PubMed

J Ethnopharmacol. 2025 Mar 5:119582. doi: 10.1016/j.jep.2025.119582. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Euphorbia pekinensis Radix (EP) is a traditional medicinal plant widely used in Mongolian and Chinese medicine for its potent therapeutic properties in treating edema, ascites, and various inflammatory conditions. However, EP has toxicity, which can cause swelling and congestion of the gastrointestinal mucosa. Chebulae Fructus is a unique processing method in Mongolian medicine that is believed to mitigate EP's toxicity and adjust its effect, though the mechanisms underlying this detoxification remain poorly understood.AIM OF THE STUDY: This study employed an integrative approach combining network pharmacology, serum pharmacochemistry, pharmacology, and metabolomics to investigate the intestinal detoxification and synergistic effects of Chebulae Fructus-processed Euphorbia pekinensis (PEP).MATERIALS AND METHODS: The blood-absorbed components of EP and PEP were identified by UPLC-MS/MS. To evaluate holistic effect of the two medicine, network pharmacology was applied to focus on serum components and identify the key compounds and targets mediating effect in addressing five TCM syndromes, as well as modern medicine symptoms including seven types of cancer and myocardial infarction. In terms of detoxification, non-targeted metabolomics was utilized to analyze significant intestinal metabolites and pathways affected by EP and PEP in normal mice.RESULTS: A total of 77 and 109 blood-absorbed components were identified from EP and PEP, respectively, including terpenoids, phenolic acids, alkaloids, flavonoids, and tannins. In network pharmacology analysis, key hub genes were identified as therapeutic targets, with PEP exhibiting possibly enhanced effects than EP since it was associated with more targets and diseases in the network. Furthermore, PEP modulated histamine metabolism and arginine biosynthesis pathways, thereby reducing intestinal inflammation.CONCLUSION: This study highlights the different anti-cancer and ascites-reducing potential of EP and PEP, emphasizing the detoxification benefits of Chebulae Fructus processing. These findings provide a foundation for the safe and effective therapeutic use of PEP for treating ascites and cancer, while minimizing intestinal toxicity, thereby promoting the safe utilization of medicinal Euphorbiaceae plants.PMID:40054641 | DOI:10.1016/j.jep.2025.119582

Asia Pac J Ophthalmol (Phila). 2025 Mar 5:100180. doi: 10.1016/j.apjo.2025.100180. Online ahead of print.ABSTRACTDiabetic retinopathy (DR) and diabetic macular edema (DME) are leading causes of vision loss globally. This is a comprehensive review focused on both medical and surgical management strategies for DR and DME. This review highlights the epidemiology of DR and DME, with a particular emphasis on the Asia-Pacific region, urban-rural disparities, ethnic variations, and grading methodologies. We examine various risk factors for DR, including glycemic control, hypertension, hyperlipidemia, obesity, chronic kidney disease, sex, myopia, pregnancy, and cataract surgery. Furthermore, we explore potential biomarkers in serum, proteomics, metabolomics, vitreous, microRNA, and genetics that may aid in the detection and management of DR. In addition to medical management, we review the evidence supporting systemic and ocular treatments for DR/DME, including anti-vascular endothelial growth factor (anti-VEGF) agents, anti-inflammatory agents, biosimilars, and integrin inhibitors. Despite advancements in treatment options such as pan-retinal photocoagulation and anti-VEGF agents, a subset of cases still progresses, necessitating vitrectomy. Challenging diabetic vitrectomies pose difficulties due to complex fibrovascular proliferations, incomplete posterior vitreous detachment, and fragile, ischemic retinas, making membrane dissection risky and potentially damaging to the retina. In this review, we address the question of challenging diabetic vitrectomies, providing insights and strategies to minimize complications. Additionally, we briefly explore newer modalities such as 3-dimensional vitrectomy and intra-operative optical coherence tomography as potential tools in diabetic vitrectomy. In conclusion, this review provides a comprehensive overview of both medical and surgical management options for DR and DME. It underscores the importance of a multidisciplinary approach, tailored to the needs of each patient, to optimize visual outcomes and improve the quality of life for those affected by these sight-threatening conditions.PMID:40054582 | DOI:10.1016/j.apjo.2025.100180

