Genome Biol. 2025 Jul 2;26(1):188. doi: 10.1186/s13059-025-03660-0.

ABSTRACT

Genetic screens offer a promising strategy for identifying tumor-specific therapeutic targets, but single-gene knockout screens often miss functionally redundant paralogs. Multiplex Cas9 and Cas12a CRISPR systems have been deployed to assay genetic interactions, but analysis pipelines vary considerably. Here we evaluate data from four in4mer CRISPR/Cas12a screens in cancer cell lines, using delta log fold change, Z-transformed dLFC, and rescaled dLFC approaches to identify synthetic lethal interactions. Both ZdLFC and RdLFC provide more consistent identification of synthetic lethal pairs across cell lines compared to the unscaled dLFC method, while ZdLFC benefits from not requiring a training set of known interactors.

PMID:40605002 | DOI:10.1186/s13059-025-03660-0

npj metabolic health and disease.. 2024 Dec 4;2(1):35. doi: 10.1038/s44324-024-00034-1.

ABSTRACT

Inflammatory diseases implicate a synchronised immune-metabolic rewiring to maintain homeostasis. The regulatory mechanisms governing the transcriptional control of immune-centric metabolic adjustments in dendritic cells (DCs) remains elusive. Recently we reported that Ncor2 (SMRT) loss of function in DCs potentiates strong inflammation. We found that SMRT depletion in DCs triggers a metabolic shift resulting in sustained and strong inflammation despite reduced glycolysis. This is in contrast to the widely accepted notion that glycolytic pathway activation is essential for inducing inflammation. Downregulation of mTOR emerged as a pivotal factor in attenuating the glycolytic rate. Significant metabolic alterations led to rewiring of the TCA-cycle by triggering anaplerotic glutamine catabolism and promoting succinate oxidation, thereby sustaining the inflammatory potential. Simultaneous treatment with succinate transport inhibitor DEBM and mTOR inducer Mhy1485 remarkably suppressed inflammation ex vivo and in vivo. Our findings also depicted an inverse correlation between SMRT levels with human autoimmune diseases.

PMID:40604291 | DOI:10.1038/s44324-024-00034-1

Nature. 2025 Jul 2. doi: 10.1038/s41586-025-09221-6. Online ahead of print.

ABSTRACT

Although most mammalian transcriptional enhancers regulate their cognate promoters over distances of tens of kilobases, some enhancers act over distances in the megabase range1. The sequence features that enable such long-distance enhancer-promoter interactions remain unclear. Here we used in vivo enhancer-replacement experiments at the mouse Shh locus to show that short- and medium-range limb enhancers cannot initiate gene expression at long-distance range. We identify a cis-acting element, range extender (REX), that confers long-distance regulatory activity and is located next to a long-range limb enhancer of Sall1. The REX element has no endogenous enhancer activity. However, addition of the REX to other short- and mid-range limb enhancers substantially increases their genomic interaction range. In the most extreme example observed, addition of REX increased the range of an enhancer by an order of magnitude from its native 73 kb to 848 kb. The REX element contains highly conserved [C/T]AATTA homeodomain motifs that are critical for its activity. These motifs are enriched in long-range limb enhancers genome-wide, including the ZRS (zone of polarizing activity (ZPA) regulatory sequence), a benchmark long-range limb enhancer of Shh2. The ZRS enhancer with mutated [C/T]AATTA motifs maintains limb activity at short range, but loses its long-range activity, resulting in severe limb reduction in knock-in mice. In summary, we identify a sequence signature associated with long-range enhancer-promoter interactions and describe a prototypical REX element that is necessary and sufficient to confer long-distance activation by remote enhancers.

PMID:40604280 | DOI:10.1038/s41586-025-09221-6

Nature. 2025 Jul;643(8070):47-59. doi: 10.1038/s41586-025-09096-7. Epub 2025 Jul 2.

