Colorectal cancer (CRC) is a major global health burden characterized by progressive genetic and metabolic alterations, with iron metabolism being increasingly recognized as a key contributor to tumorigenesis. This review provides an integrated synthesis of current evidence on iron metabolism across the continuum of colorectal cancer development, from preneoplastic lesions to advanced disease. We analyzed data from epidemiological, experimental, and mechanistic studies addressing systemic and cellular iron homeostasis, including the hepcidin-ferroportin axis, as well as iron handling within tumor cells and the tumor microenvironment. Available data indicate that colorectal epithelial cells progressively develop an iron-retentive phenotype, characterized by increased iron uptake and reduced export, leading to expansion of the intracellular labile iron pool. This imbalance contributes to oxidative stress, DNA damage, metabolic adaptation, and activation of oncogenic signaling pathways while also influencing immune responses. However, epidemiological findings on dietary iron and CRC risk remain inconsistent, highlighting the context-dependent nature of iron-related effects. In conclusion, iron metabolism represents a dynamic regulator of CRC progression and a mechanistic framework for understanding stage-specific tumor evolution, although further studies are needed to clarify how iron-dependent pathways differ across colorectal tumor subtypes and microenvironmental contexts.
Nature has devised an array of enzymatic cofactors that enable challenging chemical transformations to occur on a time scale compatible with biological life. The glycyl radical enzyme (GRE) superfamily, for example, highlights the catalytic power of protein-based amino acid radicals. GREs utilize a persistent radical housed on the α-carbon of a C-terminally conserved glycine residue to accomplish diverse chemical reactions in anaerobic environments. This radical cofactor is post-translationally installed on the mature, folded protein by a radical S-adenosyl-L-methionine (RS) activating enzyme (GRE-AE; activase) specific to each GRE. The catalytic repertoire of GREs is diverse, spanning ribonucleotide reduction for DNA synthesis, acetyl-CoA formation in anaerobic primary metabolism, dehydration reactions in secondary metabolism, decarboxylation reactions in aromatic amino acid fermentation, and hydrocarbon activation in anaerobic bacteria, enabling their survival on crude oil as a carbon source. Pyruvate formate lyase (PFL), the founding member of the GRE superfamily, was first identified several decades ago. In recent years, sequencing technology has enabled the annotation of thousands of unique GRE-encoding sequences. Several dozen of the identified GREs have been characterized further, providing insight into the structure, mechanism, and regulation of this multitudinous and diverse enzyme family. Here, we introduce the superfamily, summarize what is known about their activation and catalysis, note conserved structural features, expand on the previously identified GRE classes, highlight GRE-associated bacterial microcompartments, and discuss the future and outlook of the GRE superfamily.
Among urological cancers, bladder cancer (BC) is one of the main causes of morbidity and death. Although the lipogenic enzyme fatty acid synthase (FASN) is known to aid in the growth of tumors, its precise role and mechanism in bladder cancer remain unclear. The effects and mechanisms of FASN in BC are examined in this study. Using information from The Cancer Genome Atlas (TCGA), the expression and prognostic significance of FASN were examined. Functional assays, including CCK-8, apoptosis, Transwell, and scratch-wound experiments, were conducted in BIU-87 and T24 cells after FASN knockdown and treatment with the ERK activator TBHQ. Western blot analysis assessed key proteins of the ERK/PPARγ pathway, such as PPARα, PPARγ, and p-ERK1/2, along with the lipid metabolism marker CD36. Metabolite levels, including free fatty acids, acyl-coenzyme A, and triglycerides, were quantified. Finally, an in vivo subcutaneous xenograft model was established to validate these findings. In BC tissues, FASN expression was markedly increased and associated with lower overall survival. FASN knockdown increased apoptosis while inhibiting BC cell motility, invasion, and proliferation. These phenotypic changes were associated with downregulation of the ERK/PPARγ pathway and reduced fatty acid uptake and metabolite levels. Both in vitro and in vivo, treatment with TBHQ effectively reversed the tumor-suppressive effects and metabolic alterations induced by FASN knockdown, confirming the involvement of ERK signaling. This study therefore demonstrates that FASN promotes BC progression by modulating the ERK/PPARγ pathway and lipid metabolism. Targeting FASN or its upstream activator ERK could thus provide a therapeutic strategy to inhibit BC growth.
