, and inflammation. The KEGG pathway shows that RPP downregulates the liver metabolite of capric acid and the metabolism of fatty acid biosynthesis compared with the MOD group. Mechanistically, RPP downregulated the PPARγ signaling pathway and suppressed the expression of fatty acid biosynthesis genes (FASN, ACC1, ACSL1, and ACSL3). Furthermore, two active peptides (YLPTKQ and PKLPR) with potential therapeutic functions for ALD were screened by Caco-2 cell modeling and molecular docking techniques. In addition, RPP treatment alleviates gut microbiota dysbiosis by reversing the F/B ratio, increasing the relative abundance of Alloprevotella and Alistipes, and upregulating the level of short-chain fatty acids. In conclusion, RPP alleviates ALD steatosis through the PPARγ signaling pathway by YLPTKQ and PKLPR and regulates gut microbiota.PMID:39406388 | DOI:10.1021/acs.jafc.4c02671

Am J Physiol Gastrointest Liver Physiol. 2024 Oct 15. doi: 10.1152/ajpgi.00146.2024. Online ahead of print.ABSTRACTThe post-weaning period in pigs is a critical window where nutritional interventions are implemented to prevent post-weaning diarrhea (PWD) and antibiotic use. One common strategy is feeding of low protein diets immediately following weaning. This intervention may reduce protein fermentation and pathogen proliferation, therefore decreasing the incidence of post-weaning diarrhea. These effects may also be mitigated by providing dietary fiber. However, studies examining the role of protein and fiber on gastrointestinal microbiota and metabolism are complicated by the presence of other substrates, including polyphenols and antinutritional factors in complex ingredients. In this study, semi-purified diets formulated to meet nutrient requirements were fed to 40 weaned pigs (n = 10/diet) to examine the effects of high protein (HP), high fiber (HF), or both (HFHP) compared to a control (CON) diet with industry standard crude protein and fiber content. Critical alterations in host metabolism and cecal transcriptome were identified in response to the CON diet. Diets with lower protein levels (CON and HF) induced alteration in transcripts from the serine synthesis pathways and integrated stress response in cecal tissue alongside systemic increases in metabolic pathways related to lysine degradation. High protein diets did not induce increases in gastrointestinal pathogen abundance. These results challenge the practice of feeding low protein diets post-weaning, by demonstrating a detrimental effect on intestinal cell function and muscle accretion. This suggests that with careful ingredient selection, increased dietary protein post-weaning could better pig health and growth compared to a standard diet.PMID:39406387 | DOI:10.1152/ajpgi.00146.2024

Reprod Toxicol. 2024 Oct 13:108734. doi: 10.1016/j.reprotox.2024.108734. Online ahead of print.ABSTRACTNotable variations in semen parameters among non-smoking males have been documented post-COVID-19 pandemic. The role of smoking as a significant contributing factor to male infertility has been substantiated. Does the combined effect of smoking and SARS-CoV-2 infection impact male reproductive function? A prospective descriptive cohort study was performed using data from 90 smoking and 90 non-smoking males before and after coronavirus infection in a single center over a period of 3 months. Semen samples were collected before and within 15 days after COVID-19 infection, ensuring no more than three months elapsed between the two collections. The semen parameters evaluated included volume, concentration, progressive motility, normal morphology, and DNA fragmentation rate. Proteomic and metabolomic studies were further used to explore the differences between groups. Both non-smokers and smokers exhibited a marked reduction in sperm concentration, progressive motility, and normal morphology rate. Additionally, an increase in sperm DNA fragmentation index was noted for non-smokers and smokers. In the non-smoking group, dysregulation proteins including SEMG1, SEMG2 and DNAH5, and metabolites including L-glutamine, cis-9-Palmitoleic acid and Linoleamide were observed. In smokers, dysregulation proteins including SMCP, ROPN1B and IZUMO4, alongside metabolites including carnitine, gamma-Glutamylglutamic acid, and hypoxanthine were found. Comparative analysis between smoking and non-smoking patients post-COVID-19 also revealed significant differences in semen concentration, morphology and sperm DNA fragmentation rate. Dysregulated proteins including HSPA5, HSPA2 and PGK2, and metabolites such as acetylcarnitine, oxaloacetate and nicotinate were associated with impaired sperm function. Our study demonstrates that the virus also significantly compromises sperm quality in smoking males, who experience more pronounced declines post-infection compared to their non-smoking counterparts. This research underscores the necessity for comprehensive fertility assessments for smoking males after recovering from COVID-19.PMID:39406274 | DOI:10.1016/j.reprotox.2024.108734

