Nat Struct Mol Biol. 2025 Mar 3. doi: 10.1038/s41594-025-01482-z. Online ahead of print.

ABSTRACT

Spermatogenesis is a unidirectional differentiation process that generates haploid sperm, but how the gene expression program that directs this process is established is largely unknown. Here we determine the high-resolution three-dimensional (3D) chromatin architecture of mouse male germ cells during spermatogenesis and show that CTCF-mediated 3D chromatin dictates the gene expression program required for spermatogenesis. In undifferentiated spermatogonia, CTCF-mediated chromatin interactions between meiosis-specific super-enhancers (SEs) and their target genes precede activation of these SEs on autosomes. These meiotic SEs recruit the master transcription factor A-MYB (MYBL1) in meiotic spermatocytes, which strengthens their 3D contacts and instructs a burst of meiotic gene expression. We also find that at the mitosis-to-meiosis transition, the germline-specific Polycomb protein SCML2 facilitates the resolution of chromatin loops that are specific to mitotic spermatogonia. Moreover, SCML2 and A-MYB help shape the unique 3D chromatin organization of sex chromosomes during meiotic sex chromosome inactivation. We propose that CTCF-mediated 3D chromatin organization regulates epigenetic priming that directs unidirectional differentiation, thereby determining the cellular identity of the male germline.

PMID:40033153 | DOI:10.1038/s41594-025-01482-z

Nat Microbiol. 2025 Mar 3. doi: 10.1038/s41564-025-01938-4. Online ahead of print.

ABSTRACT

Diet, microbiome, inflammation and host genetics have been linked to colorectal cancer development; however, it is not clear whether and how these factors interact to promote carcinogenesis. Here we used Il10-/- mice colonized with bacteria previously associated with colorectal cancer: enterotoxigenic Bacteroides fragilis, Helicobacter hepaticus or colibactin-producing (polyketide synthase-positive (pks+)) Escherichia coli and fed either a low-carbohydrate (LC) diet deficient in soluble fibre, a high-fat and high-sugar diet, or a normal chow diet. Colonic polyposis was increased in mice colonized with pks+ E. coli and fed the LC diet. Mechanistically, mucosal inflammation was increased in the LC-diet-fed mice, leading to diminished colonic PPAR-γ signalling and increased luminal nitrate levels. This promoted both pks+ E. coli growth and colibactin-induced DNA damage. PPAR-γ agonists or supplementation with dietary soluble fibre in the form of inulin reverted inflammatory and polyposis phenotypes. The pks+ E. coli also induced more polyps in mismatch-repair-deficient mice by inducing a senescence-associated secretory phenotype. Moreover, oncogenic effects were further potentiated by inflammatory triggers in the mismatch-repair-deficient model. These data reveal that diet and host genetics influence the oncogenic potential of a common bacterium.

PMID:40033140 | DOI:10.1038/s41564-025-01938-4

Commun Biol. 2025 Mar 3;8(1):355. doi: 10.1038/s42003-025-07768-8.

ABSTRACT

Plants cope with the environment by displaying large phenotypic variation. Two spectra of global plant form and function have been identified: a size spectrum from small to tall species with increasing stem tissue density, leaf size, and seed mass; a leaf economics spectrum reflecting slow to fast returns on investments in leaf nutrients and carbon. When species assemble to communities it is assumed that these spectra are filtered by the environment to produce community level functional composition. It is unknown what are the main drivers for community functional composition in a large area such as Amazonia. We use 13 functional traits, including wood density, seed mass, leaf characteristics, breeding system, nectar production, fruit type, and root characteristics of 812 tree genera (5211 species), and find that they describe two main axes found at the global scale. At community level, the first axis captures not only the 'fast-slow spectrum', but also most size-related traits. Climate and disturbance explain a minor part of this variance compared to soil fertility. Forests on poor soils differ largely in terms of trait values from those on rich soils. Trait composition and soil fertility exert a strong influence on forest functioning: biomass and relative biomass production.