One of the major obstacles to the clinical application of resting-state functional magnetic resonance imaging (rs-fMRI) is the complex nature of its measurements, which limits interpretability. An approach to enhance the interpretability of the rs-fMRI metrics is to link them to more fundamental brain physiology, especially cerebral metabolism. Previous studies have established associations between glucose metabolism (CMRglu) and rs-fMRI measurements. In spite of this, oxidative metabolism (CMRO2) is more closely related to cerebral blood flow (CBF) and thus the blood-oxygenation level-dependent (BOLD) signal, and its relationship with CMRglu is complex. Additionally, most currently published rs-fMRI metrics are uncorrected for macrovascular contribution, which may obscure the neuronal contributions. In this study, we measured resting CMRO2 (along with the oxygen extraction fraction, OEF, and cerebral blood flow, CBF) using gas-free calibrated fMRI. We used linear mixed-effects (LME) models to examine associations between CMRO2 and various rs-fMRI metrics before and after macrovascular correction. We found that (1) significant associations existed between CMRO2 and multiple rs-fMRI metrics, with the strongest association found for the global functional density (gFCD) and the weakest for seed-based functional connectivity (FC); (2) associations with rs-fMRI metrics also varied for OEF and CBF; (3) significant sex differences were observed in the above associations; (4) the use of macrovascular correction substantially strengthened the goodness fit of all LME models examined. The latter improvement further validates the use of macrovascular correction in rs-fMRI. These results provide a framework for linking rs-fMRI metrics to fundamental brain physiology, thus improving interpretability of rs-fMRI measurements. This is the first study to formally link whole-brain MRI-based baseline CMRO2 and rs-fMRI metrics, and helps to push the envelope for rs-fMRI in future clinical applications.
Type 2 diabetes mellitus is a systemic metabolic disorder with an extensive spectrum of complications, which still persist despite improvements in glycemic control. Emerging evidence suggests that gut dysbiosis may be an underpinning factor in the pathogenesis of both microvascular and macrovascular complications associated with diabetes. This narrative review explores the relationship between gut microbiota and the development of diabetes complications, including nephropathy, retinopathy, neuropathy, cardiovascular, cerebrovascular, peripheral vascular, and reproductive system disorders. First, existing evidence regarding the nature of shared and organ-specific microbial patterns is summarized. Next, key mechanistic pathways of inflammation and metabolism underlying tissue damage induced by dysbiosis are illustrated. Lastly, the role of gut microbiota and inflammaging as modifiers of these processes is described. Emerging clinical and translational implications are finally discussed, underscoring the promises of microbiota-based diagnostics as well as therapeutics that could serve as add-on approaches to the management of diabetic complications, alongside the application of artificial intelligence-based approaches to microbiome data analysis which may enhance biomarker discovery and risk stratification. Overall, although most evidence remains associative, increasing data support that gut microbiota dysbiosis may represent a potential disease modifier in the development of various diabetic complications. Further longitudinal and mechanistic studies are needed to clarify causality and to evaluate the clinical utility of microbiome-targeted interventions, including AI-assisted predictive models, in preventing or mitigating diabetic complications.
Treating autosomal dominant polycystic kidney disease (ADPKD) has always been a challenge because the disease is too complex for single-target drugs, which are often held back by side effects. This narrative review explores a different strategy: using plant-derived polyphenols to target multiple disease pathways at the same time. Looking at research from 2005 to 2026, we break down how key compounds like resveratrol, curcumin, naringenin, quercetin, and epigallocatechin-3-gallate (EGCG) actually work. Preclinical studies show these molecules can slow down cyst growth by tackling inflammation, rapid cell division, and tissue scarring all at once, while also resetting the skewed energy metabolism of cystic cells. Some mechanisms are strikingly specific, such as naringenin's direct interaction with polycystin-2 and quercetin's ability to clear senescent cells. Yet, the real-world hurdle is poor absorption; a recent clinical trial with standard curcumin fell short simply because the compound could not reach the kidneys in high enough concentrations. Moving forward, the field needs to focus on testing these compounds in realistic animal models, designing smart nanoformulations to improve bioavailability, and exploring combinations that could safely complement current therapies like tolvaptan.