Animal. 2024 Sep 18;18(11):101338. doi: 10.1016/j.animal.2024.101338. Online ahead of print.ABSTRACTThe gastrointestinal nematode infection poses a covert threat to both humans and domestic animals worldwide, eliciting a type 2 immune response within the small intestine. Intestinal tuft cells detect the nematode and activated group 2 innate lymphoid cells. Tuft cell-derived leukotrienes (one of the metabolites of arachidonic acid) were found to drive rapid anti-helminth immunity, but it is still poorly understood whether the tuft cell-mediated type 2 immune circuit and arachidonic acid metabolism modulate anti-parasitic immunity in the gastric epithelium. This study was designed to evaluate the immunological responses of goats inoculated with or without H. contortus. Results showed that H. contortus infection induced a systemic type 2 immune response, characterised by lymphocyte proliferation and greater eosinophils both in peripheral blood and abomasal mucosa, as well as increased type 2 cytokines IL-4, IL-5, and IL-13. Infection of H. contortus altered the transcriptome of the abomasum epithelium, especially tuft cell-mediated circuit-key genes. The infection also influenced the abomasal microbiota, arachidonic acid metabolism and related lipid metabolites, accompanying with great increases in the secretion of leukotrienes and prostaglandins. These findings demonstrate the role of tuft cells mediated circuit in sensing H. contortus infection and immune activation, reveal the candidate function of arachidonic acid involved in anti-helminth immunity, and suggest novel strategies for the control of parasitic diseases in livestock and humans.PMID:39405961 | DOI:10.1016/j.animal.2024.101338

Biomed Pharmacother. 2024 Oct 13;180:117518. doi: 10.1016/j.biopha.2024.117518. Online ahead of print.ABSTRACTThe incidence of inflammatory bowel disease (IBD) is rising globally, increasing interest in food ingredients for its prevention and control. This study evaluated the effect of farnesol (FAR), a key component of pomelo flower volatile oil, on dextran sodium sulfate (DSS)-induced colitis in C57BL/6 mice. FAR significantly alleviated DSS-induced colitis and secondary liver injury, as shown by improved body weight, DAI, colon length, and pathology, as well as liver function and blood lipid indices. The mechanism involves FAR-mediated regulation of inflammatory cytokines, increased expression of tight junction protein genes, and decreased expression of lipid metabolism-related proteins. FAR also enhanced gut microbiota diversity, balancing harmful and probiotic bacteria. Fecal metabolome analysis indicated FAR's role in reversing metabolic disturbances related to inflammation and liver lipid metabolism. These findings support developing functional foods for IBD treatment using pomelo flower volatile oil.PMID:39405907 | DOI:10.1016/j.biopha.2024.117518