ABSTRACT

From fertilization onwards, the cells of the human body acquire variations in their DNA sequence, known as somatic mutations. These postzygotic mutations arise from intrinsic errors in DNA replication and repair, as well as from exposure to mutagens. Somatic mutations have been implicated in some diseases, but a fundamental understanding of the frequency, type and patterns of mutations across healthy human tissues has been limited. This is primarily due to the small proportion of cells harbouring specific somatic variants within an individual, making them more challenging to detect than inherited variants. Here we describe the Somatic Mosaicism across Human Tissues Network, which aims to create a reference catalogue of somatic mutations and their clonal patterns across 19 different tissue sites from 150 non-diseased donors and develop new technologies and computational tools to detect somatic mutations and assess their phenotypic consequences, including clonal expansions. This strategy enables a comprehensive examination of the mutational landscape across the human body, and provides a comparison baseline for somatic mutation in diseases. This will lead to a deep understanding of somatic mutations and clonal expansions across the lifespan, as well as their roles in health, in ageing and, by comparison, in diseases.

PMID:40604182 | DOI:10.1038/s41586-025-09096-7

Nat Biomed Eng. 2025 Jul 2. doi: 10.1038/s41551-025-01430-8. Online ahead of print.

ABSTRACT

High-throughput sequencing technologies generate a vast number of DNA sequence reads simultaneously, which are subsequently analysed using the information contained within these fragmented reads. The assessment of sequencing technology relies on information efficiency, which measures the amount of information entropy produced per sequencing reaction cycle. Here we propose a fuzzy sequencing strategy that exhibits information efficiency more than twice that of currently prevailing cyclic reversible terminator sequencing methods. To validate our approach, we develop a fully functional and high-throughput fuzzy sequencer. This sequencer implements an efficient fluorogenic sequencing-by-synthesis chemistry and we test it across various application scenarios, including copy-number variation detection, non-invasive prenatal testing, transcriptome profiling, mutation genotyping and metagenomic profiling. Our findings demonstrate that the fuzzy sequencing strategy outperforms existing methods in terms of information efficiency and delivers accurate resequencing results with faster turnaround times.

PMID:40603748 | DOI:10.1038/s41551-025-01430-8

npj metabolic health and disease.. 2024 Jan 29;2(1):1. doi: 10.1038/s44324-023-00003-0.

ABSTRACT

Several studies proposed a role for the sweet taste receptor in energy intake and blood glucose regulation, but little is yet known about the impact of the individual sweet taste perception. Here, we found in a cross-over human intervention study with 29 male participants that modulating the sweetness of an isocaloric sucrose solution did not influence postprandial plasma concentrations of blood glucose and associated hormones over 120 min and 2 h post-load energy intake. Independent of the sweetness of the test solution, tests persons with a higher sucrose detection threshold had an average of 402 ± 78.8 kcal (39 ± 21%) higher energy intake and a higher glucose/insulin ratio, combined with a higher liking for sweet tasting food, than the test persons of the low threshold group. The body composition suggested a higher fat-free mass in the high threshold group that may have influenced energy intake and post-prandial glucose responses.

PMID:40603623 | DOI:10.1038/s44324-023-00003-0

npj metabolic health and disease.. 2024 Sep 23;2(1):25. doi: 10.1038/s44324-024-00028-z.

ABSTRACT

Traditional risk factors and biomarkers of cardiovascular diseases (CVD) have been mainly discovered through clinical observations. Nevertheless, there is still a gap in knowledge in more sophisticated CVD risk factor stratification and more reliable treatment outcome prediction, highlighting the need for a more comprehensive understanding of disease mechanisms at the molecular level. This need has been addressed by integrating information derived from multiomics studies, which provides systematic insights into the different layers of the central dogma in molecular biology. With the advancement of technologies such as NMR and UPLC-MS, metabolomics have become a powerhouse in pharmaceutical and clinical research for high-throughput, robust, quantitative characterisation of metabolic profiles in various types of biospecimens. In this review, we highlight the versatile value of metabolomics spanning from targeted and untargeted identification of novel biomarkers and biochemical pathways, to tracing drug pharmacokinetics and drug-drug interactions for more personalised medication in CVD research (Fig. 1).

PMID:40603608 | DOI:10.1038/s44324-024-00028-z

Dev Cell. 2025 Jun 24:S1534-5807(25)00370-3. doi: 10.1016/j.devcel.2025.06.015. Online ahead of print.