Fiber intake is the most common nutritional inadequacy in the Western diet, with most adults consuming less than half of the recommended intake and only 5% meeting the RDI. A novel, short-chain β-glucan derived from oats (scOat fiber), with improved solubility, low viscosity and enhanced palatability compared to conventional oat fibers, was investigated for its benefits as a source of fiber supplementation. A 14-day pilot study evaluated the gastrointestinal tolerance and functional benefits of scOat fiber in 63 healthy adults assigned to receive 5, 10 or 20 g daily doses. The primary outcome, gastrointestinal tolerability, was assessed using the Gastrointestinal Symptom Rating Scale (GSRS). Secondary outcome included glycemic response during rice challenges, evaluated in a subgroup of 38 participants using continuous glucose monitoring (CGM). CGM was also used to explore overall glucose dynamics. Additional exploratory outcomes (mood, energy, appetite and sleep) were assessed via validated questionnaires. scOat fiber was exceptionally well tolerated across all doses, with no increase in GSRS scores, which remained in the low to mild range. Significant reductions in total GSRS scores were observed, with benefits evident after 1 week at 5 g/day and maintained over time at both 5 and 10 g/day groups. Evaluation of GSRS sub-categories revealed that the 5 g/day and 10 g/day dose groups experienced significant reductions in abdominal pain symptoms. Both dose groups also demonstrated a significant decrease in constipation at the end of the study. Postprandial glucose responses were attenuated following product use, with a significant reduction in peak glucose during rice challenges after 2 weeks in the 20 g/day group. Both 10 and 20 g/day doses were associated with significant improvement in glycemic metrics, including reductions in glucose mean, all glycemic excursions, and an increase in time-in-range. Exploratory analysis suggested that scOat Fiber may improve mental health and concentration in participants with elevated baseline symptoms. Despite the lack of a placebo control and short duration, the dose-dependent nature of the results supports the potential of scOat Fiber as a well-tolerated and functional source of fiber with benefits including glycemic control, digestive health and mental health. https://clinicaltrials.gov/study/NCT06739941, Identifier: NCT06739941.
The functional roles of gut microbiota in carnivores remain poorly understood. Here, we integrated metagenomics, metabolomics, proteomics and culture-based functional assays to characterize metabolic potential of gut microbiota across 14 captive Felidae species. Comparative metagenomics analysis revealed that the Felidae gut microbiome is distinct from that of non-Felidae and reflects carnivorous dietary patterns. Genus-level core microbiota were dominated by Clostridium, Collinsella and Bacteroides, with functional enrichment in carbohydrate and amino acid metabolism. Of 219 reconstructed metagenome-assembled genomes (MAGs), 27 were identified as core MAGs containing proteases- and lipases- encoding genes, with ATP-dependent Clp proteases predominating and enriched KEGG orthologs mainly associated with amino acid metabolism. Fecal metabolomics identified 1316 metabolites shared among Felidae species, with KEGG analysis showing they were involved in amino acid and lipid metabolism and significantly enriched in protein digestion and absorption pathway. The amino acid- and lipid-related metabolites were correlated with the relative abundance of core MAGs. Culture-based assays revealed proteolytic and lipolytic activities across isolates, supported by proteomics evidence of predominant ATP-dependent proteases. In vitro fermentation with representative isolates generated fatty-acid-dominated metabolites consistent with fecal metabolomic profiles. Together, our findings demonstrate that Felidae gut microbiota play a critical role in amino acid metabolism for carnivory.