PMID:40033015 | DOI:10.1038/s42003-025-07768-8

Nat Rev Rheumatol. 2025 Mar 3. doi: 10.1038/s41584-025-01231-y. Online ahead of print.

NO ABSTRACT

PMID:40032952 | DOI:10.1038/s41584-025-01231-y

Genome Res. 2025 Mar 3:gr.280021.124. doi: 10.1101/gr.280021.124. Online ahead of print.

ABSTRACT

SQANTI-reads leverages SQANTI3, a tool for the analysis of the quality of transcript models, to develop a read-level quality control framework for replicated long-read RNA-seq experiments. The number and distribution of reads, as well as the number and distribution of unique junction chains (transcript splicing patterns), in SQANTI3 structural categories are informative of raw data quality. Multisample visualizations of QC metrics are presented by experimental design factors to identify outliers. We introduce new metrics for 1) the identification of potentially under-annotated genes and putative novel transcripts and for 2) quantifying variation in junction donors and acceptors. We applied SQANTI-reads to two different datasets, a Drosophila developmental experiment and a multiplatform dataset from the LRGASP project and demonstrate that the tool effectively reveals the impact of read coverage on data quality, and readily identifies strong and weak splicing sites.

PMID:40032587 | DOI:10.1101/gr.280021.124

Genome Res. 2025 Mar 3:gr.279865.124. doi: 10.1101/gr.279865.124. Online ahead of print.

ABSTRACT

Long-read sequencing (LRS) technologies have revolutionized transcriptomic research by enabling the comprehensive sequencing of full-length transcripts. Using these technologies, researchers have reported tens of thousands of novel transcripts, even in well-annotated genomes, while developing new algorithms and experimental approaches to handle the noisy data. The LRGASP community effort benchmarked LRS methods in transcriptomics and validated many novel, lowly-expressed, sample-specific transcripts identified by long reads. These molecules represent deviations of the major transcriptional program, that were easily overlooked by short-read sequencing methods but are now captured by the full-length, single-molecule approach. This Perspective discusses the challenges and opportunities associated with LRS' capacity to unravel this fraction of the transcriptome, both in terms of transcriptome biology and genome annotation. For transcriptome biology, we need to develop novel experimental and computational methods to effectively differentiate technology errors from rare but real molecules. For genome annotation, we must agree on the strategy to capture molecular variability while still defining reference annotations that are useful for genome research.

PMID:40032585 | DOI:10.1101/gr.279865.124

Environ Pollut. 2025 Mar 1:125914. doi: 10.1016/j.envpol.2025.125914. Online ahead of print.

ABSTRACT

Microplastics are an increasingly prevalent form of pollution in coastal ecosystems. Current research focuses on understanding the impacts of such synthetic particles on the health and functioning of aquatic organisms. Recent studies have shown that invertebrates can accumulate microplastics in their tissue, impacting key functions such as growth, reproduction, feeding activity, and metabolism. Owing to their chemical composition, microplastics accumulating in the digestive tract of animals may alter the diversity and abundance of microbiota. Despite the important implications of such microbiota shifts on digestive ability and fitness, investigations on microplastics as causative agents are so far limited. In this study, we tested the effect of microfibers, on the digestive gland microbiota of the blue mussel Mytilus edulis after a 52-day exposure. Our findings show that exposure to microplastics can alter the composition of the digestive gland microbiota, with significant decreases in the classes of Actinobacteria, Bacteroidia, and significant increases for Alphaproteobacteria and Gammaproteobacteria. Furthermore, an increase in the number of genera containing potential pathogenic species for bivalves, such as Francisella and Vibrio, was detected. This suggests that accumulated microplastics pose a dual threat to filter-feeding organisms and the ecosystem services they provide. Further comparative studies are necessary to establish whether the microbiota shift is linked to the specific chemical composition of microplastics or whether there is an indirect link such as physiological stress resulting from ingestion.

