Antioxidants (Basel). 2025 Jan 11;14(1):80. doi: 10.3390/antiox14010080.

ABSTRACT

Glucosinolates (GSLs) are nitrogen/sulfur-containing glycosides widely present in the order of Brassicales, particularly in the Brassicaceae family. Camelina (Camelina sativa (L.) Crantz) is an oilseed plant belonging to this family. Its seeds, in addition to a distinctive fatty acid composition, contain three aliphatic GSLs: glucoarabin, glucocamelinin, and homoglucocamelinin. Our study explored the impact of these GSLs purified from Camelina press cake, a by-product of Camelina oil production, on yeast chronological aging, which is the established model for simulating the aging of post-mitotic quiescent mammalian cells. Supplementing yeast cells with GSLs extends the chronological lifespan (CLS) in a dose-dependent manner. This enhancement relies on an improved mitochondrial respiration efficiency, resulting in a drastic decrease of superoxide anion levels and an increase in ATP production. Furthermore, GSL supplementation affects carbon metabolism. In particular, GSLs support the pro-longevity preservation of TCA cycle enzymatic activities and enhanced glycerol catabolism. These changes contribute positively to the phosphorylating respiration and to an increase in trehalose storage: both of which are longevity-promoting prerequisites.

PMID:39857414 | DOI:10.3390/antiox14010080

Nat Cancer. 2025 Jan 24. doi: 10.1038/s43018-024-00900-3. Online ahead of print.

ABSTRACT

Mutations in cancer risk genes increase susceptibility, but not all carriers develop cancer. Indeed, while DNA mutations are necessary drivers of cancer, only a small subset of mutated cells go on to cause the disease. To date, the mechanisms underlying individual cancer susceptibility remain unclear. Here, we took advantage of a unique mouse model of intrinsic developmental heterogeneity (Trim28+/D9) to investigate whether early-life epigenetic variation influences cancer susceptibility later in life. We found that heterozygosity of Trim28 is sufficient to generate two distinct early-life epigenetic states associated with differing cancer susceptibility. These developmentally primed states exhibit differential methylation patterns at typically silenced heterochromatin, detectable as early as 10 days of age. The differentially methylated loci are enriched for genes with known oncogenic potential, frequently mutated in human cancers and correlated with poor prognosis. This study provides genetic evidence that intrinsic developmental heterogeneity can prime individual, lifelong cancer susceptibility.

PMID:39856421 | DOI:10.1038/s43018-024-00900-3

Int J Obes (Lond). 2025 Jan 24. doi: 10.1038/s41366-025-01724-6. Online ahead of print.

ABSTRACT

BACKGROUND: Metabolic dysregulation, a defining feature of obesity, disrupts essential signalling pathways involved in nutrient sensing and mitochondria homeostasis. The nuclear factor erythroid 2-related factor 2 (NRF-2) serves as a pivotal regulator of the cellular stress response, and recent studies have implicated it in the pathogenesis of obesity, diabetes, and metabolic syndrome. Curcumin, a polyphenolic compound derived from turmeric, has been identified as a potent activator of NRF-2. Evidence suggests curcumin impacts obesity and metabolic disorders by modulating gut microbiota composition, increasing energy expenditure, and regulating lipid metabolism. Orlistat, an anti-obesity drug, inhibits fat absorption in the gastrointestinal tract, but its side effects limits its broader use.

OBJECTIVES: The present study aims to investigate the potential synergetic effect of a hybrid combination between orlistat and curcumin. Additionally, we provide a detailed understanding of the molecular mechanisms through which this combination mitigates glucose-induced lipid accumulation in Caenorhabditis elegans, with a focus on the role of the skinhead 1 (SKN-1) transcription factor, an orthologue of NRF2.

METHODS: We assessed the lipid accumulation and the changes in skn-1 transcriptional activity in C. elegans using confocal GFP-based detection, alongside mRNA expression analysis of genes from lipid metabolism and oxidative stress response in wild-type, QV225 and LD1 strains. Furthermore, we evaluated locomotion, chemotaxis and mitochondrial dynamics to enhance our understanding of the proposed molecular-based model.