Relict yew plants (Taxus L.) are not only ornamental plants with valuable wood but also have the ability to synthesize the unique compound taxol, which is successfully used in the treatment of cancer due to its powerful cytotoxic effect. Due to the presence of taxol, all parts of yew plants are extremely poisonous, but there have been cases where animals have eaten yew cones without fatal consequences. The biosynthesis of taxol is carried out due to the interaction of the isoprenoid and phenolic pathways of the secondary metabolism of plants. Despite the close attention of researchers to the peculiarities of taxol metabolism, there is very little data on the tissue and intracellular localization of both taxols and phenolic compounds in yew plants. Polyphenols are known to be physiologically active mediators involved in respiration, photosynthesis, plant growth and development, as well as in the process of in vitro dedifferentiation. Since Taxus is a relict species and has a limited and hard-to-reach range in nature, technologies that allow yew plants to be restored without removing plant material from the natural environment are of great practical importance: overcoming deep physiological dormancy of seeds, microclonal reproduction and initiation of plant growth. In vitro cultures are possible sources of biologically active and medicinal products. The aims and objectives of this study are to determine the characteristics of the formation and localization of phenolic compounds with high biological activity in various organs of plants of the genus Taxus and to determine the biological activity of ethanolic extracts from this plant. The objects of this study were the generative organs of Taxus canadensis, collected during the entire growing season (April-October) from plants growing in the Moscow region. The localization of various classes of polyphenols was determined by histochemical methods using light microscopy. Histochemical studies have shown the abundant presence of polyphenols in yew megastrobiles, microstrobiles, cones, seeds and aril. Ethanolic plant extracts were used to determine the biological activity. Flavans were dominant in the aril at various stages of vegetation, which was confirmed by our biochemical and histochemical studies. Extractive substances of T. canadensis show high antibacterial activity, especially in its shoot extracts. Ethanolic extracts from plant shoots showed greater biological activity than seed extracts. Aril extracts had the lowest cytotoxicity.
The refractory nature of diabetic foot ulcers (DFUs) stems from persistent immunometabolic dysregulation. Although a myriad of reviews have extensively categorized hydrogel dressings, most remain confined to passive material classifications and isolated phenotypic targets. To bridge this gap, this review delineates an integrated "hydrogel engineering-immunometabolic regulation-tissue regeneration" framework. We redefine hydrogels as "intelligent bioreactors" that actively construct a "pro-healing niche," dissecting the underlying mechano-metabolic crosstalk (e.g., VASP/HIF-1α and mTOR signaling). Furthermore, we elucidate the interventional mechanisms of diverse hydrogel strategies-including externally triggered, dynamically responsive, nanocomposite, and mechanically programmed platforms-across four critical pathways: glycolysis, lipid metabolism, amino acid metabolism, and oxidative stress. Crucially, by extracting raw healing data to calculate relative improvement rates and daily relative improvement rates, we quantitatively benchmark the discrepancies in healing kinetics among distinct strategies. Building upon this, we propose scenario-oriented clinical selection pathways: prioritizing near-infrared (NIR)-responsive or photocatalytic hydrogels for severely hypoxic DFUs, and recommending ultrasound-driven sequential "sterilization-then-antioxidation" hydrogels for neuropathic ulcers complicated by multidrug-resistant bacterial infections. Additionally, via precise metabolic reprogramming, these tailored hydrogels actively drive macrophage repolarization, restore T cell subset balance, and enhance dendritic cell efferocytosis. Finally, by integrating biomarker-driven standardized evaluations, GMP-compliant scale-up engineering, and AI-assisted modular production platforms, this review outlines a step-by-step clinical translational roadmap. This strategic roadmap aims to bridge the gap between laboratory prototypes and personalized precision medicine, ultimately providing a comprehensive blueprint for next-generation metabolic therapeutics in chronic wound management.
Perioperative acute kidney injury (AKI) is one of the common and burdensome complications following surgical procedures. The traditional "prerenal" model centered on systemic hemodynamic disturbances fails to adequately account for occult hypoxia that can occur despite relatively stable macro-parameters, as well as significant clinical heterogeneity. Recent clinical and translational studies suggest that perioperative AKI is better characterized as a syndrome involving imbalances in local microcirculation, cellular energy metabolism, and the immune-inflammatory network. Although perioperative AKI is not a typical autoinflammatory disease, the sterile inflammation driven by DAMPs shares common mechanistic features with autoinflammatory syndromes, such as NLRP3 inflammasome activation and its mediated inflammatory amplification. Based on this, this article proposes a "renal microcirculatory hypoxia-mitochondrial injury-immunometabolic reprogramming" pathological triangle model as a conceptual framework for understanding the occurrence, development, and heterogeneity of perioperative AKI. This model emphasizes the shifting dominance of these three components across distinct time windows, as well as their coupled nature and mutually amplifying positive feedback loops. On this basis, this article further discusses imbalance phenotype hypotheses, including microcirculation-dominant, mitochondria-dominant, and immunometabolism-dominant types, and proposes a multidimensional stratification approach corresponding to the pathological triangle model, focusing on renal microcirculation/tissue oxygenation assessment, mitochondrial-related biomarkers, and immunometabolic readouts. Additionally, potential time-windowed intervention pathways are outlined, ranging from preoperative risk optimization, intraoperative perfusion and oxygen delivery management, to postoperative mitochondrial protection and immunometabolic regulation. This article aims to provide a more integrated pathophysiological framework for the mechanistic classification, risk stratification, and multi-target intervention strategies for perioperative AKI.