PMID:40032227 | DOI:10.1016/j.envpol.2025.125914

Bone. 2025 Mar 1:117444. doi: 10.1016/j.bone.2025.117444. Online ahead of print.

ABSTRACT

Fracture healing is a complex biological process involving orchestrated interactions among cells, growth factors, and transcriptional pathways. Despite significant advancements in understanding bone repair, non-union and delayed healing remain prevalent, especially in patients with comorbidities such as aging, diabetes, or substance use. Murine models serve as a cornerstone in fracture healing research, offering genetic manipulability, cost-effectiveness, and biological relevance to humans. This scoping review consolidates findings from studies conducted between 2010 and 2024, focusing on mechanistic pathways derived from transcriptional analysis in secondary bone healing as identified through bulk RNA sequencing of murine models. Key mechanistic pathways were categorized and analyzed across the distinct phases of fracture healing-reactive, reparative, and remodeling-highlighting their unique roles in inflammation, ECM remodeling, cell proliferation, and tissue mineralization. The most recurrent mechanistic pathways included ECM-receptor interaction, focal adhesion, and signaling mechanisms such as MAPK and TGF-beta. Variability in methodologies and limited overlap among studies underscore the need for standardized protocols in RNA sequencing analysis. Additionally, comparisons across long bone fractures, hole defects, and craniofacial bone healing revealed shared molecular mechanisms alongside unique challenges, particularly in craniofacial models. This scoping review underscores the promise of integrating systems biology approaches with transcriptomic data to elucidate the intricate regulatory networks governing fracture repair. Addressing the identified gaps in early-phase healing and harmonizing research methodologies will advance therapeutic strategies to reduce non-union rates and improve clinical outcomes.

PMID:40032014 | DOI:10.1016/j.bone.2025.117444

Proc Natl Acad Sci U S A. 2025 Mar 11;122(10):e2417943122. doi: 10.1073/pnas.2417943122. Epub 2025 Mar 3.

ABSTRACT

Sperm morphogenesis is a tightly regulated differentiation process, disruption of which leads to sperm malfunction and male infertility. Here, we show that Tex38 knockout (KO) male mice are infertile. Tex38 KO spermatids exhibit excess retention of residual cytoplasm around the head, resulting in abnormal sperm morphology with backward head bending. TEX38 interacts and colocalizes with ZDHHC19, a testis-enriched acyltransferase catalyzing protein S-palmitoylation, at the plasma membrane of spermatids. ZDHHC19 and TEX38 are each downregulated in mouse testes lacking the other protein. TEX38 stabilizes and localizes ZDHHC19 to the plasma membrane of cultured cells and vice versa, consolidating their interdependence. Mice deficient in ZDHHC19 or harboring a C142S mutation that disables the palmitoyltransferase activity of ZDHHC19 display phenotypes resembling those of Tex38 KO mice. Strikingly, ZDHHC19 palmitoylates ARRDC5, an arrestin family protein regulating sperm differentiation. Overall, our findings indicate that TEX38 forms a stable complex with ZDHHC19 at the plasma membrane of spermatids, which governs downstream S-palmitoylation of proteins essential for morphological transformation of spermatids.

PMID:40030029 | DOI:10.1073/pnas.2417943122

PLoS Biol. 2025 Mar 3;23(3):e3003030. doi: 10.1371/journal.pbio.3003030. Online ahead of print.

ABSTRACT

In Drosophila, two interacting adhesion protein families, Defective proboscis responses (Dprs) and Dpr interacting proteins (DIPs), coordinate the assembly of neural networks. While intercellular DIP::Dpr interactions have been well characterized, DIPs and Dprs are often co-expressed within the same cells, raising the question as to whether they also interact in cis. We show, in cultured cells and in vivo, that DIP-α and DIP-δ can interact in cis with their ligands, Dpr6/10 and Dpr12, respectively. When co-expressed in cis with their cognate partners, these Dprs regulate the extent of trans binding, presumably through competitive cis interactions. We demonstrate the neurodevelopmental effects of cis inhibition in fly motor neurons and in the mushroom body. We further show that a long disordered region of DIP-α at the C-terminus is required for cis but not trans interactions, likely because it alleviates geometric constraints on cis binding. Thus, the balance between cis and trans interactions plays a role in controlling neural development.