RESULTS: Our findings reveal that the orlistat/curcumin combination exerts an anti-obesogenic effect through SKN-1/NRF2-dependent regulation of conserved genes involved in carbohydrate and lipid metabolism in C. elegans. Moreover, the combination stimulates mitochondrial potential, further contributing to the observed synergistic effects.

CONCLUSION: The hybrid combination of orlistat and curcumin demonstrates significant anti-obesity activity by regulating nutrient-sensing pathways through SKN-1/NRF-2 modulation. This approach may allow for the reduction of orlistat dosage, thereby minimizing its adverse effects while maintaining its therapeutic efficacy.

PMID:39856245 | DOI:10.1038/s41366-025-01724-6

Nat Commun. 2025 Jan 24;16(1):989. doi: 10.1038/s41467-025-55923-w.

ABSTRACT

NKp46 is a critical regulator of natural killer (NK) cell immunity, but its function in non-NK innate immune cells remains unclear. Here, we show that NKp46 is indispensable for expressing IL-2 receptor-α (IL-2Rα) by non-NK liver-resident type-1 innate lymphoid cells (ILC1s). Deletion of NKp46 reduces IL-2Rα on ILC1s by downregulating NF-κB signaling, thus impairing ILC1 proliferation and cytotoxicity in vitro and in vivo. The binding of anti-NKp46 antibody to NKp46 triggers the activation of NF-κB, the expression of IL-2Rα, interferon-γ (IFN-γ), tumor necrosis factor (TNF), proliferation, and cytotoxicity. Functionally, NKp46 expressed on mouse ILC1s interacts with tumor cells through cell-cell contact, increasing ILC1 production of IFN-γ and TNF, and enhancing cytotoxicity. In a mouse model of acute myeloid leukemia, deletion of NKp46 impairs the ability of ILC1s to control tumor growth and reduces survival. This can be reversed by injecting NKp46+ ILC1s into NKp46 knock-out mice. Human NKp46+ ILC1s exhibit stronger cytokine production and cytotoxicity than their NKp46- counterparts, suggesting that NKp46 plays a similar role in humans. These findings identify an NKp46-NF-κB-IL-2Rα axis and suggest that activating NKp46 with an anti-NKp46 antibody may provide a potential strategy for anti-tumor innate immunity.

PMID:39856052 | DOI:10.1038/s41467-025-55923-w

New Phytol. 2025 Jan 24. doi: 10.1111/nph.20420. Online ahead of print.

ABSTRACT

Temperature is a critical environmental factor affecting nearly all plant processes, including growth, development, and yield. Yet, despite decades of research, we lack the ability to predict plant performance at different temperatures, limiting the development of climate-resilient crops. Further, there is a pressing need to bridge the gap between the prediction of physiological and molecular traits to improve our understanding and manipulation of plant temperature responses. Here, we developed the first enzyme-constrained model of Arabidopsis thaliana's metabolism, facilitating predictions of growth-related phenotypes at different temperatures. We showed that the model can be employed for in silico identification of genes that affect plant growth at suboptimal growth temperature. Using mutant lines, we validated the genes predicted to affect plant growth, demonstrating the potential of metabolic modeling in accurately predicting plant thermal responses. The temperature-dependent enzyme-constrained metabolic model provides a template that can be used for developing sophisticated strategies to engineer climate-resilient crops.

PMID:39856022 | DOI:10.1111/nph.20420

Sheng Wu Gong Cheng Xue Bao. 2025 Jan 25;41(1):199-215. doi: 10.13345/j.cjb.240350.