The diagnosis of Sjögren's Disease (SjD) remains challenging due to the non-specific nature of sicca symptoms and the need for invasive biopsies. This pilot study aimed to investigate the potential of salivary Substance P (SP), a neuropeptide involved in glandular regulation and neurogenic inflammation, as a novel, non-invasive biomarker to differentiate patients with SjD from those with non-autoimmune Non-Sjögren sicca syndrome (NSS). Unstimulated whole saliva samples were collected from three groups of female participants: 13 patients classified as SjD according to ACR/EULAR criteria, 13 patients with idiopathic NSS symptoms who did not meet the criteria, and 13 healthy controls (CTRL). Salivary SP concentrations were measured using a specific enzyme-linked immunosorbent assay (ELISA). Clinical, serological, and histopathological data were recorded for correlation analyses. Receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic performance of salivary SP. Salivary SP levels were significantly higher in SjD patients (mean 92.2 ± 15.503 pg/ml) compared to both NSS patients (30.39 ± 4.08 pg/ml, p < 0.005) and healthy controls (39.93 ± 5.97 pg/ml, p < 0.005). No significant difference was found between the NSS and CTRL groups. ROC analysis demonstrated that salivary SP could distinguish SjD from NSS, with an area under the curve (AUC) of 0.8225 (p = 0.005). At a cut-off value of 47.63 pg/ml, sensitivity was 77% and specificity was 85%. A positive association was observed between salivary SP levels and the presence of ANA autoantibodies in the SjD cohort. Salivary SP appears to be elevated in patients with SjD compared to those with NSS in this preliminary study, suggesting a potential diagnostic signal that warrants further investigation. Although the observed differences hint at possible utility as a non-invasive biomarker related to neuroimmune dysregulation, the diagnostic accuracy observed should be interpreted with caution due to the limited sample size and the exploratory nature of the findings. Larger, prospective, and well-powered studies are needed to confirm these preliminary observations, to assess the robustness of salivary SP as a diagnostic tool, and to determine its potential clinical applicability.
Background and Objectives: MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and have emerged as potential biomarkers in type 2 diabetes mellitus and its complications. This pilot exploratory study aimed to identify circulating miRNAs with differential expression in plasma from patients with newly diagnosed type 2 diabetes mellitus compared to age- and sex-matched healthy controls. Materials and Methods: Peripheral venous blood samples were collected from diabetic patients (n = 24) and controls (n = 12). Due to the exploratory nature of the study and limited sample material, samples were pooled within each group prior to plasma separation. Total RNA, including miRNAs, was extracted from plasma and analyzed using a high-throughput qPCR panel. Two normalization methods were applied to assess miRNA expression, and overlapping results were used for downstream analysis. Fold regulation was calculated using the 2^(-ΔCt) method. Results: A total of 33 and 42 miRNAs were identified as differentially expressed using the first and second normalization methods, respectively. Fourteen miRNAs were consistently downregulated across both methods. Several of these miRNAs, including hsa-miR-26a-5p, hsa-miR-146a-5p, hsa-miR-186-5p, hsa-miR-19a-3p, and hsa-miR-652-3p, have been previously associated with glucose metabolism, inflammation, and diabetic complications, such as retinopathy, neuropathy, and endothelial dysfunction. The pooling strategy enabled an efficient exploratory assessment of miRNA expression patterns while reducing inter-individual variability. Conclusions: This exploratory pilot study identifies a panel of circulating miRNAs with altered expression in pooled plasma samples from patients with newly diagnosed type 2 diabetes mellitus. These findings provide preliminary insights that warrant further validation in larger, individual-level studies to assess their diagnostic and prognostic potential.
