Biomed Pharmacother. 2025 Jan 21;183:117862. doi: 10.1016/j.biopha.2025.117862. Online ahead of print.

ABSTRACT

The strategy of drug repositioning has historically played a significant role in the identification of new treatments for Parkinson's disease. Still today, numerous clinical and preclinical studies are investigating drug classes, already marketed for the treatment of metabolic disorders, for their potential use in Parkinson's disease patients. While drug repurposing offers a promising, fast, and cost-effective path to new treatments, these drugs still require thorough preclinical evaluation to assess their efficacy, addressing the specific neurodegenerative mechanisms of the disease. This review explores the state-of-the-art approaches to drug repurposing for Parkinson's disease, highlighting particularly relevant aspects. Preclinical studies still predominantly rely on traditional neurotoxin-based animal models, which fail to effectively replicate disease progression and are characterized by significant variability in model severity and timing of drug treatment. Importantly, for almost all the drugs analyzed here, there is insufficient data regarding the mechanism of action responsible for the therapeutic effect. Regarding drug efficacy, these factors may obviously render results less reliable or comparable. Accordingly, future preclinical drug repurposing studies in the Parkinson's disease field should be carried out using next-generation animal models like α-synuclein-based models that, unfortunately, have to date been used mostly for studies of disease pathogenesis and only rarely in pharmacological studies.

PMID:39842271 | DOI:10.1016/j.biopha.2025.117862

Nature. 2025 Jan 22. doi: 10.1038/s41586-024-08468-9. Online ahead of print.

ABSTRACT

Bipolar disorder is a leading contributor to the global burden of disease1. Despite high heritability (60-80%), the majority of the underlying genetic determinants remain unknown2. We analysed data from participants of European, East Asian, African American and Latino ancestries (n = 158,036 cases with bipolar disorder, 2.8 million controls), combining clinical, community and self-reported samples. We identified 298 genome-wide significant loci in the multi-ancestry meta-analysis, a fourfold increase over previous findings3, and identified an ancestry-specific association in the East Asian cohort. Integrating results from fine-mapping and other variant-to-gene mapping approaches identified 36 credible genes in the aetiology of bipolar disorder. Genes prioritized through fine-mapping were enriched for ultra-rare damaging missense and protein-truncating variations in cases with bipolar disorder4, highlighting convergence of common and rare variant signals. We report differences in the genetic architecture of bipolar disorder depending on the source of patient ascertainment and on bipolar disorder subtype (type I or type II). Several analyses implicate specific cell types in the pathophysiology of bipolar disorder, including GABAergic interneurons and medium spiny neurons. Together, these analyses provide additional insights into the genetic architecture and biological underpinnings of bipolar disorder.

PMID:39843750 | DOI:10.1038/s41586-024-08468-9

J Pharm Biomed Anal. 2025 Jan 20;256:116684. doi: 10.1016/j.jpba.2025.116684. Online ahead of print.

ABSTRACT

Alkaptonuria (AKU) is a rare autosomal-recessive disease which is characterized through black urine and ochronosis. It is caused by deficiency of the enzyme Homogentisate 1,2-dioxygenase in the Phenylalanine/Tyrosine degradation pathway which leads to the accumulation of Homogentisic acid (HGA). Urine was provided by AKU patients and healthy controls. Several different methods were developed in this study each with a specific goal. Firstly, a simple and inexpensive RP-UHPLC-UV method for routine monitoring of HGA as a key metabolite employing a Phenylhexyl stationary phase chemistry. Validation was performed in accordance to FDA guidelines and method selectivity was further evaluated via on-line high-resolution sampling 2D-LC-QToF-MS, coupling the Phenylhexyl phase in the first dimension with a C18 phase in the second dimension. Secondly, a targeted and accurate RP-UHPLC-MRM-QTRAP assay, providing quantitative analysis of the relevant pathway metabolites based on a Phenylhexyl stationary phase, and lastly an untargeted HILIC-UHPLC-QToF-MS/MS method with SWATH (sequential window acquisition of all theoretical mass spectra) acquisition employing a sulfobetaine-type HILIC-Z superficially porous particle column, with the aim of uncovering more details about the metabolic profile of this genetic disorder. By untargeted analysis 204 metabolites could be detected and annotated in positive and negative ESI mode in total. Two separate LC methods were employed, differing in their conditions depending on the ionization mode (20 mM ammonium formate as buffer additive adjusted to a pH = 3.5 with formic acid in ESI+ mode and 20 mM ammonium acetate adjusted to a pH = 7.5 with acetic acid in ESI- mode). By effectively combining the aforementioned methods, a comprehensive workflow was developed, allowing the effective analysis of both patient and control urine samples.