ABSTRACT

Petroleum hydrocarbon pollution has become one of the global environmental problems, posing a serious threat to the environment and human health. Microbial remediation plays an important role in the remediation of petroleum hydrocarbon-contaminated environment. Nevertheless, the stress factors present in the environment polluted by petroleum hydrocarbons limit the effectiveness of microbial remediation. This paper reviews the common stress factors in petroleum hydrocarbon-polluted environment and the response mechanisms of microorganisms to these factors. Furthermore, we introduce the methods to improve microbial tolerance, such as irrational modification, rational modification based on systems biology tools or tolerance mechanisms, and the construction of microbial consortia. The application of these methods is expected to improve the viability and remediation efficiency of microorganisms in petroleum hydrocarbon-contaminated environment and provide new perspectives and technical support for environmental remediation.

PMID:39855688 | DOI:10.13345/j.cjb.240350

Biotechnol Adv. 2025 Jan 22:108520. doi: 10.1016/j.biotechadv.2025.108520. Online ahead of print.

ABSTRACT

Sustainable agriculture practices are indispensable for achieving a hunger-free world, especially as the global population continues to expand. Biotic stresses, such as pathogens, insects, and pests, severely threaten global food security and crop productivity. Traditional chemical pesticides, while effective, can lead to environmental degradation and increase pest resistance over time. Plant-derived natural products such as secondary metabolites like alkaloids, terpenoids, phenolics, and phytoalexins offer promising alternatives due to their ability to enhance plant immunity and inhibit pest activity. Recent advances in molecular biology and biotechnology have improved our understanding of how these natural compounds function at the cellular level, activating specific plant defense through complex biochemical pathways regulated by various transcription factors (TFs) such as MYB, WRKY, bHLH, bZIP, NAC, and AP2/ERF. Advancements in multi-omics approaches, including genomics, transcriptomics, proteomics, and metabolomics, have significantly improved the understanding of the regulatory networks that govern PSM synthesis. These integrative approaches have led to the discovery of novel insights into plant responses to biotic stresses, identifying key regulatory genes and pathways involved in plant defense. Advanced technologies like CRISPR/Cas9-mediated gene editing allow precise manipulation of PSM pathways, further enhancing plant resistance. Understanding the complex interaction between PSMs, TFs, and biotic stress responses not only advances plant biology but also provides feasible strategies for developing crops with improved resistance to pests and diseases, contributing to sustainable agriculture and food security. This review emphasizes the crucial role of PSMs, their biosynthetic pathways, the regulatory influence of TFs, and their potential applications in enhancing plant defense and sustainability. It also highlights the astounding potential of multi-omics approaches to discover gene functions and the metabolic engineering of genes associated with secondary metabolite biosynthesis. Taken together, this review provides new insights into research opportunities for enhancing biotic stress tolerance in crops through utilizing plant secondary metabolites.

PMID:39855404 | DOI:10.1016/j.biotechadv.2025.108520

Cell. 2025 Jan 20:S0092-8674(24)01436-3. doi: 10.1016/j.cell.2024.12.023. Online ahead of print.

ABSTRACT

Despite recent advances in imaging- and antibody-based methods, achieving in-depth, high-resolution protein mapping across entire tissues remains a significant challenge in spatial proteomics. Here, we present parallel-flow projection and transfer learning across omics data (PLATO), an integrated framework combining microfluidics with deep learning to enable high-resolution mapping of thousands of proteins in whole tissue sections. We validated the PLATO framework by profiling the spatial proteome of the mouse cerebellum, identifying 2,564 protein groups in a single run. We then applied PLATO to rat villus and human breast cancer samples, achieving a spatial resolution of 25 μm and uncovering proteomic dynamics associated with disease states. This approach revealed spatially distinct tumor subtypes, identified key dysregulated proteins, and provided novel insights into the complexity of the tumor microenvironment. We believe that PLATO represents a transformative platform for exploring spatial proteomic regulation and its interplay with genetic and environmental factors.

PMID:39855194 | DOI:10.1016/j.cell.2024.12.023

PLoS Biol. 2025 Jan 24;23(1):e3002722. doi: 10.1371/journal.pbio.3002722. eCollection 2025 Jan.