PMID:40029885 | DOI:10.1371/journal.pbio.3003030

Methods Mol Biol. 2025;2909:165-178. doi: 10.1007/978-1-0716-4442-3_12.

ABSTRACT

Combining mathematical modeling with experiments enables quantitative understanding of cell signaling, transcriptional regulation, and cell fate decisions. Here, we provide a systems biology approach to link signal transduction with B cells fate decisions, to enable quantitative prediction of B-cell proliferation, and differentiation. We describe methodology to run simulations that reveal how signal transduction regulates gene expression and predicts cell fate decision. We describe how to quantitively validate modeling predictions with wet-lab experiments.

PMID:40029522 | DOI:10.1007/978-1-0716-4442-3_12

Microbiol Spectr. 2025 Mar 3:e0212924. doi: 10.1128/spectrum.02129-24. Online ahead of print.

ABSTRACT

Micromonospora strains proved to be a model organism for drug discovery and plant growth promotion (PGP). Strain DSM 115977 T was subjected to polyphasic taxonomic analysis and genome mining for biosynthetic gene clusters and PGP-associated genes in order to determine its taxonomic rank and assess its biosynthetic potential. The strain was found to form a novel species within the evolutionary radiation of the genus Micromonospora. The strain contained glucose, mannose, xylose, and ribose as whole-cell sugars and the isomer DL-diaminopimelic acid in its peptidoglycan. Strain DSM 115977T had iso-C15:0, iso-C16:0, C17:1cis 9, C17:0, iso-C17:0, and 10-methyl-C17:0 as fatty acid profile (>5%) and MK10-H4 and MK10-H6 as the predominant menaquinones (>10%). The polar lipid profile consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol, glycophosphatidylinositol, glycophospholipids, phosphoaminolipid, unidentified lipids, and phospholipids. The genome of the strain had a size of 7.0 Mbp with a DNA G + C content of 73.4%. It formed a well-supported sub-clade with its close phylogenomic neighbor, Micromonospora echinofusca DSM 43913T (98.7%). Digital DNA-DNA hybridization and average nucleotide identity derived from sequence comparisons between the strain and its close phylogenomic neighbors were below the thresholds of 70 and 95-96% for prokaryotic species demarcation, respectively. Based on these findings, strain DSM 115977T (Asg4T = KCTC 59188T) merits to be considered as the type strain of a new species for which the name Micromonospora reichwaldensis sp. nov. is proposed. Genome mining for biosynthetic gene clusters encoding specialized secondary metabolites highlighted its ability to produce potentially novel therapeutic compounds. The strain is rich in plant growth-promoting genes whose predicted products directly and indirectly affect the development and immune system of the plant.

IMPORTANCE: In view of the significant pharmaceutical, biotechnological, and ecological potentials of micromonosporae, it is particularly interesting to enhance the genetic diversity of this genus by focusing on the isolation of novel strain from underexplored habitats, with the promise that novel bacteria will lead to new chemical entities. In this report, modern polyphasic taxonomic study confirmed the assignment of strain DSM 115977T to a novel species for which the name Micromonospora reichwaldensis sp. nov. is proposed. The strain harbors in its genomic sequence several biosynthetic gene clusters for secondary metabolites and genes associated with plant growth-promoting features. The results of this study provide a very useful basis for launching more in-depth research into agriculture and/or drug discovery.

PMID:40029309 | DOI:10.1128/spectrum.02129-24

Plant J. 2025 Mar;121(5):e70047. doi: 10.1111/tpj.70047.