Biomed Pharmacother. 2024 Oct 13;180:117546. doi: 10.1016/j.biopha.2024.117546. Online ahead of print.ABSTRACTSelaginella tamariscina extracts (STS), total flavonoids of Selaginella tamariscina (TFST) and the main active component amentoflavone (AMT) have hypoglycaemic-mitigating effects, but their efficacy and mechanism of action in db/db mice are unknown. This study aimed to evaluate the hypoglycaemic effects of Selaginella tamariscina and its extracts in db/db diabetic mice and explore their mechanisms through gut microbiota modulation and metabolomics. Sixty male db/db mice were divided into model (db/db), STS (1.1 g/kg), TFST (140 mg/kg), AMT (60 mg/kg), mulberry twig alkaloid tablets (MTA, 24 mg/kg), and metformin (Met, 160 mg/kg) groups. Another 10 db/m mice served as controls. Treatments lasted 4 weeks. Blood glucose, body weight, diabetes symptoms, lipid levels, pathological changes, oxidative stress markers and liver damage levels were assessed. The gut microbiota composition was analyzed via 16S rDNA sequencing, and urinary metabolomics was conducted to understand metabolic changes. Selaginella tamariscina and its extracts significantly improved hyperglycaemia, insulin sensitivity, lipid metabolism, oxidative stress and liver injury in db/db mice, among which TFST was the most effective, with an effect comparable to that of Met and superior to that of MTA. TFST regulates gut microbiota disorders and metabolic profiles in db/db diabetic mice and modulates Alloprevotella levels, affecting butyric acid content and, thus, exerting a hypoglycaemic effect. These findings suggest that TFST modulates Alloprevotella, influencing butyric acid levels, which improves glycaemic control, enhances insulin sensitivity, and prevents oxidative stress and tissue damage. In conclusion, TFST has potential as a natural therapeutic agent for the control of T2DM.PMID:39405904 | DOI:10.1016/j.biopha.2024.117546

J Pharm Biomed Anal. 2024 Oct 3;252:116502. doi: 10.1016/j.jpba.2024.116502. Online ahead of print.ABSTRACTAsari radix et rhizoma is the sole plant from the Aristolochiaceae family officially sanctioned for medicinal in China, primarily employed for treating colds and headaches, and is widely utilized in clinical practice. Initially, the entire plant was specified for medicinal use, but since 2005, the authorized part has been restricted to the roots and rhizomes. The chemical constituents are directly linked to its efficacy and safety, yet a comparative analysis of the chemical profiles between the overground and underground parts has not been reported. This paper represents the first comparative study of the chemical constituents in the two parts, achieved through the synergistic application of solid phase micro extraction coupled with gas chromatography mass spectrometry (SPME-GC-MS) and liquid chromatography Orbitrap MS (LC-Orbitrap-MS). Using SPME-GC-MS, 51 constituents were identified from both parts, with 89 % being shared components, indicating a close similarity in their volatile compositions. Through LC-Orbitrap-MS, 308 constituents were identified, sharing 76 % commonality, revealing a more pronounced disparity in non-volatile components. Plant metabolomics screening pinpointed 8 volatile and 14 non-volatile components capable of distinguishing the two parts, with the latter being more stable and thus better suited as markers for differentiation. This research furnishes a scientific rationale for selecting distinct parts of Asari radix et rhizoma and for implementing monitoring strategies in clinical application.PMID:39405788 | DOI:10.1016/j.jpba.2024.116502

J Pharm Biomed Anal. 2024 Oct 10;252:116516. doi: 10.1016/j.jpba.2024.116516. Online ahead of print.ABSTRACTQiliqiangxin (QLQX) capsule consists of 11 herbs, namely Huang qi (astragalus membranaceus), Ren shen (ginseng), Fu zi (radix aconiti carmichaeli), Dan shen (salvia miltiorrhiza), Ting li zi (lepidium seed), Ze xie (rhizoma alismatis), Yu zhu (radix polygonati officinalis), Gui zhi (cassia twig), Hong hua (carthamus tinctorious), Xiang jia Pi (cortex periplocae), Chen Pi (pericarpium citri reticulatae), and it is a standardized commercial formula designed to address yang deficiency and to restore the balance of qi in the heart. QLQX is also known to invigorate the blood and promote the circulation of the blood and to promote the use of fluids to relieve water retention and edema, and can be used in cardiovascular diseases such as mild to moderate congestive heart failure resulting from coronary artery disease and hypertension. The further research on the effect of QLQX on cardiac function in mice after myocardial infarction was manipulated. QLQX was given to mice in myocardial infarction model by gavage with appropriate dosage and the samples were analyzed at the end of the animal experiments through the UHPLC-Q-Exactive LC-MS. The liquid mass spectrometry was used to collect and followed by further analysis of the corresponding metabolites and metabolic pathways using metabolomics analysis. As a result, 9 differential metabolites were identified, with 15 being up-regulated and 4 down-regulated following intervention with QLQX. Then the metabolic pathways by KEGG enrichment pathway bubble diagram was analyzed, and 4 metabolic pathways were obtained, and combined with the metabolites that had been screened and analyzed together, finally the two differential metabolites, 2,5-Dihydroxybenzenesulfonic Acid and o-Cresol sulfate were found. The Glycerophospholipid metabolism pathway was closely related to the remaining seven differential metabolites, and the pathway might be an important pathway related to the effects of QLQX on cardiac function in mice.PMID:39405786 | DOI:10.1016/j.jpba.2024.116516