ABSTRACT

Successful resolution of approach-avoidance conflict (AAC) is fundamentally important for survival, and its dysregulation is a hallmark of many neuropsychiatric disorders, and yet the underlying neural circuit mechanisms are not well elucidated. Converging human and animal research has implicated the anterior/ventral hippocampus (vHPC) as a key node in arbitrating AAC in a region-specific manner. In this study, we sought to target the vHPC CA1 projection pathway to the nucleus accumbens (NAc) to delineate its contribution to AAC decision-making, particularly in the arbitration of learned reward and punishment signals, as well as innate signals. To this end, we used pathway-specific chemogenetics in male and female Long Evans rats to inhibit the NAc shell projecting vHPC CA1 neurons while rats underwent a test in which cues of positive and negative valence were presented concurrently to elicit AAC. Additional behavioral assays of social preference and memory, reward and punishment cue processing, anxiety, and novelty processing were administered to further interrogate the conditions under which the vCA1-NAc shell pathway is recruited. Chemogenetic inhibition of the vCA1-NAc shell circuit resulted in animals exhibiting increased decision-making time and avoidance bias specifically in the face of motivational conflict, as the same behavioral phenotype was absent in separate conditioned cue preference and avoidance tests. vCA1-NAc shell inhibition also led to a reduction in seeking social interaction with a novel rat but did not alter anxiety-like behaviors. The vCA1-NAc shell circuit is therefore critically engaged in biasing decisions to approach in the face of social novelty and approach-avoidance conflict. Dysregulation of this circuit could lead to the precipitation of addictive behaviors in substance abuse, or maladaptive avoidance in situations of approach-avoidance conflict.

PMID:39854559 | DOI:10.1371/journal.pbio.3002722

Sci Adv. 2025 Jan 24;11(4):eads1911. doi: 10.1126/sciadv.ads1911. Epub 2025 Jan 24.

ABSTRACT

Tigilanol tiglate (EBC-46) is a selective modulator of protein kinase C (PKC) isoforms that is Food and Drug Administration (FDA) approved for the treatment of mast cell tumors in canines with up to an 88% cure rate. Recently, it has been FDA approved for the treatment of soft tissue sarcomas in humans. The role of EBC-46 and, especially, its analogs in efforts to eradicate HIV, treat neurological and cardiovascular disorders, or enhance antigen density in antigen-targeted chimeric antigen receptor-T cell and chimeric antigen receptor-natural killer cell immunotherapies has not been reported. Enabled by our previously reported scalable synthesis of EBC-46, we report herein the systematic design, synthesis, and evaluation of EBC-46 analogs, including those inaccessible from the natural source and their PKC affinities, ability to translocate PKC, nuclear factor κB activity, and efficacy in reversing HIV latency in Jurkat-Latency cells. Leading analogs show exceptional PKC affinities, isoform selectivities, and functional activities, serving as promising candidates for therapeutic applications.

PMID:39854456 | DOI:10.1126/sciadv.ads1911

Proc Natl Acad Sci U S A. 2025 Jan 28;122(4):e2426163122. doi: 10.1073/pnas.2426163122. Epub 2025 Jan 24.

NO ABSTRACT

PMID:39854239 | DOI:10.1073/pnas.2426163122

Syst Biol Reprod Med. 2025 Dec;71(1):1. doi: 10.1080/19396368.2024.2447691. Epub 2025 Jan 24.

NO ABSTRACT

PMID:39854222 | DOI:10.1080/19396368.2024.2447691

Diabetes. 2025 Jan 24:db240497. doi: 10.2337/db24-0497. Online ahead of print.