J Adv Res. 2025 Mar 5:S2090-1232(25)00149-3. doi: 10.1016/j.jare.2025.03.008. Online ahead of print.ABSTRACTINTRODUCTION: Endophytic fungi are essential microorganisms in promoting plant health. However, the mechanism of endophytic fungi regulating root microbiota to enhance crop production and resistance remains unclear.OBJECTIVES: We aimed i) to explore the microbial alteration driven by endophytic Acrocalymma vagum in developing crop yield and rice resistance; ii) to reveal the mechanism of root-released compound stimulated by A. vagum in recruiting benefit microbes.METHODS: The microbiome was applied in a culture-dependent and culture-independent method to study the microbial communities of the A. vagum-rice holobiont using 16S rRNA and ITS gene metabarcoding. Non-target metabolome identified distinct metabolites responsible for community variations. Label-free proteomic analyses investigated the association between primary genes related to the holobiont formation. CRISPR/Cas9 technique and homologous recombination replacement were used to characterize the functions of putative genes.RESULTS: A. vagum enhanced cultivated rice yield by 5.73 ± 1.76 % and induced 83.24 ± 9.86 % control efficiency against rice blast. We discovered that A. vagum simplified rice microbial structure based on co-occurrence networks, by lowering the proportion of potentially pathogenic predominant Burkholderia and driving rice to recruit beneficial Lactobacillus, Sarocladium and Nigrospora to promote rice growth with the increases of 44.41 ± 5.10 % shoot height and 70.21 ± 9.57 % shoot biomass. Moreover, the holobiont released coumaric and trans-ferulic acids to attract beneficial microbes. 206 rice proteins were notably up-regulated in the holobiont, particularly the OsPrxs. CRISPR/Cas9-edited mutants of OsPRX70 and OsPRX95 reduced the promotion effect of A. vagum on rice growth. Furthermore, the pathways of 39 overexpressed proteins in A. vagum were enriched in invading the host and inducing resistance. The knockouts of AvGH3, AvGH7, AvMFS1, and AvCBA transformed A. vagum role from endophyte to pathogen.CONCLUSIONS: The A. vagum-rice holobiont releases recruitment signals and improves the rice community structure. We provide ecological and molecular evidence to confirm the mutualism of endophyte-plant-promoting growth and disease resistance.PMID:40054578 | DOI:10.1016/j.jare.2025.03.008

Environ Res. 2025 Mar 5;274:121306. doi: 10.1016/j.envres.2025.121306. Online ahead of print.ABSTRACTThe widespread use of neonicotinoid pesticides has severely impacted honey bees, driving population declines. Gut microbiota are increasingly recognized for their role in mitigating pesticide toxicity. This study evaluated the ability of Gilliamella sp. G0441, a core microbiome member of the Asian honey bee (Apis cerana), to confer resistance to the toxicity of a neonicotinoid nitenpyram. Newly emerged Asian honey bees were first colonized with gut microbiota in the source colony, then divided into four treatments: SS (fed sucrose solution throughout), SN (fed sucrose solution, then exposed to nitenpyram), GS (fed Gilliamella, then sucrose solution), and GN (fed Gilliamella, then exposed to nitenpyram), and their responses-mortality, food consumption, body weight, and sucrose sensitivity-were assessed. The protective effects of Gilliamella administration on the host were further validated using a microbiota-free bee model. Gilliamella supplementation significantly mitigated nitenpyram-induced appetite suppression, weight loss, impaired learning, and gut microbiota disruption. Mechanistic analyses revealed that nitenpyram disrupted brain metabolism via the intestinal MAPK pathway, reducing ascorbate and aldarate metabolism. Prophylactic Gilliamella treatment reversed these effects, restored metabolic balance, and modulated esterase E4 expression, enhancing pesticide resistance. This study underscores Gilliamella's vital role in honey bee resilience to neonicotinoids, offering insights into the microbiota-gut-brain axis (MGBA) as a pathway for enhancing pesticide tolerance and ecological health.PMID:40054557 | DOI:10.1016/j.envres.2025.121306

Eur J Pharm Biopharm. 2025 Mar 5:114690. doi: 10.1016/j.ejpb.2025.114690. Online ahead of print.ABSTRACTProgesterone (PRG), a steroidal hormone, is commonly utilized in the clinical practice of obstetrics and gynecology. The high frequency of PRG injections, however, has brought significant pain and inconvenience to patients. In this study, we developed a long-acting injection leveraging the phase transition mechanism for the long-term treatment in Assisted Reproductive Technology (ART). The components we selected all possess excellent biocompatibility. Pharmacokinetic studies revealed that the PRG-loaded phospholipid phase transition gels (PRG-PPTGs) released the PRG continuously for over 7 days. Notably, pharmacological investigation demonstrated that PRG-PPTGs, when administered weekly, effectively promoted uterine development. Our findings suggested that PRG-PPTGs successfully achieve both the prevention of burst release and the reduction of dosing frequency, highlighting the potential of PPTGs as promising long-acting composite system for hydrophobic drugs.PMID:40054507 | DOI:10.1016/j.ejpb.2025.114690