ABSTRACT

Plants are essential for human survival. Over the past three decades, work with the reference plant Arabidopsis thaliana has significantly advanced plant biology research. One key event was the sequencing of its genome 25 years ago, which fostered many subsequent research technologies and datasets. Arabidopsis has been instrumental in elucidating plant-specific aspects of biology, developing research tools, and translating findings to crop improvement. It not only serves as a model for understanding plant biology and but also biology in other fields, with discoveries in Arabidopsis also having led to applications in human health, including insights into immunity, protein degradation, and circadian rhythms. Arabidopsis research has also fostered the development of tools useful for the wider biological research community, such as optogenetic systems and auxin-based degrons. This 4th Multinational Arabidopsis Steering Committee Roadmap outlines future directions, with emphasis on computational approaches, research support, translation to crops, conference accessibility, coordinated research efforts, climate change mitigation, sustainable production, and fundamental research. Arabidopsis will remain a nexus for discovery, innovation, and application, driving advances in both plant and human biology to the year 2030, and beyond.

PMID:40028766 | DOI:10.1111/tpj.70047

F1000Res. 2024 Sep 13;13:1055. doi: 10.12688/f1000research.155928.1. eCollection 2024.

ABSTRACT

CSNK1A1 is a key regulator of various signalling pathways, including the Wnt/β-catenin pathway. Playing a central role in cellular function and disease pathology, CSNK1A1 has emerged as an attractive protein target for therapeutic development. In this study we characterize ten CSNK1A1 commercial antibodies for western blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. This study is part of a larger, collaborative initiative seeking to address antibody reproducibility issues by characterizing commercially available antibodies for human proteins and publishing the results openly as a resource for the scientific community. While the use of antibodies and protocols vary between laboratories, we encourage readers to use this report as a guide to select the most appropriate antibodies for their specific needs.

PMID:40028451 | PMC:PMC11868743 | DOI:10.12688/f1000research.155928.1

F1000Res. 2025 Feb 20;13:886. doi: 10.12688/f1000research.154058.2. eCollection 2024.

ABSTRACT

BACKGROUND: The mass vaccination campaign against COVID-19 has been commonly considered the best response to the global COVID-19 pandemic crisis. However, assessment of its real-world effect can be performed by analysis of all-cause mortality by vaccination status. The UK is perhaps the only country which has made publicly available all-cause mortality data by vaccination status.

METHODS: Data from April 2021 to May 2023 published by the UK Office for National Statistics (ONS) were retrospectively analyzed by age groups and vaccination status; the standardized mortality ratio (SMR) for all-cause and non-COVID-19 mortality was calculated against the corresponding unvaccinated groups.

RESULTS: We found that across all age groups, all-cause mortality SMRs increased from a certain date, dependent on the age group. Across all age groups, all-cause mortality SMRs were initially much lower than 1. However, due to their increase, by a certain date for the 18-39, 80-89 and 90+ age groups they exceeded the reference value. For the other age groups, the date at which the SMR would reach 1 can be predicted, provided the trend is maintained. Non-COVID-19 SMRs' trends were very similar. Their initial values much lower than 1 are suggestive of significant biases in the ONS dataset, leading to underestimate the risks for the vaccinated people, as it is implausible that COVID-19 vaccines protect against non-COVID-19 deaths.

CONCLUSIONS: The increase over time in all-cause death SMRs in vaccinated people compared to unvaccinated, and their excess from the reference values for certain age groups, should be carefully considered to understand the underlying factors. Furthermore, since the initial values of the SMRs are much lower than 1, we assume the presence of significant biases in the ONS dataset, leading to understimate the risks for the vaccinated people, as it is implausible that COVID-19 vaccines protect against non-COVID-19 deaths. It would be desirable for other major countries to systematically collect all-cause mortality by vaccination status and, in the meantime, a pending indepth investigations, much greater caution should be exercised in promoting mass vaccination campaigns.

PMID:40028449 | PMC:PMC11868741 | DOI:10.12688/f1000research.154058.2

iScience. 2025 Jan 27;28(2):111904. doi: 10.1016/j.isci.2025.111904. eCollection 2025 Feb 21.