Small-molecule drug development faces high attrition rates driven by complex pharmacokinetics and unforeseen toxicities. While deep learning offers high predictive accuracy, its opaque "black-box" nature hinders mechanistic transparency, clinical trust, and regulatory approval. This review synthesizes how Interpretable Machine Learning, synergized with systems pharmacology, advances this paradigm by enhancing mechanistic transparency in drug development. By providing insights into algorithmic decisions, Interpretable Machine Learning helps researchers identify molecular features that are statistically associated with absorption, distribution, metabolism, and excretion optimization and preemptively mitigate toxicophores, while noting that these associations require experimental validation to establish genuine causality. Furthermore, integrating multi-omics data via Interpretable Machine Learning guides rational polypharmacology, bridging in silico target identification with "dry-wet loop" validations. Crucially, Interpretable Machine Learning accelerates clinical translation by discovering causal biomarkers, refining patient stratification, and generating transparent "Model Cards" to satisfy U.S. Food and Drug Administration/European Medicines Agency regulations. We also discuss future challenges: data heterogeneity, out-of-distribution generalizability, and the evolution toward Causal Artificial Intelligence. Ultimately, the integration of Interpretable Machine Learning provides a framework for more transparent and evidence-based drug design, realizing the promise of precision medicine.
Paeoniae Decoction (PD) is a classic Chinese medicine formula for treating intestinal diseases. However, its direct intervention effect on intestinal fibrosis and the underlying molecular mechanisms have not been fully elucidated. To evaluate the effect of PD on inflammatory bowel disease (IBD) associated intestinal fibrosis and to systematically investigate its potential molecular mechanisms utilizing integrated multi-omics. The chemical constituents of PD were characterized and quantified utilizing ultra-high performance liquid chromatography-Quadrupole-Orbitrap mass spectrometry (LC-Q-Orbitrap-MS) and LC-MS/MS. A chronic experimental colitis-associated intestinal fibrosis mouse model lasting 56 days and involving four repeated cycles of dextran sulfate sodium (DSS) injury was established. The therapeutic efficacy of PD was evaluated through endoscopy, histopathological analysis, and collagen staining. Label-free quantitative proteomics and untargeted metabolomics and network pharmacology were employed to elucidate the target networks. In vitro mechanisms were further validated in TGF-β1-stimulated NCM460 cells using wound healing assays, immunofluorescence, and Western blotting to evaluate the epithelial-mesenchymal transition (EMT) process and the TGF-β/Smad signaling pathway. Finally, molecular docking was used to verify the direct binding of the main bioactive components of PD to the key pathway targets. Chemical profiling identified 16 common constituents across independent batches of PD. In vivo, PD administration significantly ameliorated intestinal fibrosis and reduced massive extracellular matrix (ECM) deposition in the mucosal and submucosal layers. Integrated omics analyses revealed that PD profoundly modulated the TGF-β signaling pathway, ECM-receptor interaction, and the Sphingolipid signaling pathway. Mechanistically, PD dose-dependently inhibited myofibroblast activation, downregulating the expression of α-SMA, Vimentin, Collagen I, and Collagen III. In vitro, PD serum suppressed TGF-β1-induced cell migration, preserved the epithelial marker E-cadherin, and inhibited the nuclear translocation of Snail by significantly decreasing the phosphorylation of Smad2 and Smad3. Furthermore, PD reversed pro-fibrotic sphingolipid metabolism and upregulated taurine and glutathione metabolism associated with antioxidant defense. PD effectively alleviates chronic colitis-associated intestinal fibrosis by inhibiting the TGF-β/Smad signaling pathway-mediated EMT process, reducing ECM deposition, and reprogramming the fibrotic metabolic microenvironment.