Neurochem Int. 2025 Mar 5:105961. doi: 10.1016/j.neuint.2025.105961. Online ahead of print.ABSTRACTChemotherapy-induced peripheral neuropathy (CIPN) severely diminishes the quality of life for cancer survivors, yet effective treatments remain scarce. Esketamine, a commonly used anesthetic, has demonstrated neuroprotective effects by restoring gut microbiome dysbiosis. In this study, we investigated the impact of esketamine on nociceptive sensitivity in a mouse model of CIPN and explored the potential involvement of the gut microbiome. In mice treated with oxaliplatin, repeated esketamine doses (in contrast to a single dose) significantly improved the paw withdrawal threshold (PWT). Western blot and qPCR analyses further revealed that repeated esketamine administration markedly reduced microglial activation and neuroinflammation in the dorsal root ganglion (DRG), underscoring its potent anti-inflammatory properties. Moreover, fecal 16S rRNA analysis indicated that esketamine partially restored the abnormal gut microbiota composition (β-diversity). Plasma metabolome analysis showed that repeated esketamine treatment significantly lowered the elevated levels of 6H-indolo[2,3-b]quinoline and restored the reduced levels of (3-exo)-3-[3-methyl-5-(1-methylethyl)-4H-1,2,4-triazol-4-yl]-8-azabicyclo[3.2.1]octane observed in oxaliplatin-treated mice. In addition, fecal microbiota transplantation from esketamine-treated CIPN mice notably improved both the diminished PWT and DRG neuroinflammation in oxaliplatin-treated mice. Collectively, these findings suggest that repeated esketamine administration may alleviate mechanical allodynia in CIPN mice by modulating neuroinflammation, gut microbiota, and associated metabolites.PMID:40054499 | DOI:10.1016/j.neuint.2025.105961

Cell. 2025 Mar 6;188(5):1178-1197. doi: 10.1016/j.cell.2025.01.038.ABSTRACTMicrobiome research has expanded significantly in the last two decades, yet translating findings into clinical applications remains challenging. This perspective discusses the persistent issue of correlational studies in microbiome research and proposes an iterative method leveraging in silico, in vitro, ex vivo, and in vivo studies toward successful preclinical and clinical trials. The evolution of research methodologies, including the shift from small cohort studies to large-scale, multi-cohort, and even "meta-cohort" analyses, has been facilitated by advancements in sequencing technologies, providing researchers with tools to examine multiple health phenotypes within a single study. The integration of multi-omics approaches-such as metagenomics, metatranscriptomics, metaproteomics, and metabolomics-provides a comprehensive understanding of host-microbe interactions and serves as a robust hypothesis generator for downstream in vitro and in vivo research. These hypotheses must then be rigorously tested, first with proof-of-concept experiments to clarify the causative effects of the microbiota, and then with the goal of deep mechanistic understanding. Only following these two phases can preclinical studies be conducted with the goal of translation into the clinic. We highlight the importance of combining traditional microbiological techniques with big-data approaches, underscoring the necessity of iterative experiments in diverse model systems to enhance the translational potential of microbiome research.PMID:40054445 | DOI:10.1016/j.cell.2025.01.038

Food Chem. 2025 Mar 1;478:143658. doi: 10.1016/j.foodchem.2025.143658. Online ahead of print.ABSTRACTCurrently, understanding of how banana cultivars differ in metabolism during ripening is limited. This study compared the pulp metabolites of six banana cultivars using NMR. Bananas with B genome were found to have higher amounts of total starch, amylose, amylopectin, and resistant starch compared to those without B genome. NMR identified 21 key metabolites distinguish these cultivars. These metabolites included four soluble sugars, three organic acids, eleven amino acids, one alcohol, one choline, and one other compound. Notably, the levels of four soluble sugars varied significantly among the cultivars. 'Gongjiao' and 'Guangfen No. 1' had a slightly sour taste due to higher levels of malate and citrate. The accumulation of eleven key amino acids differed among varieties and changed unpredictably during ripening. Other important metabolites also played a role in distinguishing six banana varieties. This research provided new insights into how metabolites were used to differentiate between banana cultivars.PMID:40054203 | DOI:10.1016/j.foodchem.2025.143658