PMID:39842076 | DOI:10.1016/j.jpba.2025.116684

NPJ Antimicrob Resist. 2024 Feb 20;2(1):4. doi: 10.1038/s44259-024-00022-x.

ABSTRACT

Antimicrobial peptides (AMPs) are key components of innate immunity across all domains of life. Natural and synthetic AMPs are receiving renewed attention in efforts to combat the antimicrobial resistance (AMR) crisis and the loss of antibiotic efficacy. The gram-negative pathogen Pseudomonas aeruginosa is one of the most concerning infecting bacteria in AMR, particularly in people with cystic fibrosis (CF) where respiratory infections are difficult to eradicate and associated with increased morbidity and mortality. Cationic AMPs exploit the negatively charged lipopolysaccharides (LPS) on P. aeruginosa to bind and disrupt bacterial membrane(s), causing lethal damage. P. aeruginosa modifies its LPS to evade AMP killing. Free-LPS is also a component of CF sputum and feeds pro-inflammatory cycles. Glatiramer acetate (GA) is a random peptide co-polymer-of glycine, lysine, alanine, tyrosine-used as a drug in treatment of multiple sclerosis (MS); we have previously shown GA to be an AMP which synergises with tobramycin against CF P. aeruginosa, functioning via bacterial membrane disruption. Here, we demonstrate GA's direct binding and sequestration/neutralisation of P. aeruginosa LPS, in keeping with GA's ability to disrupt the outer membrane. At CF-relevant LPS concentrations, however, membrane disruption by GA was not strongly inhibited. Furthermore, exposure to GA did not result in increased Lipid A modification of LPS or in increased gene expression of systems involved in AMP sensing and LPS modification. Therefore, despite the electrostatic targeting of LPS by GA as part of its activity, P. aeruginosa does not demonstrate LPS modification in its defence.

PMID:39843948 | DOI:10.1038/s44259-024-00022-x

NPJ Antimicrob Resist. 2024 Nov 14;2(1):38. doi: 10.1038/s44259-024-00060-5.

ABSTRACT

Polymicrobial communities inhabit the cystic fibrosis (CF) airway, whereby microbial interactions can occur. One prominent CF pathogen is Mycobacterium abscessus, whose treatment is largely unsuccessful. This creates a need to discover novel antimicrobial agents to treat M. abscessus, however the methods used within antibiotic discovery are typically monomicrobial. This review will discuss this pathogen whilst considering the CF polymicrobial environment, to highlight future perspectives to improve M. abscessus drug discovery.

PMID:39843836 | DOI:10.1038/s44259-024-00060-5

NPJ Antimicrob Resist. 2024 Nov 5;2(1):34. doi: 10.1038/s44259-024-00054-3.

ABSTRACT

Mycobacterium abscessus complex (MABSC) comprises a group of environmental microorganisms, which are a concerning cause of opportunistic respiratory infections in patients with cystic fibrosis or bronchiectasis. Only 45.6% of MABSC treatments are successful, and therefore this is a need to discover new antimicrobials that can treat these pathogens. However, the transferability of outcomes to the clinic is flawed by an inability to accurately represent the lung environment within the laboratory. Herein, we apply two preestablished formulations of sputum media (ACFS and SCFM1) to MABSC antibiotic susceptibility testing. Using conventional broth microdilution, we have observed strain and antibiotic dependent alterations in antimicrobial sensitivity in each sputum media compared standard laboratory media (7H9), with an overall reduction in susceptibility within the physiologically relevant conditions. We provide a timely contribution to the field of M. abscessus antibiotic discovery by emphasising the need for improved physiological relevance.

PMID:39843503 | DOI:10.1038/s44259-024-00054-3

Biomed Pharmacother. 2025 Jan 21;183:117819. doi: 10.1016/j.biopha.2025.117819. Online ahead of print.