J Pharm Biomed Anal. 2024 Oct 9;252:116512. doi: 10.1016/j.jpba.2024.116512. Online ahead of print.ABSTRACTSnake melon (Cucumis melo var. flexuosus, CM) is a gourd with health-promoting nutritional traits and unexplored phytochemicals. This study aims to comprehensively investigate the phytoconstituents in the fruits, leaves, roots, seeds, and stems of CM, using liquid chromatography-quadrupole time-of-flight tandem mass spectrometry. Consequently, 118 metabolites were identified, encompassing phenolic compounds, flavonoids, megastigmanes, lignans, cucurbitacins, and fatty acids. Multivariate data analysis revealed differences in the metabolite composition of CM organs and correlated these variations with the potential in-vitro anti-inflammatory properties assessed against RAW 264.7 macrophages through the down-regulation of cyclo-oxygenase-Ⅱ, nuclear factor-kappa B, and tumor necrosis factor-α. The results indicated that leaf and seed extracts showed the highest anti-inflammatory activity due to their enrichment in several flavonoids, phenolic glycosides, and a megastigmane. These findings emphasize the health benefits of CM organs as potential functional foods and functional food by-products, serving as a natural source for developing new anti-inflammatory agents.PMID:39405783 | DOI:10.1016/j.jpba.2024.116512

Drug Resist Updat. 2024 Oct 10;77:101159. doi: 10.1016/j.drup.2024.101159. Online ahead of print.ABSTRACTAlthough immune checkpoint inhibitors (ICIs) have revolutionized immuno-oncology with effective clinical responses, only 30 to 40 % of patients respond to ICIs, highlighting the need for reliable biomarkers to predict and enhance therapeutic outcomes. This study investigated how amino acid, glycolysis, and bile acid metabolism affect ICI efficacy in non-small cell lung cancer (NSCLC) patients. Through targeted metabolomic profiling and machine learning analysis, we identified amino acid metabolism as a key factor, with histidine (His) linked to favorable outcomes and homocysteine (HCys), phenylalanine (Phe), and sarcosine (Sar) linked to poor outcomes. Importantly, the His/HCys+Phe+Sar ratio emerges as a robust biomarker. Furthermore, we emphasize the role of glycolysis-related metabolites, particularly lactate. Elevated lactate levels post-immunotherapy treatment correlate with poorer outcomes, underscoring lactate as a potential indicator of treatment efficacy. Moreover, specific bile acids, glycochenodeoxycholic acid (GCDCA) and taurolithocholic acid (TLCA), are associated with better survival and therapeutic response. Particularly, TLCA enhances T cell activation and anti-tumor immunity, suggesting its utility as a predictive biomarker and therapeutic agent. We also suggest a connection between gut microbiota and TLCA levels, with the Eubacterium genus modulating this relationship. Therefore, modulating specific metabolic pathways-particularly amino acid, glycolysis, and bile acid metabolism-could predict and enhance the efficacy of ICI therapy in NSCLC patients, with potential implications for personalized treatment strategies in immuno-oncology. ONE SENTENCE SUMMARY: Our study identifies metabolic biomarkers and pathways that could predict and enhance the outcomes of immune checkpoint inhibitor therapy in NSCLC patients.PMID:39405736 | DOI:10.1016/j.drup.2024.101159