Plant Physiol Biochem. 2025 Feb 25;222:109710. doi: 10.1016/j.plaphy.2025.109710. Online ahead of print.ABSTRACTCentella asiatica is a well-known herbal plant that makes a significant contribution to the treatment of various chronic ailments. Triterpenoid saponins are the main active components extracted from C. asiatica, which have rich pharmacological activity. However, only a few studies have systematically elucidated the molecular mechanism underlying the biosynthesis of triterpenoid saponins in C. asiatica. Here, we report a chromosome-level reference genome of C. asiatica, by using Illumina, PacBio HiFi, and Hi-C technologies. The assembled genome exhibits high quality with a size of 455 Mb and a contig N50 of 36 Mb. A total of 26,479 protein-coding genes were predicted. Comparative genomic analysis revealed that the gene families involved in triterpenoid saponin biosynthesis, including squalene synthase (SS) and farnesyl diphosphate synthase (FPS), rapidly expanded in the C. asiatica genome. In particular, we have discovered two whole-genome duplication events in C. asiatica genomes. A further comprehensive analysis of the metabolome and transcriptome was performed using different tissues of C. asiatica in order to identify the key genes associated with triterpenoid saponin biosynthesis. Consequently, seven enzyme genes were considered to play important roles in triterpenoid biosynthesis. Subsequent functional characterization of CaOSC4 demonstrated that it is responsible for the biosynthesis of three ursane-type triterpenoids in C. asiatica. Our research establishes a genomic data platform that can be employed in the excavation of genes and precision breeding in C. asiatica. Additionally, the results offer new insights into the biosynthesis of triterpenoid saponins.PMID:40054110 | DOI:10.1016/j.plaphy.2025.109710

Comp Biochem Physiol Part D Genomics Proteomics. 2025 Mar 4;55:101466. doi: 10.1016/j.cbd.2025.101466. Online ahead of print.ABSTRACTDue to the unique physicochemical properties of saline-alkaline water, aquatic organisms find it challenging to survive under such conditions. This study established a freshwater control group (C), a 20 mmol/L NaHCO3 exposure group (T), a 40 mmol/L NaHCO3 exposure group (F), a 20 mmol/L NaHCO3 exposure with α-ketoglutarate (AKG)-supplemented feed group (TA), and a 40 mmol/L NaHCO3 exposure with AKG-supplemented feed group (FA). Histopathological analysis, biochemical assays, and UPLC-QTOF/MS metabolomics were employed to explore the potential mechanisms by which AKG alleviates oxidative damage in freshwater teleosts induced by saline-alkaline stress. Histopathological results showed that as the concentration of carbonate alkali exposure increased, the severity of kidney lesions in crucian carp (Carassius auratus) worsened. However, in the TA and FA groups, the damage showed varying degrees of repair, with the kidney tissue morphology in the TA group almost restored to the state of the C group. Under carbonate alkali exposure, compared to the C group, the activity of antioxidant enzymes Catalase and Superoxide dismutase in crucian carp kidneys decreased in a dose-dependent manner, but increased upon AKG supplementation. Conversely, the levels of Malondialdehyde, blood ammonia, Urea nitrogen, and Uric acid showed the opposite trend. Metabolomics analysis revealed that carbonate-alkali stress caused a series of metabolic disruptions in fish, including amino acid metabolism, lipid metabolism, and energy metabolism. AKG positively regulated metabolic pathways such as the pentose phosphate pathway, arachidonic acid metabolism, and amino acid metabolism, thereby enhancing the antioxidant, anti-inflammatory, and immune capabilities of fish under saline-alkaline stress, alleviating oxidative damage induced by the stress. Overall, our research indicates that saline-alkaline stress significantly alters kidney function and metabolic characteristics, disrupts the antioxidant system and energy homeostasis, inhibits protein catabolism, and induces kidney damage in crucian carp. Exogenous AKG supplementation effectively mitigates oxidative damage and metabolic disorders in crucian carp kidneys under carbonate-alkaline stress. This study elucidates the physiological mechanisms by which AKG alleviates kidney tissue damage under saline-alkaline stress at the metabolic level, providing scientific evidence for the development of aquaculture in saline-alkaline water.PMID:40054055 | DOI:10.1016/j.cbd.2025.101466