ABSTRACT

A hypertonic solution of Ibuprofen (Ibu) was designed to nebulize, associating a low concentration of Ibu with L-Arginine (AR), to increase solubility and serve as a nitric oxide donor. To provide preclinical research human bronchial epithelial cells derived from a cystic fibrosis patient homozygous for the ΔF508 CFTR mutation (CFBE41o-) and mouse RAW 264.7 macrophages were pre-treated with Ibu (10-100 μM), AR (20 and 200 μM), or the combination Ibu-AR (10-100 μM). After Angiotensin II (AngII) or LPS/Interferon ϒ (IFN) stimulation, Reactive Oxygen Species (ROS) generation, Nitric Oxide (NO) formation, and the expression of inflammatory markers were determined. Ibu-AR (10/20 μM) significantly reduced ROS generation stimulated by AngII (p < 0.01) in CFBE41o- cells preserved the NO pathway and inhibited LPS-stimulated nitrite generation (p < 0.001). In macrophages, the combination Ibu-Ar, in a ratio of 1:2-1:6, efficiently scavenged excessive ROS generated by LPS, and significantly induced NO generation (p < 0.001), but inhibited nitrite formation. In LPS/IFNϒ-activated Raw, gene signature of M1polarization including tumor necrosis factor (TNF-α), NADPH Oxidase 2 (NOX-2), MCP-1, and inducible nitric oxide synthase (iNOS) were significantly downregulated by Ibu-AR, as well TNF-α, IL-6, and iNOS protein expressions. The inhibitory effect produced by Ibu-AR on M1 macrophages was associated with the inhibition of p-ERK1/2 and p-STAT3. Ibu-AR represents an effective therapeutic strategy for reducing oxidative stress, preserving NO bioavailability, and modulating inflammation in chronic inflammatory diseases.

PMID:39842270 | DOI:10.1016/j.biopha.2025.117819

Sleep Med. 2025 Jan 19;127:120-126. doi: 10.1016/j.sleep.2025.01.018. Online ahead of print.

ABSTRACT

AIM: This study aimed to assess the relationship between sleep quality, malnutrition risk, and nutritional status in adolescents with cystic fibrosis(CF).

MATERIAL AND METHOD: This cross-sectional study was conducted with 55 adolescents (aged 10-18 years) diagnosed with CF. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI), and malnutrition risk was evaluated based on disease-specific criteria. Nutritional status was assessed using body mass index (BMI), BMI percentiles, dietary energy intake, and food group consumption. Multiple linear regression analyses were used to determine the relationship between sleep quality, malnutrition risk, and nutritional status.

RESULTS: Among the participants, 50.9 % had poor sleep quality, and 29.1 % were classified as high-risk for malnutrition. Poor sleep quality was significantly associated with increased malnutrition risk (p < 0.05), independent of dietary energy intake and BMI percentiles. Lower BMI percentile was strongly associated with higher malnutrition risk (p < 0.001), identifying BMI as a critical predictor. Specifically, 27.3 % of participants had a BMI <10th percentile, which contributed to their classification as high-risk for malnutrition. However, dietary energy intake did not significantly predict malnutrition risk despite its relevance in dietary management.

CONCLUSION: This study emphasizes the crucial role of sleep quality in assessing malnutrition risk among adolescents with CF. Poor sleep quality was associated with higher malnutrition risk, suggesting that sleep disturbances may contribute to nutritional challenges. Sleep quality should be considered a key factor in assessing malnutrition risk among adolescents with CF and integrated into clinical practice to develop comprehensive management strategies addressing sleep disturbances and nutritional challenges, improving health outcomes.

PMID:39842132 | DOI:10.1016/j.sleep.2025.01.018

Eur Respir Rev. 2025 Jan 22;34(175):240133. doi: 10.1183/16000617.0133-2024. Print 2025 Jan.

ABSTRACT

INTRODUCTION: People with idiopathic pulmonary fibrosis (IPF) and other forms of progressive pulmonary fibrosis (PPF) have a high symptom burden and a poor health-related quality of life (HRQoL). Despite efforts to offer specialised treatment, clinical care for these patients remains suboptimal and several nonmedical needs remain unaddressed. Developing a core outcome set (COS) can help to identify a minimum set of agreed-upon outcomes that should be measured and acted-upon in clinical care.