Natural hallucinogenic compounds have arisen independently across plants, fungi, and animals, evolving into a diverse chemical arsenal that includes phenethylamines, indolealkylamines, and terpenoid scaffolds. Beyond clinical and cultural frameworks, their ecological origins and evolutionary trajectories may help explain why such potent modulators of perception, emotion, and cognition persist in nature. Here, integrating chemical ecology, comparative genomics, biosynthetic logic, and evolutionary biology, we propose that these molecules may function as defensive agents or symbiosis-associated manipulators of herbivore and pollinator behavior. A "building-block" biosynthetic logic links primary metabolism to convergent psychotropic scaffolds via a recurrent set of tailoring reactions, including decarboxylations and methylations. Recent advances illuminate mescaline biosynthesis in cacti, horizontal gene transfer of psilocybin clusters in fungi, and symbiont-derived alkaloids in grasses. We also assess the debate surrounding endogenous mammalian tryptamines, arguing that the leading hypothesis points toward sigma-1 receptor-mediated cytoprotection and stress responses, supported by convergent pharmacological and cellular evidence, rather than inherent hallucinogenic functions. Across kingdoms, natural hallucinogens appear to converge on conserved neural targets, including serotonergic and other neuromodulatory systems that are shared across phyla. From this perspective, human psychoactivity is likely an evolutionary by-product of molecules selected for ecological interactions with animals possessing deeply conserved receptor architectures. Framing hallucinogens through chemical ecology not only clarifies their origins but also highlights translational opportunities in target discovery, pathway engineering, and sustainable production, while emphasizing the need to integrate conservation, ethical sourcing, and benefit-sharing into the current hallucinogenic renaissance.
The selection of biomaterial is crucial for the long-term success of implants. Materials that perform an adequate function and reduce negative biological responses should be taken. Due to their good mechanical strength, stainless steel, titanium, and Co-based alloys have been utilized for implant purposes; however, their permanent nature and very low corrosion rates may lead to long-term clinical complications. Researchers are looking for biomaterials that combine suitable mechanical properties with controlled and uniform degradation behavior. In the last decade, magnesium and iron-based alloys have been seen as a good alternative and examined as promising biodegradable metals for implant applications. However, their excessively rapid corrosion (Mg) or extremely slow degradation (Fe) imposes significant limitations on their clinical applicability. In recent times, zinc-based alloys have been seen as new materials that will challenge magnesium and iron-based alloys. Zn2+ ions released from zinc metal corrosion play a crucial role in bone metabolism, enzymatic activity, and cellular proliferation. However, the low mechanical strength and limited ductility of pure zinc restrict its direct utilization in load-bearing implants. Therefore, the fabrication of high-strength and ductile zinc-based alloys while maintaining biocompatibility and suitable corrosion rate remains a main research challenge. This article critically assesses and compares the mechanical properties, corrosion behavior, and biocompatibility of magnesium-, zinc-, and titanium-based alloys, and inspects the impact of advanced fabrication methods, particularly additive manufacturing, on microstructure evolution and implant performance.
l- valine has extensive market demand, and its current industrial production primarily relies on microbial fermentation. With the continuous combination and accumulation of metabolic engineering strategies, rational modification of microbial strains for l- valine metabolism has encountered bottlenecks, leading to limitations in yield improvement. As a complementary strategy, irrational modification approaches are widely applied in the biological field to enhance the synthesis efficiency of target products. However, irrational modification faces challenges such as the vast scale of mutant libraries and the time-consuming, low-efficiency nature of traditional screening methods for high-yield strains. Therefore, there is an urgent need for a tool that enables rapid and efficient screening of target products to shorten the cycle of irrational strain modification. In this study, we started with an l- valine-producing strain, Corynebacterium glutamicum SX-4, which was previously constructed via rational metabolic