ABSTRACT

Zebrafish has full capacity of heart regeneration, but little is known about how blood cells, especially platelets, are involved in this regenerative process. Here, we report that cloche/npas4l is a pro-regenerative platelet factor for heart regeneration. We found that haploinsufficiency of npas4l disrupted cardiomyocyte (CM) and endothelial cell (EC) proliferation and heart regeneration after injury. A single-cell transcriptomic atlas identified that npas4l was dynamically expressed in platelets after heart injury and controlled robust interactions between platelet-CMs or -ECs. Decreasing platelets impaired CM/EC proliferation, and overexpression of npas4l in platelets sufficiently induced CM/EC proliferation in uninjured hearts, as well as rescued CM/EC proliferation defects in cloche mutants. Mechanistically, Npas4l positively controlled a panel of ligand expression, including bmp6 in platelets, to fine-tune CM proliferation and heart regeneration. Therefore, this work demonstrates platelet Npas4l signaling and presents mechanisms on how platelets modulate CM/EC proliferation via ligand-receptor network during zebrafish heart regeneration.

PMID:40602409 | DOI:10.1016/j.devcel.2025.06.015

Comput Biol Med. 2025 Jun 30;196(Pt A):110589. doi: 10.1016/j.compbiomed.2025.110589. Online ahead of print.

ABSTRACT

Cancer represents a major public health challenge, demanding the continuous search for therapeutic strategies. The PD-1/PD-L1 pathway is crucial in tumor immune evasion, and its inhibition imposes difficulties such as antibody-related adverse effects and reduced affinity of small molecules to these checkpoint proteins. Previously, we uncovered a novel binding site within the C'D loop of PD-1. The 1508 ligand interaction induced a structural modification of this loop, which had not been explored in the PD-1/PD-L1 complex. In this work, we employed a robust computational pipeline to validate C'D loop modulation by small ligands as a promising strategy to impair the PD-1/PD-L1 interaction. Thus, we characterized the molecular recognition and binding mechanisms of 1508, revealing critical interaction dynamics within the C'D loop cavity through Supervised Molecular Dynamics (SuMD) and Umbrella Sampling (US). Using Gaussian Accelerated Molecular Dynamics (GaMD), we identified new conformations of PD-1 potentially unfavorable to the complexation to PD-L1. We specifically identified conformational constraints in the backbone of the C'D loop, particularly involving residues S87-P89. These constraints were accompanied by simultaneous structural modifications in the FG loop (A129-I134), resulting in a combined destabilizing effect as evidenced by molecular docking analysis of the ternary complex comprising PD-1, 1508, and PD-L1. These findings highlight the C'D loop as a promising druggable hotspot and validate the effectiveness of the computational pipeline in characterizing PD-1/PD-L1 pathway inhibitors.

PMID:40602317 | DOI:10.1016/j.compbiomed.2025.110589

ACS Chem Biol. 2025 Jul 2. doi: 10.1021/acschembio.5c00323. Online ahead of print.

ABSTRACT

Dye-decolorizing peroxidase (DyP)-type peroxidases are heme-containing enzymes that play a role in lignin synthesis and degradation and dye decolorization. Despite numerous studies about this class of enzymes, the enzyme remains under-explored. We used 1000 DyP sequences retrieved from the NCBI database to forge a phylogenetic tree. Nodes in the tree, where sequences displayed a degree of conservation, were used to design degenerate primers to locate DyP-peroxidase sequences from the DNA extract of a tannery wastewater sample. After PCR amplification and visualization using agarose electrophoresis, a band at the expected size of a DyP peroxidase (500-700 bp) was seen. TA cloning followed by blue-white colony selection validated our finding after amplicon sequencing of the PCR product to confirm the presence of an Acinetobacter species DyP-peroxidase. Our metagenomic DyP displayed 99% similarity to the DyP-peroxidase sequence found in the Acinetobacter baumannii ATCC 19606 strain. As a result, and due to the minute differences between our found DyP and the ATCC 19606 strain DyP, we expressed the latter cloned in a pET28b(+) vector and purified it from culture medium using Escherichia coli SoluBl21 as a host strain. A crude oxidation assay using 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) deemed the enzyme active as shown by the formation of a green color. The crystal structure of the enzyme was solved at 2.6 Å resolution (PDB ID 9OBR) using X-ray crystallography and presented as a hexamer in solution.