ABSTRACT

Nonrapid eye movement sleep is characterized by high-amplitude and low-frequency electroencephalography signals. These signals are thought to be produced by the synchronized activity of cortical neurons, demonstrating the alternating bursting (up) and resting (down) states. Here, such an activity is referred to as up-down oscillation (UDO). Previously, we discussed the importance of the Ca2+-dependent hyperpolarization pathway in the generation of UDO by simulating neuronal activity based on the Hodgkin-Huxley-type model. We herein focus on intracellular Na+ dynamics. The Na+-centered model indicates that the activation of voltage-gated Na+ channels leads to intracellular Na+ accumulation, which in turn activates Na+-dependent K+ (KNa) channels or Na+/K+ ATPases, resulting in the down state. Activation kinetics of voltage-gated Na+ channels are important in shaping the UDO firing. Therefore, our model demonstrates that voltage-gated Na+ and KNa channels or Na+/K+ ATPases are candidate pathways for UDO induction.

PMID:40028276 | PMC:PMC11869597 | DOI:10.1016/j.isci.2025.111904

ACS Omega. 2025 Feb 11;10(7):6446-6469. doi: 10.1021/acsomega.4c06456. eCollection 2025 Feb 25.

ABSTRACT

Recent investigations have shown serotonin's stimulatory effect on several types of cancers and carcinoid tumors. Nowadays there has been a significant increase in interest in 5-HT7 and 5-HT5A receptors in the context of cancer treatment. The possible role of 5-HT6R in the pathogenesis and progression of glioma remains an interesting and relatively unexplored issue. We developed a new group of long-chain 2-aminoquinazoline sulfonamides as new multifunctional serotonin receptor ligands, focused on 5-HT6R. The chosen group was further evaluated for antiproliferative effects on 1321N1 astrocytoma cells, along with U87MG, U-251, and LN-229 glioblastoma cell lines. Certain compounds were subjected to in vitro absorption, distribution, metabolism, excretion, and toxicity (ADMET) testing, for assessing factors such as lipophilicity, plasma protein binding, phospholipid affinity, potential for drug-drug interactions (DDI), membrane permeability (PAMPA), metabolic stability, and hepatotoxicity. Additionally, in vivo testing was performed using the Danio rerio model. The developed group includes the selective 5-HT6R antagonist PP 15, dual ligand for 5-HT1AR/5-HT6R PP 13, and dual ligand for 5-HT5AR/5-HT6R PP 10. The use of multifunctional ligands was associated with high anticancer activity both against selected glioma cell lines and other cancers (IC50 < 25 μM).

PMID:40028084 | PMC:PMC11866022 | DOI:10.1021/acsomega.4c06456

Imeta. 2024 Dec 28;4(1):e263. doi: 10.1002/imt2.263. eCollection 2025 Feb.

ABSTRACT

Given the key role of energy grasses in biomass energy, electricity, biofuels, and carbon sequestration, the Energy Grass Omics Database (EGDB) integrates germplasm data with genomics, transcriptomics, epigenomics, and phenomics data to support functional genomic research on diverse energy grass species. EGDB also currently supplies the largest epigenetic data set of energy grasses: a high-resolution chromatin modification, chromatin accessibility, and gene expression landscape of pearl millet to provide insights into regulatory traits essential for sustainable energy production.

PMID:40027491 | PMC:PMC11865331 | DOI:10.1002/imt2.263

Imeta. 2025 Feb 21;4(1):e70000. doi: 10.1002/imt2.70000. eCollection 2025 Feb.