J Hazard Mater. 2024 Oct 9;480:136120. doi: 10.1016/j.jhazmat.2024.136120. Online ahead of print.ABSTRACTAlthough animal studies have evaluated lead (Pb) toxicity, they are limited to soluble forms, such as Pb-acetate, which do not reflect the range found in the exposome. Recent studies on Pb speciation of residential soils in urban areas revealed that the initial Pb sources are not persistent and are extensively repartitioned into adsorbed forms of Pb rather than insoluble phosphates. We investigated the inhalation and neurological toxicity of dusts generated from a surficial soil sample collected from a residential site with an exposomic mixture of various Pb species, both adsorbed phases (Fe and Mn oxide, humate bound Pb) and mineral phases (Pb hydroxycarbonate, pyromorphite, galena). Mice inhaled East Chicago dust (ECD) generated from a composite soil sample for 4 h/day, 7 days/week, for 4 weeks. Mice were necropsied immediately, 1, 14 and 30 days post exposure to evaluate both toxicity and recovery. Exposure to ECD caused changes in memory and spatial learning in the Morris Water Maze test. RNAseq analysis of the hippocampus region revealed multiple differentially expressed genes and impacts on pathways involved in ion channel complexes, and neuron-to-neuron synapse. Metabolomics analysis of plasma highlighted significant alterations in metabolic processes immediately after exposure that resolved after 14 days of rest.PMID:39405708 | DOI:10.1016/j.jhazmat.2024.136120

J Hazard Mater. 2024 Oct 9;480:136086. doi: 10.1016/j.jhazmat.2024.136086. Online ahead of print.ABSTRACTHeavy metals (HMs) present in the natural aquatic environment can form a ternary aggregate of "EPS-DOM-HMs" with the prevalent microalgae extracellular polymers substances (EPS) and macromolecular dissolved organic matters (DOMs), which show special molecular structure and biological interaction. This study reveals the formation of "EPS-TA-HMs" and the mechanism of their physiological and metabolic effects on Raphidocelis subcapitata. Results indicate that TA-Cr(III) can bind to EPS to form ternary aggregates with substances coexisting large and small hydrodynamic diameters and that the interactions are dominated by hydrophobic interactions of the protein binding to the pyrrole ring of the polyphenol and hydrogen bonding interactions formed by OC-(N R O). The protein structure of EPS has the largest proportion of proline, glycine, aspartic acid, and tryptophan. These interactions promoted the secretion of EPS components and reduced the growth inhibition of Raphidocelis subcapitata by 45.9 % compared with Cr(III) exposure. TEM analysis combined with EDS analysis indicated that Cr(III) was taken intracellularly and TA-Cr(III) was not. In addition, metabolomics analyses revealed that microalgae initiate adaptive mechanisms via the activation of a two-component system (i.e., maintenance of high metabolic activity). This study underscored the morphology of HMs in real aquatic environments and the mechanisms of metabolic effects on aquatic organisms.PMID:39405697 | DOI:10.1016/j.jhazmat.2024.136086

Transl Oncol. 2024 Oct 13;50:102152. doi: 10.1016/j.tranon.2024.102152. Online ahead of print.ABSTRACTBACKGROUND: Plasma-derived Extracellular Vesicles (EVs) have been suggested as novel biomarkers in melanoma, due to their ability to reflect the cell of origin and ease of collection. This study aimed to identify novel EV biomarkers that can discriminate between disease stages. This was achieved by characterising the plasma-derived EVs of patients with melanoma, and comparing their proteomic and metabolomic profile to those from healthy controls.METHODS: EVs were isolated from the plasma of 36 patients with melanoma and 13 healthy controls using Size Exclusion Chromatography. Proteomic and Metabolomic Analyses were performed, and machine learning algorithms were used to identify potential proteins and metabolites to differentiate the plasma-derived EVs from melanoma patients of different disease stages.RESULTS: The concentration and size of the EV population isolated was similar between groups. Proteins (APOC4, PRG4, PLG, TNC, VWF and SERPIND1) and metabolites (lyso PC a C18:2, PC ae C44:3) previously associated with melanoma pathogenesis were identified as relevant in differentiating between disease stages.CONCLUSION: The results further support the continued investigation of circulating plasma-derived EVs as biomarkers in melanoma. Furthermore, the potential of combined proteo-metabolomic signatures for differentiation between disease stages may provide valuable insights into early detection, prognosis, and personalised treatment strategies.PMID:39405606 | DOI:10.1016/j.tranon.2024.102152