J Proteome Res. 2025 Mar 7. doi: 10.1021/acs.jproteome.4c01068. Online ahead of print.ABSTRACTComputational toolkits for data exploration and visualization from widely used omics platforms often lack flexibility and customization. While many tools generate standardized output, advanced programming skills are necessary to create high-quality visualizations. Therefore, user-friendly tools that simplify this crucial, yet time-consuming, step are essential. We developed EasyPubPlot (Easy Publishable Plotting), a straightforward, easy-to-use, no-coding, user experience-oriented, open-source, and shiny web application along with its associated R package to streamline data exploration and visualization for functional omics-empowered research. EasyPubPlot generates publishable scores plots, volcano plots, heatmaps, box plots, dot plots, and bubble plots with minimal necessary steps. The tool was designed to guide new users to accurate and efficient navigation. Step-by-step tutorials for each type of plot are also provided. Herein, we demonstrated EasyPubPlot's competent functionality and versatility by showcasing metabolomics, proteomics, and transcriptomics data. Collectively, EasyPubPlot reduces the gap between data analysis and stunning visualization, thereby diminishing friction and focusing on science. The app can be downloaded and installed locally (https://github.com/Pharmaco-OmicsLab/EasyPubPlot) or used through a web application (https://pharmaco-omicslab.shinyapps.io/EasyPubPlot).PMID:40053871 | DOI:10.1021/acs.jproteome.4c01068

Sci Adv. 2025 Mar 7;11(10):eads4957. doi: 10.1126/sciadv.ads4957. Epub 2025 Mar 7.ABSTRACTMetabolic dysregulation and altered metabolite concentrations are widely recognized as key characteristics of aging. Comprehensive exploration of endogenous metabolites that drive aging remains insufficient. Here, we conducted an untargeted metabolomics analysis of aging mice, revealing citrulline as a consistently down-regulated metabolite associated with aging. Systematic investigations demonstrated that citrulline exhibited antiaging effects by reducing cellular senescence, protecting against DNA damage, preventing cell cycle arrest, modulating macrophage metabolism, and mitigating inflammaging. Long-term citrulline supplementation in aged mice yielded beneficial effects and ameliorated age-associated phenotypes. We further elucidated that citrulline acts as an endogenous metabolite antagonist to inflammation, suppressing proinflammatory responses in macrophages. Mechanistically, citrulline served as a potential inhibitor of mammalian target of rapamycin (mTOR) activation in macrophage and regulated the mTOR-hypoxia-inducible factor 1α-glycolysis signaling pathway to counter inflammation and aging. These findings underscore the significance of citrulline deficiency as a driver of aging, highlighting citrulline supplementation as a promising therapeutic intervention to counteract aging-related changes.PMID:40053596 | DOI:10.1126/sciadv.ads4957

Chin J Integr Med. 2025 Mar 7. doi: 10.1007/s11655-025-4121-5. Online ahead of print.ABSTRACTOBJECTIVE: To evaluate the anti-hepatocellular carcinoma (HCC) activity of total alkaloids from Gelsemium elegans Benth. (TAG) in vivo and in vitro and to elucidate their potential mechanisms of action through transcriptomic analysis.METHODS: TAG extraction was conducted, and the primary components were quantified using high-performance liquid chromatography (HPLC). The effects of TAG (100, 150, and 200 µg/mL) on various tumor cells, including SMMC-7721, HepG2, H22, CAL27, MCF7, HT29, and HCT116, were assessed. Effects of TAG on HCC proliferation and apoptosis were detected by colony formation assays and cell stainings. Caspase-3, Bcl-2, and Bax protein levels were detected by Western blotting. In vivo, a tumor xenograft model was developed using H22 cells. Totally 40 Kunming mice were randomly assigned to model, cyclophosphamide (20 mg/kg), TAG low-dose (TAG-L, 0.5 mg/kg), and TAG high-dose (TAG-H, 1 mg/kg) groups, with 10 mice in each group. Tumor volume, body weight, and tumor weight were recorded and compared during 14-day treatment. Immune organ index were calculated. Tissue changes were oberseved by hematoxylin and eosin staining and immunohistochemistry. Additionally, transcriptomic and metabolomic analyses, as well as quatitative real-time polymerase chain reaction (RT-qPCR), were performed to detect mRNA and metabolite expressions.RESULTS: HPLC successfully identified the components of TAG extraction. Live cell imaging and analysis, along with cell viability assays, demonstrated that TAG inhibited the proliferation of SMMC-7721, HepG2, H22, CAL27, MCF7, HT29, and HCT116 cells. Colony formation assays, Hoechst 33258 staining, Rhodamine 123 staining, and Western blotting revealed that TAG not only inhibited HCC proliferation but also promoted apoptosis (P<0.05). In vivo experiments showed that TAG inhibited the growth of solid tumors in HCC in mice (P<0.05). Transcriptomic analysis and RT-qPCR indicated that the inhibition of HCC by TAG was associated with the regulation of the key gene CXCL13.CONCLUSION: TAG inhibits HCC both in vivo and in vitro, with its inhibitory effect linked to the regulation of the key gene CXCL13.PMID:40053191 | DOI:10.1007/s11655-025-4121-5