ABSTRACT

PPARγ is the pharmacological target of thiazolidinediones (TZDs), potent insulin sensitizers that prevent metabolic disease morbidity but are accompanied by side effects such as weight gain, in part due to non-physiological transcriptional agonism. Using high throughput genome engineering, we targeted nonsense mutations to every exon of PPARG, finding an ATG in Exon 2 (chr3:12381414, CCDS2609 c.A403) that functions as an alternative translational start site. This downstream translation initiation site gives rise to a PPARγ protein isoform (M135), preferentially generated from alleles containing nonsense mutations upstream of c.A403. PPARγ M135 retains the DNA and ligand binding domains of full-length PPARγ but lacks the N-terminal AF-1 domain. Despite being truncated, PPARγ M135 shows increased transactivation of target genes, but only in the presence of agonists. Accordingly, human missense mutations disrupting AF-1 domain function actually increase agonist-induced cellular PPARγ activity compared to wild-type (WT), and carriers of these AF-1 disrupting variants are protected from metabolic syndrome. Thus, we propose the existence of PPARγ M135 as a fully functional, alternatively translated isoform that may be therapeutically generated to treat insulin resistance-related disorders.

PMID:39854214 | DOI:10.2337/db24-0497

STAR Protoc. 2025 Jan 23;6(1):103584. doi: 10.1016/j.xpro.2024.103584. Online ahead of print.

ABSTRACT

Here, we present a protocol to generate dual-target compounds (DT-CPDs) interacting with two distinct target proteins using a transformer-based chemical language model. We describe steps for installing software, preparing data, and pre-training the model on pairs of single-target compounds (ST-CPDs), which bind to an individual protein, and DT-CPDs. We then detail procedures for assembling ST- and corresponding DT-CPD data for specific protein pairs and evaluating the model's performance on hold-out test sets. For complete details on the use and execution of this protocol, please refer to Srinivasan and Bajorath.1.

PMID:39854202 | DOI:10.1016/j.xpro.2024.103584

Adv Sci (Weinh). 2025 Jan 24:e2413367. doi: 10.1002/advs.202413367. Online ahead of print.

ABSTRACT

Glioblastoma multiforme (GBM) is a highly aggressive and malignant brain tumor originating from glial cells, characterized by high recurrence rates and poor patient prognosis. The heterogeneity and complex biology of GBM, coupled with the protective nature of the blood-brain barrier (BBB), significantly limit the efficacy of traditional therapies. The rapid development of nanoenzyme technology presents a promising therapeutic paradigm for the rational and targeted treatment of GBM. In this review, the underlying mechanisms of GBM pathogenesis are comprehensively discussed, emphasizing the impact of the BBB on treatment strategies. Recent advances in nanoenzyme-based approaches for GBM therapy are explored, highlighting how these nanoenzymes enhance various treatment modalities through their multifunctional capabilities and potential for precise drug delivery. Finally, the challenges and therapeutic prospects of translating nanoenzymes from laboratory research to clinical application, including issues of stability, targeting efficiency, safety, and regulatory hurdles are critically analyzed. By providing a thorough understanding of both the opportunities and obstacles associated with nanoenzyme-based therapies, future research directions are aimed to be informed and contribute to the development of more effective treatments for GBM.

PMID:39854126 | DOI:10.1002/advs.202413367

Am J Hum Biol. 2025 Jan;37(1):e24212. doi: 10.1002/ajhb.24212.

ABSTRACT

INTRODUCTION: The maximal fat oxidation (MFO) and the exercise intensity that provokes MFO (FATMAX) are inversely associated with cardiometabolic risk factors in healthy young sedentary adults. However, how both cardiorespiratory fitness (CRF) level and sex influence MFO during exercise and the FATMAX is seldom analyzed.

OBJECTIVES: This study is aimed at determining the influence of CRF and sex on MFO.

METHODS: Twenty healthy young adults (i.e., 12 men and 8 women) completed a graded treadmill protocol to determine MFO, MFO relative to lean mass (MFOlean), FATMAX and maximum oxygen uptake (VO2max).