engineering. We developed a biosensor that exhibited a positive correlation with intracellular l- valine concentration. The response accuracy and dynamic range of the sensor were optimized by incorporating ribosome-binding sites of varying strengths. Furthermore, we employed atmospheric and room temperature plasma mutagenesis to construct a comprehensive mutant library for random, non-rational strain modification. High-throughput screening of this library was performed via droplet microfluidics. The selected mutant strain, A23, achieved an l- valine titer of 21.36 g/L in shake-flask fermentation after 48 h, which represented a 46.5% increase over that of the starting strain. This integrated strategy provides a valuable framework and reference for irrational modification studies aimed at producing other amino acids. l- 缬氨酸具有广泛市场需求，目前工业生产 l- 缬氨酸方法主要是微生物发酵法。随着代谢工程策略的不断组合叠加，理性改造菌株代谢 l- 缬氨酸遇到瓶颈导致产量提升受限;非理性改造策略作为提升目标产物合成效率的一种补充策略被广泛应用于生物领域，然而非理性改造面临菌株突变文库庞大、传统高产菌株筛选方式耗时长、效率低等困境，因此需要一种快速高效筛选目标产物的工具缩短非理性改造菌株的周期。本研究基于一株经理性代谢工程改造的谷氨酸棒状杆菌 l-缬氨酸生产菌SX-4，构建了一种与 l-缬氨酸浓度呈正相关的生物传感器。通过更换不同强度的核糖体结合位点(ribosome binding site, RBS)序列优化响应精准度、拓宽响应范围;进一步利用常压室温等离子体诱变(atmospheric and room temperature plasma, ARTP)技术构建大量诱变菌株文库，并利用液滴微流控技术实现了 l-缬氨酸高产菌株的高通量筛选。所获得的菌株A23于摇瓶培养48 h， l-缬氨酸产量为21.36 g/L，相较于出发菌株提升了46.5%。本研究为其他氨基酸非理性改造研究提供了理论基础与借鉴。.
Despite increasing efforts to improve cardiovascular disease (CVD) risk evaluation and management, it remains a leading cause of mortality and morbidity worldwide. This has driven interest in high-density lipoprotein (HDL)-related biomarkers as indicators of oxidative stress and atherogenic processes not fully captured by traditional lipid measurements. In this study, we examined specific paraoxonase 1 (PON1) activity and its relationship with anthropometric, blood pressure, and lipid metabolism measures in 100 middle-aged Lithuanian individuals at high cardiovascular risk. HDL fractions were isolated using iodixanol-based density gradient centrifugation. PON1 concentration and arylesterase activity were measured, and specific activity was defined as arylesterase activity normalized to PON1 concentration. No significant associations were observed between specific PON1 activity and age, body mass index, waist circumference, blood pressure, smoking status, or statin use. Specific PON1 activity was independently associated with lower risk-weighted apolipoprotein B and lower low-density lipoprotein cholesterol levels. These exploratory findings suggest that higher specific PON1 activity may reflect a less atherogenic lipid profile in individuals at high cardiovascular risk, as indicated by its association with LDL-C and with risk-weighted apolipoprotein B. Because direct oxidative stress and inflammatory markers were not measured, interpretations regarding oxidative burden should be considered indirect and hypothesis-generating. Given the cross-sectional nature of the study and the relatively small sample size, these results should be interpreted as exploratory and hypothesis-generating. Further longitudinal studies in larger populations are needed to confirm these observations.
Exercise is increasingly recognized as a modulator of host-microbiome interactions, yet its role in irritable bowel syndrome (IBS) remains poorly characterized. In this prospective, single-arm, before-and-after interventional study, we used an integrated multi-omics approach based on metataxonomics and metabolomics to assess the effects of a structured 12-week moderate aerobic exercise program in 80 patients with mild-to-moderate IBS, stratified by Global Physical Capacity Score (GPCS). Biochemical and inflammatory markers have been gathered. Exercise did not alter overall microbial diversity but selectively enriched short-chain fatty acid (SCFA)-producing taxa and remodeled the volatile organic compound (VOC) profile toward a more efficient metabolic state. Notably, conventional biochemical and inflammatory markers failed to distinguish response subgroups, whereas GPCS stratification revealed distinct microbial and metabolomic trajectories. Individuals with higher baseline physical capacity had higher acetate levels and lower levels of VOCs associated with dysbiosis and oxidative stress. Our results suggest that baseline physical capacity is a primary determinant of the microbiome's responsiveness to exercise, challenging the reliance on static biochemical profiling. Despite the lack of a control group and the exploratory nature of some metabolomic signals, this study provides a framework for precision exercise interventions in IBS. Our work identifies GPCS as a clinically relevant stratification tool. The full trial protocol is registered on ClinicalTrials.gov under the identifier NCT05453084.