Arq Bras Cir Dig. 2025 Feb 28;38:e1870. doi: 10.1590/0102-6720202500001e1870. eCollection 2025.ABSTRACTBACKGROUND: Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), lacks a known etiology. Although clinical symptoms, imaging, and colonoscopy are common diagnostic tools, fecal calprotectin (FC) serves as a widely used biomarker to track disease activity. Metabolomics, within the omics sciences, holds promise for identifying disease progression biomarkers. This approach involves studying metabolites in biological media to uncover pathological factors.AIMS: The purpose of this study was to explore fecal metabolomics in IBD patients, evaluate its potential in differentiating subtypes, and assess disease activity using FC.METHODS: Cross-sectional study including IBD patients, clinical data, and FC measurements (=200 μg/g as an indicator of active disease).RESULTS: Fecal metabolomics utilized chromatography mass spectrometry/solid phase microextraction with MetaboAnalyst 5.0 software for analysis. Of 52 patients (29 UC, 23 CD), 36 (69.2%) exhibited inflammatory activity. We identified 56 fecal metabolites, with hexadecanoic acid, squalene, and octadecanoic acid notably distinguishing CD from UC. For UC, octadecanoic and hexadecanoic acids correlated with disease activity, whereas octadecanoic acid was most relevant in CD.CONCLUSIONS: These findings highlight the potential of metabolomics as a noninvasive complement for evaluating IBD, aiding diagnosis, and assessing disease activity.PMID:40052996 | DOI:10.1590/0102-6720202500001e1870

J Clin Endocrinol Metab. 2025 Feb 10:dgaf081. doi: 10.1210/clinem/dgaf081. Online ahead of print.ABSTRACTCONTEXT: Primary aldosteronism (PA) is commonly caused by somatic mutations of CACNA1D encoding Cav1.3, one of the four L-type calcium channels. The over-the-counter drug, cinnarizine, fits the Cav1.3 crystal structure pore domain.OBJECTIVE: We hypothesized that Cav1.3 blockade by cinnarizine may achieve similar, or greater, reduction in aldosterone secretion than nonselective Cav1.2/1.3 blockade by nifedipine.METHODS: Separate wells of angiotensin II-stimulated HAC15 cells were treated with either cinnarizine (1-30 μM) or nifedipine (1-100 μM). Aldosterone concentrations were measured in culture medium; RNA extraction and quantitative polymerase chain reaction were performed to evaluate CYP11B2 expression. A prospective, open-label, crossover study was conducted of 15 adults with PA, treated with 2 weeks of cinnarizine 30 mg 3 times a day or nifedipine extended release 60 mg daily, separated by a 2-week washout. The hierarchical primary outcome was change in aldosterone-to-renin ratio (ARR), urinary tetrahydroaldosterone (THA), and plasma aldosterone concentration (PAC). Blood pressure change was a secondary outcome. Parametric analysis was undertaken on log-transformed data. (ClinicalTrials.gov: NCT05686993).RESULTS: Both drugs reduced aldosterone concentrations and CYP11B2 expression in vitro. Mean changes ± SEM in fold change of aldosterone concentrations and CYP11B2 were -0.47 ± 0.05 and -0.56 ± 0.07, respectively, with cinnarizine 30 μM and -0.59 ± 0.05 and -0.78 ± 0.07 with nifedipine 100 μM. In the clinical crossover trial, ARR was reduced by nifedipine but not cinnarizine (F = 3.25; P = .047); PAC rose with both drugs (F = 4.77; P = .013), but urinary THA was unchanged.CONCLUSION: A Cav1.3 ligand, cinnarizine, reduced aldosterone secretion from adrenocortical cells, but at maximum-soluble concentrations was less effective than the nonselective calcium blocker, nifedipine. At clinical doses, cinnarizine did not reduce plasma ARR in patients with PA, and, as in vitro, was inferior to nifedipine. The limited efficacy of high-dose nifedipine may be due to incomplete Cav1.3 blockade, or to a role for non-L-type calcium channels in aldosterone secretion.PMID:40052842 | DOI:10.1210/clinem/dgaf081