PMID:40601836 | DOI:10.1021/acschembio.5c00323

Sci Transl Med. 2025 Jul 2;17(805):eads4773. doi: 10.1126/scitranslmed.ads4773. Epub 2025 Jul 2.

ABSTRACT

Coinciding with the global outbreak of clade IIb mpox virus (MPXV), the Democratic Republic of the Congo (DRC) recently experienced a rapid surge in mpox cases with clade I MPXV. On 14 August 2024, the World Health Organization declared the continued cross-border spread of this clade in Africa a public health emergency of international concern (PHEIC). Clade I MPXV is known to be more fatal than clade IIb, but its clinical characteristics and prognosis differ between patients. Here, we used mathematical modeling to quantify temporal changes in total lesion counts during clade I MPXV infections, using data from a large cohort of patients with mpox in the DRC from 2007 to 2011. We further analyzed individuals' clinical data to explore predictive biomarkers of high lesion counts. Our analysis indicates that patients with clade I mpox can be stratified into two groups according to lesion severity and that viral load in peripheral blood at symptom onset may serve as a predictor for this classification [area under the curve (AUC) = 0.70]. Our estimates also suggest substantial individual heterogeneity in the time period during which patients have lesions, ranging from 20 to 65 days. Understanding the severity and duration of lesions in different patients, as characterized by our approach, may contribute to more tailored treatment strategies and control measures in ongoing clade I mpox outbreaks.

PMID:40601777 | DOI:10.1126/scitranslmed.ads4773

Sci Transl Med. 2025 Jul 2;17(805):eadt2426. doi: 10.1126/scitranslmed.adt2426. Epub 2025 Jul 2.

ABSTRACT

Ritscher-Schinzel syndrome (RSS) is a congenital malformation syndrome characterized by cerebellar, cardiac, and craniofacial malformations and phenotypes associated with liver, skeletal, and kidney dysfunction. The genetic cause of RSS remains to be fully defined, and limited information is available regarding the root cause of the multiple tissue phenotypes. Causative mutations in the Commander multiprotein assembly are an emerging feature of this syndrome. Commander organizes the sorting nexin-17 (SNX17)-dependent recycling of hundreds of integral membrane proteins through the endosomal network. Here, we identify previously unrecognized cohorts of patients with RSS that we genetically and clinically analyzed to identify causative genes in the copper metabolic murr1 domain-containing (COMMD) proteins COMMD4, COMMD9, and coiled-coil domain containing 93 (CCDC93) subunits of the Commander complex. Using interactome analysis, we determined that these mutations disrupted Commander assembly and, through cell surface proteomics, that this reduces tissue-specific presentation of cell surface integral membrane proteins essential for kidney, bone, and brain development. We established that these integral proteins contained ΦxNPxY/F or ΦxNxxY/F sorting motifs in their cytoplasmic-facing domains (where Φ is a hydrophobic residue and x is any residue) that are recognized by SNX17 to drive their Commander-dependent endosomal recycling. Last, through generation of mouse models of RSS, we show replication of RSS-associated clinical phenotypes including proteinuria, skeletal malformation, and neurological impairment. Our data establish RSS as a "recyclinopathy" that arises from a dysfunction in the Commander endosomal recycling pathway.

PMID:40601774 | DOI:10.1126/scitranslmed.adt2426

Proc Natl Acad Sci U S A. 2025 Jul 8;122(27):e2414426122. doi: 10.1073/pnas.2414426122. Epub 2025 Jul 2.