Ticks Tick Borne Dis. 2024 Oct 13;15(6):102404. doi: 10.1016/j.ttbdis.2024.102404. Online ahead of print.ABSTRACTThe control and prevention of ticks and tick-borne diseases rely on chemical insecticides and repellents. Plant-derived compounds potentially represent new and safer repellents. Cinnamaldehyde, a component of cinnamon oil, exhibits antibacterial, anti-inflammatory, acaricidal, and repellent activity against ticks. Here we studied the molecular mechanism of the repellent effect of cinnamaldehyde on Haemaphysalis longicornis. A 2 % cinnamaldehyde treatment resulted in >90 % nymph repellency within 6 h. Nymphs were exposed to cinnamaldehyde for 30 min, and subsequent transcriptome and metabolome analyses revealed the involvement of H. longicornis Acetylcholinesterases (HL-AchEs) in the response process. HL-AchEs was transcribed in all tick developmental stages and tissues. Following cinnamaldehyde treatment, the transcript and specific activity of the enzyme of AchE were significantly altered. Following RNAi, electroantennography (EAG) tests demonstrated a significant decrease in response to various repellents as well as a significant decrease in repellency. Our findings have revealed that HL-AchEs mediates cinnamaldehyde-induced tick repellency, and the results provide insights into the mechanism of plant-derived tick repellents.PMID:39405601 | DOI:10.1016/j.ttbdis.2024.102404

J Med Chem. 2024 Oct 15. doi: 10.1021/acs.jmedchem.4c01926. Online ahead of print.ABSTRACTPregnane X receptor (PXR) is a ligand-activated transcription factor that binds diverse compounds and upregulates drug metabolism machinery in response. PXR activation is detrimental to drug efficacy and safety because it reduces active drug concentrations and increases reactive metabolites, leading to toxicity and/or drug-drug interactions. Thus, effort must be expended in drug development pipelines to assess PXR activation by lead candidates and chemically modify agonists to reduce PXR liabilities while maintaining on-target potencies. Coadministration of drugs with PXR antagonists could prevent PXR-mediated metabolism events, but such compounds are rare and may themselves be converted to agonists by metabolic enzymes or PXR mutations. Here, we report the design, synthesis, optimization, and biological validation of proteolysis targeting chimeras that induce PXR degradation through E3 ubiquitin ligase recruitment. PXR degradation blocks agonist-induced gene expression and enhances anticancer effects of the chemotherapy paclitaxel, a known PXR agonist and substrate of downstream metabolic enzymes.PMID:39405362 | DOI:10.1021/acs.jmedchem.4c01926

PLoS Genet. 2024 Oct 15;20(10):e1011432. doi: 10.1371/journal.pgen.1011432. Online ahead of print.ABSTRACTSeveral protein ensembles facilitate crossover recombination and the associated assembly of synaptonemal complex (SC) during meiosis. In yeast, meiosis-specific factors including the DNA helicase Mer3, the "ZZS" complex consisting of Zip4, Zip2, and Spo16, the RING-domain protein Zip3, and the MutSγ heterodimer collaborate with crossover-promoting activity of the SC component, Zip1, to generate crossover-designated recombination intermediates. These ensembles also promote SC formation - the organized assembly of Zip1 with other structural proteins between aligned chromosome axes. We used proximity labeling to investigate spatial relationships between meiotic recombination and SC proteins in S. cerevisiae. We find that recombination initiation and SC factors are dispensable for proximity labeling of Zip3 by ZZS components, but proteins associated with early steps in recombination are required for Zip3 proximity labeling by MutSγ, suggesting that MutSγ joins Zip3 only after a recombination intermediate has been generated. We also find that zip1 separation-of-function mutants that are crossover deficient but still assemble SC fail to generate protein ensembles where Zip3 can engage ZZS and/or MutSγ. The SC structural protein Ecm11 is proximity labeled by ZZS proteins in a Zip4-dependent and Zip1-independent manner, but labeling of Ecm11 by Zip3 and MutSγ requires, at least in part, Zip1. Finally, mass spectrometry analysis of biotinylated proteins in eleven proximity labeling strains uncovered shared proximity targets of SC and crossover-associated proteins, some of which have not previously been implicated in meiotic recombination or SC formation, highlighting the potential of proximity labeling as a discovery tool.PMID:39405359 | DOI:10.1371/journal.pgen.1011432