FASEB J. 2025 Mar 15;39(5):e70411. doi: 10.1096/fj.202402726R.ABSTRACTViral infections can cause cellular dysregulation of metabolic reactions. Viruses alter host metabolism to meet their replication needs. The impact of viruses on specific metabolic pathways is not well understood, even in well-studied viruses, such as human adenovirus. Adenoviral infection is known to influence cellular glycolysis and respiration; however, global effects on overall cellular metabolism in response to infection are unclear. Furthermore, few studies have employed an untargeted approach, combining emphasis on viral dosage and infection. To address this, we employed untargeted metabolomics to quantify the dynamic metabolic shifts in fibroblasts infected with human adenovirus serotype 5 (HAdV-5) at three dosages (0.5, 1.0, and 2.0 multiplicity of infection [MOI]) and across 4 time points (6-, 12-, 24-, and 36-h post-infection [HPI]). The greatest differences in individual metabolites were observed at 6- and 12-h post-infection, correlating with the early phase of the HAdV-5 infection cycle. In addition to its effects on glycolysis and respiration, adenoviral infection downregulates cysteine and unsaturated fatty acid metabolism while upregulating aspects of purine metabolism. These results reveal specific metabolic pathways dysregulated by adenoviral infection and the associated dynamic shifts in metabolism, suggesting that viral infections alter energetics via profound changes in lipid, nucleic acid, and protein metabolism. The results revealed previously unconsidered metabolic pathways disrupted by HAdV-5 that can alter cellular metabolism, thereby prompting further investigation into HAdV mechanisms and antiviral targeting.PMID:40052831 | DOI:10.1096/fj.202402726R

Elife. 2025 Mar 7;13:RP102205. doi: 10.7554/eLife.102205.ABSTRACTThe most common primary malignancy of the liver, hepatocellular carcinoma (HCC), is a heterogeneous tumor entity with high metastatic potential and complex pathophysiology. Increasing evidence suggests that tissue mechanics plays a critical role in tumor onset and progression. Here, we show that plectin, a major cytoskeletal crosslinker protein, plays a crucial role in mechanical homeostasis and mechanosensitive oncogenic signaling that drives hepatocarcinogenesis. Our expression analyses revealed elevated plectin levels in liver tumors, which correlated with poor prognosis for HCC patients. Using autochthonous and orthotopic mouse models we demonstrated that genetic and pharmacological inactivation of plectin potently suppressed the initiation and growth of HCC. Moreover, plectin targeting potently inhibited the invasion potential of human HCC cells and reduced their metastatic outgrowth in the lung. Proteomic and phosphoproteomic profiling linked plectin-dependent disruption of cytoskeletal networks to attenuation of oncogenic FAK, MAPK/Erk, and PI3K/Akt signatures. Importantly, by combining cell line-based and murine HCC models, we show that plectin inhibitor plecstatin-1 (PST) is well-tolerated and potently inhibits HCC progression. In conclusion, our study demonstrates that plectin-controlled cytoarchitecture is a key determinant of HCC development and suggests that pharmacologically induced disruption of mechanical homeostasis may represent a new therapeutic strategy for HCC treatment.PMID:40052672 | DOI:10.7554/eLife.102205