ABSTRACT

The ability of cells to overcome cell cycle arrest and adapt to the presence of unrepairable DNA damage is under the control of Polo-like kinases (PLKs) in eukaryotes. How DNA damage checkpoints are silenced or bypassed during the adaptation response is unknown, but the process requires enrichment of the Cdc5 PLK to microtubule organizing centers (MTOCs), such as the yeast centrosomes or spindle pole bodies (SPBs). Here, we found that SPBs play an active role as supramolecular organizing centers that coordinate Cdc5 recruitment and signaling to downstream effectors during the adaptation response to DNA damage. We show that SPB components Nud1, Spc110, and Spc72 are key effectors of Cdc5 recruitment to SPBs in the presence of sustained DNA damage. Following recruitment, Cdc5 transduces a phospho-signal to key structural subunits of the SPB, including Cnm67 and Mps3. We demonstrate these phosphorylation events are required to bypass cell cycle checkpoint arrest and enable effective adaptation to DNA damage. This response is specific because it cannot be recapitulated by a generic inactivation of MTOC activity. Collectively, our results indicate that centrosomes can act as supramolecular platforms to coordinate dynamic recruitment and substrate selection of PLKs during the DNA damage response (DDR).

PMID:40601630 | DOI:10.1073/pnas.2414426122

Elife. 2025 Jul 2;14:RP105017. doi: 10.7554/eLife.105017.

ABSTRACT

While it is accepted that extracellular vesicles (EVs)-mediated transfer of microRNAs contributes to intercellular communication, the knowledge about molecular mechanisms controlling the selective and dynamic miRNA-loading in EVs is still limited to few specific RNA-binding proteins interacting with sequence determinants. Moreover, although mutagenesis analysis demonstrated the presence/function of specific intracellular retention motifs, the interacting protein/s remained unknown. Here, PCBP2 was identified as a direct interactor of an intracellular retention motif: CLIP coupled to RNA pull-down and proteomic analysis demonstrated that it binds to miRNAs embedding this motif and mutagenesis proved the binding specificity. Notably, PCBP2 binding requires SYNCRIP, a previously characterized miRNA EV-loader as indicated by SYNCRIP knock-down. SYNCRIP and PCBP2 may contemporarily bind to miRNAs as demonstrated by EMSA assays and PCBP2 knock-down causes EV loading of intracellular microRNAs. This evidence highlights that multiple proteins/miRNA interactions govern miRNA compartmentalization and identifies PCBP2 as a dominant inhibitor of SYNCRIP function in murine hepatocytes.

PMID:40601477 | DOI:10.7554/eLife.105017

Gut Microbes. 2025 Dec;17(1):2526132. doi: 10.1080/19490976.2025.2526132. Epub 2025 Jul 2.

ABSTRACT

Colorectal cancer (CRC) remains a major burden of cancer-related morbidity and mortality globally, especially when detected at later stages. Early detection through improved and more accessible diagnostics is critical for reducing the severity of CRC. As our understanding of CRC and the microbial inhabitants of the gastrointestinal tract continues to improve, it has become increasingly recognized that the bacterial component of the gut microbiome may provide diagnostic utility for detecting CRC. This is because CRC is often accompanied by shifts in bacterial taxa, and the metabolites produced or utilized by the CRC-associated gut bacterial community. Advances in sequencing and metabolite profiling technologies paired with our growing understanding of CRC-associated microbial taxa, present an opportunity for new gut microbiome-based diagnostics. In this narrative review, we discuss bacterial taxa and gut metabolites that have been investigated as predictive features for CRC diagnosis. We aim to highlight the tremendous progress that has been made in identifying gut microbiome-based features and why they should be further explored as potential CRC diagnostics. We also identify challenges that future work must address, including the impact of patient lifestyle, variation in methodology, and nonstandard data management practices. Resolving these areas of study design and implementation is key to understanding the complex bacterial communities and their by-products associated with CRC, and the development of microbial diagnostics that can detect them.

PMID:40601369 | DOI:10.1080/19490976.2025.2526132

Microbiol Spectr. 2025 Jul 2:e0001325. doi: 10.1128/spectrum.00013-25. Online ahead of print.