JCI Insight. 2024 Oct 15:e181172. doi: 10.1172/jci.insight.181172. Online ahead of print.ABSTRACTLeft ventricular hypertrophy (LVH) and dyslipidemia are strong, independent predictors for cardiovascular disease, but their relationship is less well-studied. A longitudinal lipidomic profiling of left ventricular mass (LVM) and LVH is still lacking. Using LC-MS, we repeatedly measured 1,542 lipids from 1,755 unique American Indians attending two exams (mean~5-year apart). Cross-sectional associations of individual lipid species with LVM index (LVMI) were examined by generalized estimating equation (GEE), followed by replication in an independent bi-racial cohort (65% white, 35% black). Baseline plasma lipids associated with LVH risk beyond traditional risk factors were identified by Cox frailty model in American Indians. Longitudinal associations between changes in lipids and changes in LVMI were examined by GEE, adjusting for baseline lipids, baseline LVMI, and covariates. Multiple lipid species (e.g., glycerophospholipids, sphingomyelins, acylcarnitines) were significantly associated with LVMI or the risk of LVH in American Indians. Some lipids were confirmed in black and white individuals. Moreover, some LVH-related lipids were inversely associated with risk of coronary heart disease (CHD). Longitudinal changes in several lipid species (e.g., glycerophospholipids, sphingomyelins, cholesterol esters) were significantly associated with changes in LVMI. These findings provide insights into the role of lipid metabolism in LV remodeling and the risk of LVH or CHD.PMID:39405119 | DOI:10.1172/jci.insight.181172

Food Funct. 2024 Oct 15. doi: 10.1039/d4fo03657c. Online ahead of print.ABSTRACTEpidemiological and animal studies have indicated that calcium and boron are essential for bone development and metabolism. However, limited information is available regarding the effects of boron supplementation on bone development and metabolism in newly weaned infants with either calcium deficiency or calcium sufficiency. This study assessed the effects of dietary boron supplementation (0 and 3 mg kg-1) on bone development and metabolism, in a newly weaned mouse model, under both calcium deficiency and sufficiency feeding conditions. The results show that mice fed a calcium sufficient diet exhibited lower fat percentage and final body weight than those fed a calcium deficient diet. Boron supplementation reduced the serum high-density lipoprotein cholesterol level and up-regulated the mRNA levels of FABP3, PPAR-γ, and CaMK in the intestinal mucosa. Importantly, boron supplementation increased the tibial weight in mice on a calcium-sufficient diet and enhanced the tibial volume in those on a calcium-deficient diet. Metabolomic analysis highlighted calcium and boron's impact on metabolites like carboxylic acids and derivatives, fatty acyls, steroids and steroid derivatives, benzene and substituted derivatives, organonitrogen compounds, organooxygen compounds, and phenols, and were related to lipid metabolism and the neural signaling pathway. Transcriptomic analysis corroborated the role of calcium and boron in modulating bone metabolism via the JAK-STAT, calcium signaling, lipid metabolism, and inflammatory pathways. Multi-omics analysis indicated a strong correlation between calcium signaling pathways, lipid metabolism signaling, and dietary calcium and boron contents. This research provides insights into these complex mechanisms, potentially paving the way for novel interventions against calcium and boron deficiencies and bone metabolism abnormalities in clinical settings.PMID:39405052 | DOI:10.1039/d4fo03657c