AIM: As a first step towards developing a COS for IPF/PPF, we aimed to identify outcome domains investigated in IPF/PPF research.

METHODS: Conducted within the COCOS-IPF (Co-designing a Core Outcome Set for and with patients with IPF) project, this scoping review follows Joanna Briggs Institute methodology and PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines to search PubMed, Embase and Web of Science for quantitative, qualitative and mixed-methods papers. We extracted each paper's outcomes verbatim and classified them using the COMET (Core Outcome Measures in Effectiveness Trials) taxonomy. Then, the research team structured outcomes or concepts with similar meanings inductively into outcome domains.

RESULTS: We included 428 papers, extracting 1685 outcomes. Most outcomes (n=1340) were identified in quantitative sources, which we could classify in 64 outcome domains, with the main domains being "all-cause survival" (n=237), "lung function" (n=164) and "exercise capacity" (n=99). Qualitative sources identified 51 outcome domains, with the most frequent being "capability to do activities you enjoy" (n=31), "anxiety, worry and fear" (n=26) and "dealing with disease progression" (n=25).

CONCLUSIONS: The identified outcomes, spanning diverse domains, highlight the complexity of patient experiences and can form the basis to develop a COS for IPF/PPF clinical care, as well as future research.

PMID:39843158 | DOI:10.1183/16000617.0133-2024

BMJ Case Rep. 2025 Jan 21;18(1):e263676. doi: 10.1136/bcr-2024-263676.

ABSTRACT

A woman in her mid-70s presented with worsening dyspnoea, cough and fatigue initially treated for pneumonia. Despite antibiotics, her condition deteriorated, prompting further investigation. Medical history included previous breast implants, the latter of which had ruptured years earlier and was subsequently removed prior to the current presentation. Imaging revealed bilateral lung consolidations and lymphadenopathy. Bronchoalveolar lavage indicated macrophagic alveolitis, while biopsies showed chronic inflammation and the presence of silicone. Diagnosis of chronic pulmonary silicone embolism was made, a rare condition linked to the migration of silicone particles into the lungs, causing inflammation. Treatment involved corticosteroids, leading to symptom resolution. This case highlights the diagnostic challenges of silicone pneumonitis, which can manifest years after implant rupture and removal. Clinicians should be aware of this condition to avoid misdiagnosis and delayed treatment, as symptoms may persist even after implant removal due to irreversible lung fibrosis.

PMID:39842899 | DOI:10.1136/bcr-2024-263676

Pneumologie. 2025 Jan 22. doi: 10.1055/a-2512-8349. Online ahead of print.

ABSTRACT

Patients with interstitial lung disease (ILD) and especially with idiopathic pulmonary fibrosis(IPF) suffer from reduced survival expectation and risk of exacerbations. Lung cancer is a relevant comorbidity in ILD patients and associated with impaired survival.The most frequent ILD among patients with NSCLC (Non-small cell lung cancer) is idiopathic pulmonary fibrosis (IPF), which is associated with an greater decline in lung function and a higher risk of death.The prevalence of lung cancer in patients with ILD is up to 10% and in autopsy studies a prevalence up to 48% has been found.There are no guidelines for patients with lung cancer and ILD. Moreover, no adequate evidence is available.Therefore, we reviewed currently available literature to present an overview of the state of the art.In this review we focus on staging and treatment of the comorbidity of lung cancer and ILD.

PMID:39842452 | DOI:10.1055/a-2512-8349

NPJ Antimicrob Resist. 2024 Oct 3;2(1):29. doi: 10.1038/s44259-024-00047-2.

ABSTRACT

While the rise of antibiotic resistance poses a global health challenge, the development of new antibiotics has slowed down over the past decades. This turned the attention of researchers towards the rational design of drug combination therapies to combat antibiotic resistance. In this review we discuss how drug combinations can exploit the deleterious pleiotropic effects of antibiotic resistance and conclude that each drug interaction has its prospective therapeutic application.