ABSTRACT

Due to varying sequencing strategies, current gut virome findings show significant variability. Specifically, bulk- and virus-like particle (VLP)-enriched metagenomic sequencing (termed bulk and VLP, respectively) present unique advantages and limitations, affecting viral genome discovery, taxonomic annotation, and community structure analysis. A comprehensive comparison of these strategies is crucial for thoroughly understanding the gut virome. This study comprehensively compared gut viromes identified from paired bulk and VLP data from 151 adult and 141 infant fecal samples. The VLP method showed superior performance to bulk in viral genome discovery in both data sets by recovering longer and more complete viral genomes, with higher sensitivity for low-abundant ones, resulting in a higher taxonomic annotation rate. However, we observed no correlations in the viral community structure (i.e., Shannon diversities) between bulk- and VLP-derived viromes, implying biases introduced during VLP enrichment. Such biases could be caused by the bacterial host features, such as the structural differences in cell walls and the prevalence and abundance of the viruses. Viruses that are of low prevalence, low abundance, or have Gram-positive bacteria as their hosts were enriched in VLP-derived viromes, in both the adult and infant data sets. Significant complementarity was observed between bulk and VLP viromes, with only about a quarter (26.7% in infants; 29.3% in adults) of VLP-viral genomes overlapping with bulk viruses. Together, our study identifies causal factors underlying the biases of bulk and VLP strategies in human gut virome studies and advocates the use of both strategies to enhance a comprehensive understanding of gut viromes.

IMPORTANCE: The two mainstream gut phageome profiling strategies, namely bulk and virus-like particle (VLP), generated significantly overlapped results and have their own merits and drawbacks. Particularly, VLP exhibits higher efficiency in obtaining more, longer, and more complete viral genomes. However, VLP sequencing has the potential to alter the natural structure of viral communities, often resulting in the identification of viruses with lower prevalence and those specifically associated with Gram-positive bacterial hosts. While bulk metagenome features a more stable and diverse community, which can well reveal the interactions between viruses and bacteria. Nevertheless, bulk sequencing can suffer from lower coverage, leading to fragmented sequences and potentially missing some viral species. Therefore, it is essential to recognize that these methods are complementary rather than competitive in the comprehensive characterization of the gut phageome.

PMID:40600714 | DOI:10.1128/spectrum.00013-25

Eur J Endocrinol. 2025 Jul 2:lvaf138. doi: 10.1093/ejendo/lvaf138. Online ahead of print.

ABSTRACT

OBJECTIVE: Gene dosage is at the core of biological activity of the Steroidogenic Factor-1 (SF-1/NR5A1) transcription factor. Its overexpression in adrenocortical carcinoma (ACC) is associated with enhanced proliferation and invasive capacities, steroid modulation, immune suppression and poor prognosis. Surprisingly, three independent studies showed less than 10% agreement in identifying SF-1-regulated genes in the same ACC cell line, raising concerns about technical reproducibility and methodological consistency. This study aimed to reconcile discrepancies in SF-1-regulated gene identification across independent studies using a systematic approach.

DESIGN AND METHODS: We reanalysed datasets from those studies using an in silico SF-1 regulon obtained from ACC TCGA data as an external reference to evaluate transcriptional patterns. Additionally, we assessed how threshold selection impacts the overlap between experiments and optimized this process. Furthermore, we performed functional experiments to evaluate how variations in SF-1 dosage impact target gene expression.

RESULTS: Our analysis revealed comparable transcriptional patterns across all studies, reconciling transcriptional signatures and phenotypes. Threshold optimization identified consensus sets of genes responsive to SF-1 perturbations. Functional experiments confirmed that variations in SF-1 dosage significantly impact gene expression, explaining discrepancies in previous studies, and evidenced negative autoregulation of the SF-1 transcript by its encoded protein both in ACC cells and in a mouse model of Sf-1 overexpression in the adrenal cortex.

CONCLUSIONS: Our findings deepen our understanding of SF-1 regulatory activity in ACC and demonstrate that dosage is critical for observed gene expression patterns. Our integrative approach improves reproducibility and biological interpretation, offering a framework to reconcile cross-study findings.

PMID:40600578 | DOI:10.1093/ejendo/lvaf138

Curr Cancer Drug Targets. 2025 Jun 23. doi: 10.2174/0115680096372733250611114329. Online ahead of print.