RESULTS: The k-means cluster analysis was used to divide the sample into two different groups for CRF level (56.54 ± 2.54 and 46.94 ± 3.07 mL/kg/min, p < 0.001, respectively). The high-level group revealed higher MFO relative to lean mass (MFOlean) (3.34 ± 1.44 and 2.73 ± 0.87 g · min-1 · kg, p = 0.001, respectively), and FATMAX in km · h-1 (FATMAXv) (7.67 ± 0.90 and 7.00 ± 0.97 km · h-1, p = 0.044, respectively) but not for MFO (0.67 ± 0.19 and 0.71 ± 0.20 p = 0.124, respectively). When divided for sex, men exhibited higher values for MFO (0.76 ± 0.21 vs. 0.69 ± 0.19 g · min-1, p = 0.039) and FATMAXv (7.67 ± 0.96 vs. 7.30 ± 0.98 km · h-1, p = 0.036), while women showed higher values for MFOlean (3.92 ± 1.35 vs. 2.40 ± 0.46 g · min-1 · kg, p = 0.015).

CONCLUSION: This study highlights the significant influence of CRF level and sex on MFO and FATMAX, offering valuable insights for tailoring exercise programs and optimizing health and performance interventions.

PMID:39853816 | DOI:10.1002/ajhb.24212

Ann Neurol. 2025 Jan 24. doi: 10.1002/ana.27087. Online ahead of print.

ABSTRACT

Congenital titinopathy has recently emerged as one of the most common congenital muscle disorders.

OBJECTIVE: To better understand the presentation and clinical needs of the under-characterized extreme end of the congenital titinopathy severity spectrum.

METHODS: We comprehensively analyzed the clinical, imaging, pathology, autopsy, and genetic findings in 15 severely affected individuals from 11 families.

RESULTS: Prenatal features included hypokinesia or akinesia and growth restriction. Six pregnancies were terminated. Nine infants were born at or near term with severe-to-profound weakness and required resuscitation. Seven died following withdrawal of life support. Two surviving children require ongoing respiratory support. Most cohort members had at least 1 disease-causing variant predicted to result in some near-normal-length titin expression. The exceptions, from 2 unrelated families, had homozygous truncating variants predicted to induce complete nonsense mediated decay. However, subsequent analyses suggested that the causative variant in each family had an additional previously unrecognized impact on splicing likely to result in some near-normal-length titin expression. This impact was confirmed by minigene assay for 1 variant.

INTERPRETATION: This study confirms the clinical variability of congenital titinopathy. Severely affected individuals succumb prenatally/during infancy, whereas others survive into adulthood. It is likely that this variability is because of differences in the amount and/or length of expressed titin. If confirmed, analysis of titin expression could facilitate clinical prediction and increasing expression might be an effective treatment strategy. Our findings also further-support the hypothesis that some near-normal-length titin expression is essential to early prenatal survival. Sometimes expression of normal/near-normal-length titin is due to disease-causing variants having an additional impact on splicing. ANN NEUROL 2025.

PMID:39853809 | DOI:10.1002/ana.27087

World J Biol Psychiatry. 2025 Jan 24:1-16. doi: 10.1080/15622975.2025.2453198. Online ahead of print.

ABSTRACT

BACKGROUND: Genes associated with global developmental delay (GDD) and intellectual disability (ID) are increasingly being identified through next-generation sequencing (NGS) technologies. This study aimed to identify novel mutations in GDD/ID phenotypes through whole-exome sequencing (WES) and additional in silico analyses.

MATERIAL AND METHODS: WES was performed on 27 subjects, among whom 18 were screened for potential novel mutations. In silico analyses included protein-protein interactions (PPIs), gene-miRNA interactions (GMIs), and enrichment analyses. The identified novel variants were further modelled using I-Tasser-MTD and SWISS-MODEL, with structural superimposition performed.