PMID:39843924 | DOI:10.1038/s44259-024-00047-2

Nature. 2025 Jan 22. doi: 10.1038/s41586-024-08455-0. Online ahead of print.

ABSTRACT

Rubisco is the primary CO2-fixing enzyme of the biosphere1, yet it has slow kinetics2. The roles of evolution and chemical mechanism in constraining its biochemical function remain debated3,4. Engineering efforts aimed at adjusting the biochemical parameters of rubisco have largely failed5, although recent results indicate that the functional potential of rubisco has a wider scope than previously known6. Here we developed a massively parallel assay, using an engineered Escherichia coli7 in which enzyme activity is coupled to growth, to systematically map the sequence-function landscape of rubisco. Composite assay of more than 99% of single-amino acid mutants versus CO2 concentration enabled inference of enzyme velocity and apparent CO2 affinity parameters for thousands of substitutions. This approach identified many highly conserved positions that tolerate mutation and rare mutations that improve CO2 affinity. These data indicate that non-trivial biochemical changes are readily accessible and that the functional distance between rubiscos from diverse organisms can be traversed, laying the groundwork for further enzyme engineering efforts.

PMID:39843747 | DOI:10.1038/s41586-024-08455-0

Nature. 2025 Jan 22. doi: 10.1038/s41586-024-08422-9. Online ahead of print.

ABSTRACT

The assessment of research performance is widely seen as a vital tool in upholding the highest standards of quality, with selection and competition believed to drive progress. Academic institutions need to take critical decisions on hiring and promotion, while facing external pressure by also being subject to research assessment1-4. Here we present an outlook on research assessment for career progression with specific focus on promotion to full professorship, based on 314 policies from 190 academic institutions and 218 policies from 58 government agencies, covering 32 countries in the Global North and 89 countries in the Global South. We investigated how frequently various promotion criteria are mentioned and carried out a statistical analysis to infer commonalities and differences across policies. Although quantitative methods of assessment remain popular, in agreement with what is found in more geographically restricted studies5-9, they are not omnipresent. We find differences between the Global North and the Global South as well as between institutional and national policies, but less so between disciplines. A preference for bibliometric indicators is more marked in upper-middle-income countries. Although we see some variation, many promotion policies are based on the assumption of specific career paths that become normative rather than embracing diversity. In turn, this restricts opportunities for researchers. These results challenge current practice and have strategic implications for researchers, research managers and national governments.

PMID:39843736 | DOI:10.1038/s41586-024-08422-9

World J Microbiol Biotechnol. 2025 Jan 23;41(2):45. doi: 10.1007/s11274-025-04262-5.

ABSTRACT

Vibrio parahaemolyticus poses a notable threat to marine ecosystems and can cause infections and disease outbreaks in seafood species, which can affect humans upon consumption. The global impacts of such infections and outbreaks on human and animal health led to a growing number of studies from various countries discussing the prevention, control, treatment, and overall implications of V. parahaemolyticus. Hence, this study aims to retrieve relevant studies on V. parahaemolyticus using a bibliometric analysis to understand current research status, trends, and hotspots regarding this bacteria. Relevant literature was searched across the Scopus database, and the data were subsequently analyzed using Biblioshiny software. In addition, a manual examination was conducted to identify the hosts of V. parahaemolyticus and diseases caused by the bacteria. Overall, 7,096 records were obtained from Scopus from 1963 to 2023. A bibliometric analysis identified 17,220 authors, with China emerging as the global leader. The analysis also highlighted significant keywords such as "Vibrio parahaemolyticus," "Litopenaeus vannamei," and "innate immunity," suggesting a focus on the impact of V. parahaemolyticus on L. vannamei, specifically emphasizing the shrimp's innate immune responses. Host-disease interaction network also uncovered 53 interactions between hosts and diseases involving L. vannamei or Penaeus vannamei as the primary host, with acute hepatopancreas necrosis disease (AHPND) emerging as the most prevalent among them. This study can enhance our understanding of infections caused by V. parahaemolyticus and contribute to the development of effective strategies for their prevention and management.

PMID:39843643 | DOI:10.1007/s11274-025-04262-5

Nat Biotechnol. 2025 Jan 22. doi: 10.1038/s41587-024-02534-3. Online ahead of print.