ABSTRACT

Cancer is a major health problem and the second leading cause of death worldwide. Chemotherapy remains the mainstay therapeutic option to treat cancer patients, which consists of conventional, hormonal, and/or targeted therapies. However, the significant adverse effects, negative impact on patients' quality of life, and high costs of some medications, as well as the challenges associated with developing new drugs, are prompting the scientific community to seek innovative and alternative treatment strategies. One such strategy is drug repurposing, the use of existing drugs, already approved for other medical conditions for cancer treatment, lev-eraging their known safety and toxicity profiles. Among these groups are the selective seroto-nin reuptake inhibitors (SSRIs) that target serotonin transporter (SERT). In this review, we presented the mechanism of action of SSRIs on the systems biology level, along with their network pharmacology related to protein-protein interactions. We also showed the association of SSRIs and SERT with various diseases, including several types of cancer. Knowing the expression of SERT in cancer and being a target for SSRIs, studies have been investigating the repurposing of SSRIs for cancer treatment. This review also presents a summary of several clinical and preclinical studies that have investigated the use of SSRIs either as single agents or in combination with conventional chemotherapy for cancer treatment, showing promising results. Collectively, they have shown the antiproliferative and growth inhibition effects on cancer cells and/or tumors. We also presented the mechanism(s) of action and pathways these drugs are acting in cancer, along with molecular changes in cellular proteins and enzymes.

PMID:40600564 | DOI:10.2174/0115680096372733250611114329

Biomater Sci. 2025 Jul 2. doi: 10.1039/d4bm01601g. Online ahead of print.

ABSTRACT

Mesenchymal stem cell-derived extracellular nanovesicles (MSC-NVs) exhibit unique biological properties and tissue-regenerative effects comparable to their parent MSCs. However, despite the robust angiogenic and anti-apoptotic effects of MSC-NVs, their immunomodulatory effect is limited due to insufficient translation of anti-inflammatory cytokines from parent MSCs to isolated NVs. Hence, in this study we suggest the incorporation of interleukin (IL)-10, a key anti-inflammatory mediator in the body's immune system, on the surface of MSC-NVs via bio-orthogonal click chemistry. Metabolically engineered MSCs were serially extruded to generate azido-displaying MSC-NV-N3, followed by click chemistry-based conjugation of IL-10. Synthesized MSC-NV/IL-10 exhibited superior abilities for cell proliferation and migration of fibroblast and endothelial cells. MSC-NV/IL-10 markedly attenuated the activity of the pro-inflammatory M1 macrophage and promoted the expression of the anti-inflammatory M2 marker. We also demonstrated that MSC-NV/IL-10 induces the phenotypic transition of dendritic cells (DCs) from mature DCs to immune-tolerogenic DCs. Moreover, RNA sequencing revealed that metabolic engineering does not alter the regenerative potential or immunomodulatory functions of MSCs. In animal studies, MSC-NV/IL-10 treated mice exhibited significantly accelerated wound healing, accompanied by resolution of inflammatory responses in injured skin.

PMID:40600270 | DOI:10.1039/d4bm01601g

iScience. 2025 Apr 28;28(6):112536. doi: 10.1016/j.isci.2025.112536. eCollection 2025 Jun 20.

ABSTRACT

Gene regulatory networks (GRNs) are critically important for efforts in biomedicine and biotechnology. Here, we introduce the Regulatory Network Machine (RNM) framework, demonstrating how GRNs behave as analog computers capable of sophisticated information processing. Our RNM framework encapsulates: (1) a dissipative dynamic system with a focus on GRNs, (2) a set of inputs to the system, (3) system output states with identifiable relevance to biotechnological or biomedical objectives, and (4) Network Finite State Machines (NFSMs), which are maps detailing how the system changes equilibrium state in response to patterns of applied inputs. As an extension to attractor landscape analysis, the NFSMs map the sequential logic inherent in the GRN and, therefore, embody the "software-like" nature of the system, providing easy identification of specific applied interventions necessary to achieve desired, stable biological outcomes. We illustrate the use of our RNM framework in important biological examples, including in cancer renormalization.

PMID:40600146 | PMC:PMC12210318 | DOI:10.1016/j.isci.2025.112536