Compr Rev Food Sci Food Saf. 2025 Mar;24(2):e70156. doi: 10.1111/1541-4337.70156.ABSTRACTPlant-derived polysaccharides have emerged as sustainable biopolymers for fabricating nanoparticles (polysaccharide-based nanomaterials [PS-NPs]), presenting unique opportunities to enhance food functionality and human health. PS-NPs exhibit exceptional biocompatibility, biodegradability, and structural versatility, enabling their integration into functional foods to positively influence gut microbiota. This review explores the mechanisms of PS-NPs interaction with gut microbiota, highlighting their ability to promote beneficial microbial populations, such as Lactobacilli and Bifidobacteria, and stimulate the production of short-chain fatty acids. Key synthesis and stabilization methods of PS-NPs are discussed, focusing on their role in improving bioavailability, stability, and gastrointestinal delivery of bioactive compounds in food systems. The potential of PS-NPs to address challenges in food science, including enhancing nutrient absorption, mitigating intestinal dysbiosis, and supporting sustainable food production through innovative nanotechnology, is critically evaluated. Barriers such as enzymatic degradation and physicochemical stability are analyzed, alongside strategies to optimize their functionality within complex food matrices. The integration of PS-NPs in food systems offers a novel approach to modulate gut microbiota, improve intestinal health, and drive the development of next-generation functional foods. Future research should focus on bridging knowledge gaps in metagenomic and metabolomic profiling of PS-NPs, optimizing their design for diverse applications, and advancing their role in sustainable and health-promoting food innovations.PMID:40052474 | DOI:10.1111/1541-4337.70156

Plant J. 2025 Mar;121(5):e70086. doi: 10.1111/tpj.70086.ABSTRACTPlant specialized metabolites play key roles in diverse physiological processes and ecological interactions. Identifying structurally novel metabolites, as well as discovering known compounds in new species, is often crucial for answering broader biological questions. The Piper genus (Piperaceae family) is known for its special phytochemistry and has been extensively studied over the past decades. Here, we investigated the alkaloid diversity of Piper fimbriulatum, a myrmecophytic plant native to Central America, using a metabolomics workflow that combines untargeted LC-MS/MS analysis with a range of recently developed computational tools. Specifically, we leverage open MS/MS spectral libraries and metabolomics data repositories for metabolite annotation, guiding isolation efforts toward structurally new compounds (i.e., dereplication). As a result, we identified several alkaloids belonging to five different classes and isolated one novel seco-benzylisoquinoline alkaloid featuring a linear quaternary amine moiety which we named fimbriulatumine. Notably, many of the identified compounds were never reported in Piperaceae plants. Our findings expand the known alkaloid diversity of this family and demonstrate the value of revisiting well-studied plant families using state-of-the-art computational metabolomics workflows to uncover previously overlooked chemodiversity. To contextualize our findings within a broader biological context, we employed a workflow for automated mining of literature reports of the identified alkaloid scaffolds and mapped the results onto the angiosperm tree of life. By doing so, we highlight the remarkable alkaloid diversity within the Piper genus and provide a framework for generating hypotheses on the biosynthetic evolution of these specialized metabolites. Many of the computational tools and data resources used in this study remain underutilized within the plant science community. This manuscript demonstrates their potential through a practical application and aims to promote broader accessibility to untargeted metabolomics approaches.PMID:40052447 | DOI:10.1111/tpj.70086

Front Plant Sci. 2025 Feb 20;15:1425154. doi: 10.3389/fpls.2024.1425154. eCollection 2024.ABSTRACTTop removal is a widely utilized method in production process of tobacco, but little is known regarding the way it impacts protein and metabolic regulation. In this study, we investigated the underlying processes of alterations in cigar tobacco leaves with and without top removal, using a combined proteomic and metabolomic approach. The results revealed that: (1) Topping significantly affected superoxide anion (O2 -) levels, superoxide dismutase (SOD) activity, and malondialdehyde (MDA) content, (2) In the cigar tobacco proteome, 385 differentially expressed proteins (DEPs) were identified, with 228 proteins upregulated and 156 downregulated. Key pathways enriched included flavonoid biosynthesis, porphyrin and chlorophyll metabolism, cysteine and methionine metabolism, and amino acid biosynthesis and metabolism. A network of 161 nodes interconnected by 102 significantly altered proteins was established, (3) In the cigar tobacco metabolome, 247 significantly different metabolites (DEMs) were identified, with 120 upregulated and 128 downregulated metabolites, mainly comprising lipids and lipid-like molecules, phenylpropanoids and polyketides, organic acids and derivatives, and organic heterocyclic compounds, (4) KEGG pathway enrichment revealed upregulation of proteins such as chalcone synthase (CHS), chalcone isomerase (CHI), naringenin 3-dioxygenase (F3H), and flavonoid 3'-monooxygenase (F3'H), along with metabolites like pinocembrin, kaempferol, trifolin, rutin, and quercetin, enhancing the pathways of 'flavonoid' and 'flavone and flavonol' biosynthesis. This study sheds light on the metabolic and proteomic responses of cigar tobacco after topping.PMID:40052119 | PMC:PMC11882365 | DOI:10.3389/fpls.2024.1425154