NO ABSTRACT

PMID:39843580 | DOI:10.1038/s41587-024-02534-3

Oncogene. 2025 Jan 22. doi: 10.1038/s41388-024-03262-3. Online ahead of print.

NO ABSTRACT

PMID:39843564 | DOI:10.1038/s41388-024-03262-3

Nat Commun. 2025 Jan 22;16(1):952. doi: 10.1038/s41467-024-55806-6.

ABSTRACT

Colonies of the social bacterium Myxococcus xanthus go through a morphological transition from a thin colony of cells to three-dimensional droplet-like fruiting bodies as a strategy to survive starvation. The biological pathways that control the decision to form a fruiting body have been studied extensively. However, the mechanical events that trigger the creation of multiple cell layers and give rise to droplet formation remain poorly understood. By measuring cell orientation, velocity, polarity, and force with cell-scale resolution, we reveal a stochastic local polar order in addition to the more obvious nematic order. Average cell velocity and active force at topological defects agree with predictions from active nematic theory, but their fluctuations are substantially larger than the mean due to polar active forces generated by the self-propelled rod-shaped cells. We find that M. xanthus cells adjust their reversal frequency to tune the magnitude of this local polar order, which in turn controls the mechanical stresses and triggers layer formation in the colonies.

PMID:39843452 | DOI:10.1038/s41467-024-55806-6

Exp Anim. 2025 Jan 22. doi: 10.1538/expanim.24-0174. Online ahead of print.

ABSTRACT

Rats (Rattus norvegicus) have been widely utilized as model animals due to their physiological characteristics, making them suitable for surgical and long-term studies. They have played a crucial role in biomedical research, complementing studies conducted in mice. The advent of genome editing technologies has facilitated the generation of genetically modified rat strains, advancing studies in experimental animals. Among these innovations, Cre-driver rat models have emerged as powerful tools for spatiotemporal control of gene expression. However, their development and characterization remain less advanced compared to mouse models. In this study, we developed liver-targeting Cre knock-in rats and reporter knock-in rats to evaluate Cre recombinase expression profiles in different genetic contexts. Our results revealed that insertion orientation and promoter origin significantly influence Cre expression patterns. Notably, forward insertion of the Albumin (Alb) promoter-driven Cre sequence at the ROSA26 locus resulted in ubiquitous Cre expression, while reverse insertion confined Cre expression predominantly to the liver. Interestingly, Cre expression under an endogenous Alb promoter unexpectedly induced expression in non-liver tissues, which may suggest a potential link to the in vivo dynamics of albumin. These findings underscore the importance of rigorous characterization in Cre-based transgenic systems. By elucidating the roles of promoter origin, insertion site, and orientation, our study provides valuable insights for optimizing Cre-driver rat models. These findings pave the way for refining genetic strategies to enhance tissue specificity and reliability in functional genomics and disease modeling.

PMID:39842783 | DOI:10.1538/expanim.24-0174

Biochim Biophys Acta Rev Cancer. 2025 Jan 20:189269. doi: 10.1016/j.bbcan.2025.189269. Online ahead of print.

ABSTRACT

Tumor microenvironment (TME) has become a major focus of cancer research as a promising therapeutic target. TME comprises cancer cells surrounded by nonmalignant cells, vessels, lymphoid organs, immune cells, nerves, intercellular components, molecules and metabolites located within or near the tumor lesion. Neuromedin U (NMU), a secretory peptide identified in the TME, has gained much attention as an important player in cancer and nonmalignant cell crosstalk. NMU receptors were detected in cancer cells as well as in nonmalignant TME components, such as immune, stromal and endothelial cells. We propose here to discuss the concept that NMU secreted by cancer cells activates cellular components of TME and thus contributes to the formation of microenvironment that favors tumor growth and cancer progression. We summarized the available data on cancer tissues and cell types that have been identified as a source of NMU and/or receptor-expressing NMU targets. We made a critical selection of NMU-receptor positive cell types that are known components of the TME of most malignant tumors. Finally, we discussed whether NMUs and NMU receptors represent a potential therapeutic target for cancer treatment, and summarized information on the tools available to modulate their activity.

PMID:39842617 | DOI:10.1016/j.bbcan.2025.189269