ABSTRACT

Cholesterol gallstones (CGS) still lack effective noninvasive treatment. The etiology of experimentally proven cholesterol stones remains underexplored. This cross-sectional study aims to comprehensively evaluate potential biomarkers in patients with gallstones and assess the effects of microbiome-targeted interventions in mice. Microbiome taxonomic profiling was conducted on 191 samples via V3-V4 16S rRNA sequencing. Next, 60 samples (30 age- and sex-matched CGS patients and 30 controls) were selected for metagenomic sequencing and fecal metabolite profiling via liquid chromatography-mass spectrometry. Microbiome and metabolite characterizations were performed to identify potential biomarkers for CGS. Eight-week-old male C57BL/6J mice were given a lithogenic diet for 8 weeks to promote gallstone development. The causal relationship was examined through monocolonization in antibiotics-treated mice. The effects of short-chain fatty acids such as sodium butyrate, sodium acetate (NaA), sodium propionate, and fructooligosaccharides (FOS) on lithogenic diet-induced gallstones were investigated in mice. Gut microbiota and metabolites exhibited distinct characteristics, and selected biomarkers demonstrated good diagnostic performance in distinguishing CGS patients from healthy controls. Multi-omics data indicated associations between CGS and pathways involving butanoate and propanoate metabolism, fatty acid biosynthesis and degradation pathways, taurine and hypotaurine metabolism, and glyoxylate and dicarboxylate metabolism. The incidence of gallstones was significantly higher in the Clostridium glycyrrhizinilyticum group compared to the control group in mice. The grade of experimental gallstones in control mice was significantly higher than in mice treated with NaA and FOS. FOS could completely inhibit the formation of gallstones in mice. This study characterized gut microbiome and metabolome alterations in CGS. C. glycyrrhizinilyticum contributed to gallstone formation in mice. Supplementing with FOS could serve as a potential approach for managing CGS by altering the composition and functionality of gut microbiota.

PMID:40027485 | PMC:PMC11865347 | DOI:10.1002/imt2.70000

Diabetes Metab Syndr Obes. 2025 Feb 25;18:583-599. doi: 10.2147/DMSO.S493036. eCollection 2025.

ABSTRACT

BACKGROUND: Shenzhu Tiaopi granule (STG) has antidiabetic functions. Data-independent acquisition proteomic technology is an integral part of systems biology. Herein, proteomics was used to analyse the effects of STG on type 2 diabetes mellitus (T2DM) and the mechanism by which STG normalizes glucose metabolism.

METHODS: Goto-Kakizaki (GK) T2DM model (Mod) rats, aged 15-16 weeks and with a fasting blood glucose (FBG) level of ≥11.1 mmol/L, were treated with metformin or STG for 12 weeks. Wistar rats aged 15-16 weeks were included in the control (Con) group. Body weight, FBG, total cholesterol (TC), total triglyceride (TG) levels and low-density lipoprotein (LDL-C) levels were measured, and pathological observation, Western blot analysis and data-independent acquisition proteomics of the liver were performed.

RESULTS: Significant differences in FBG, TC, TG, LDL-C (p < 0.01) and pathological liver morphology were observed between the Mod group and Con group, whereas both metformin and STG normalized the glucose and lipid metabolism indicators (p < 0.05 or p < 0.01). In total, 5856 proteins were identified via proteomic analysis, 97 of which were significantly differentially expressed in the liver and affected fatty acid metabolism, unsaturated fatty acid biosynthesis, the peroxisome proliferator-activated receptor (PPAR) signalling pathway, pyruvate metabolism, and terpenoid backbone biosynthesis. Screening identified 10 target proteins, including perilipin-2 (Plin2), pyruvate dehydrogenase kinase 4, farnesyl diphosphate synthase (Fdps) and farnesyl-diphosphate farnesyltransferase 1. Among these proteins, the key proteins were Plin2 and Fdps, which were found to be associated with the PPAR signalling pathway and terpenoid backbone biosynthesis via relationship networks. Plin2 and Fdps are closely related to hyperglycaemia. STG can downregulate Plin2 and upregulate Fdps (p < 0.01).

CONCLUSION: STG ameliorated hyperglycaemia by significantly altering the expression of different proteins, especially Fdps and Plin2, in the livers of GK rats. These findings may reveal the potential of traditional Chinese medicine for treating T2DM.

PMID:40026899 | PMC:PMC11871873 | DOI:10.2147/DMSO.S493036