RESULTS: Novel mutations were detected in 18 patients, with 10 variants reported for the first time. Among these, three were classified as pathogenic (DNMT1:c.856dup, KCNQ2:c.1635_1636insT, and TMEM94:c.2598_2599insC), and six were likely pathogenic. DNMT1 and MRE11 were highlighted as key players in PPIs and GMIs. GMIs analysis emphasised the roles of hsa-miR-30a-5p and hsa-miR-185-5p. The top-scoring pathways included the neuronal system (R-HSA-112316, p = 7.73E-04) and negative regulation of the smooth muscle cell apoptotic process (p = 3.37E-06). Homology modelling and superimposition revealed a significant functional loss in the mutated DNMT1 enzyme structure.

CONCLUSION: This study identified 10 novel pathogenic/likely pathogenic variants associated with GDD/ID, supported by clinical findings and in silico analyses focused on DNMT1 mutations.

PMID:39853208 | DOI:10.1080/15622975.2025.2453198

Vaccines (Basel). 2025 Jan 1;13(1):33. doi: 10.3390/vaccines13010033.

ABSTRACT

Adjuvants are a diverse group of substances that can be added to vaccines to enhance antigen-specific immune responses and improve vaccine efficacy. The first adjuvants, discovered almost a century ago, were soluble crystals of aluminium salts. Over the following decades, oil emulsions, vesicles, oligodeoxynucleotides, viral capsids, and other complex organic structures have been shown to have adjuvant potential. However, the detailed mechanisms of how adjuvants enhance immune responses remain poorly understood and may be a barrier that reduces the rational selection of vaccine components. Previous studies on mechanisms of action of adjuvants have focused on how they activate innate immune responses, including the regulation of cell recruitment and activation, cytokine/chemokine production, and the regulation of some "immune" genes. This approach provides a narrow perspective on the complex events involved in how adjuvants modulate antigen-specific immune responses. A comprehensive and efficient way to investigate the molecular mechanism of action for adjuvants is to utilize systems biology approaches such as transcriptomics in so-called "systems vaccinology" analysis. While other molecular biology methods can verify if one or few genes are differentially regulated in response to vaccination, systems vaccinology provides a more comprehensive picture by simultaneously identifying the hundreds or thousands of genes that interact with complex networks in response to a vaccine. Transcriptomics tools such as RNA sequencing (RNA-Seq) allow us to simultaneously quantify the expression of practically all expressed genes, making it possible to make inferences that are only possible when considering the system as a whole. Here, we review some of the challenges in adjuvant studies, such as predicting adjuvant activity and toxicity when administered alone or in combination with antigens, or classifying adjuvants in groups with similar properties, while underscoring the significance of transcriptomics in systems vaccinology approaches to propel vaccine development forward.

PMID:39852812 | DOI:10.3390/vaccines13010033

Cells. 2025 Jan 15;14(2):119. doi: 10.3390/cells14020119.

ABSTRACT

As of 2023, there were 39.9 million people living with Human Immunodeficiency Virus type 1 (HIV-1). Although great strides have been made in treatment options for HIV-1, and our understanding of the HIV-1 life cycle has vastly improved since the start of this global health crisis, a functional cure remains elusive. One of the main barriers to a cure is latency, which allows the virus to persist despite combined antiretroviral therapy (cART). Recently, we have found that exosomes, which are small, membrane-enclosed particles released by virtually all cell types and known to mediate intercellular communication, caused an increase in RNA Polymerase II loading onto the HIV-1 promoter. This resulted in the production of both short- and long-length viral transcripts in infected cells under cART. This current study examines the effects of exosome-associated kinases on bystander cells. The phospho-kinase profiling of exosomes revealed differences in the kinase payload of exosomes derived from uninfected and HIV-1-infected cells, with CDK10, GSK3β, and MAPK8 having the largest concentration differences. These kinases were shown to be biologically active and capable of phosphorylating substrates, and they modulated changes in the cell cycle dynamics of exposed cells. Given the relevance of such effects for the immune response, our results implicate exosome-associated kinases as new possible key contributors to HIV-1 pathogenesis that affect bystander cells. These findings may guide new therapeutic avenues to improve the current antiretroviral treatment regimens.

PMID:39851547 | DOI:10.3390/cells14020119