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Biomedicine & Pharmacotherapy =... Jun 2024The global public health crisis caused by the COVID-19 pandemic has intensified the global concern regarding viral respiratory tract infections. Despite their... (Review)
Review
The global public health crisis caused by the COVID-19 pandemic has intensified the global concern regarding viral respiratory tract infections. Despite their considerable impact on health, society and the economy, effective management of these conditions remains a significant challenge. Integrating high-throughput analyses is pivotal for early detection, prognostication of adverse outcomes, elucidating pathogenetic pathways and developing therapeutic approaches. In recent years, microRNAs (miRNAs), a subset of small noncoding RNAs (ncRNAs), have emerged as promising tools for molecular phenotyping. Current evidence suggests that miRNAs could serve as innovative biological markers, aiding in informed medical decision-making. The cost-effective quantification of miRNAs in standardized samples using techniques routinely employed in clinical laboratories has become feasible. In this context, samples obtained from the airways represent a valuable source of information due to their direct exposure to the infectious agent and host response within the respiratory tract. This review explores viral and host miRNA profiling in airway-derived biosamples as a source of molecular information to guide patient management, with a specific emphasis on SARS-CoV-2 infection.
PubMed: 38908203
DOI: 10.1016/j.biopha.2024.116984 -
Journal of Environmental Management Jun 2024Microbial fuel cells (MFCs) have been recently proven to synthesise biosurfactants from waste products. In classic bioreactors, the efficiency of biosynthesis process...
Microbial fuel cells (MFCs) have been recently proven to synthesise biosurfactants from waste products. In classic bioreactors, the efficiency of biosynthesis process can be controlled by the concentration of nitrogen content in the electrolyte. However, it was not known whether a similar control mechanism could be applied in current-generating conditions. In this work, the effect of nitrogen concentration on biosurfactant production from waste cooking oil was investigated. The concentration of NHCl in the electrolyte ranged from 0 to 1 g L. The maximum power density equal to 17.5 W m was achieved at a concentration of 0.5 g L (C/N = 2.32) and was accompanied by the highest surface tension decrease (to 54.6 mN m) and an emulsification activity index of 95.4%. Characterisation of the biosurfactants produced by the LC-MS/MS method showed the presence of eleven compounds belonging to the mono- and di-rhamnolipids group, most likely produced by P. aeruginosa, which was the most abundant (19.6%) in the community. Importantly, we have found a strong correlation (R = -0.96) of power and biosurfactant activity in response to C/N ratio. This study shows that nitrogen plays an important role in the current-generating metabolism of waste cooking oil. To the best of our knowledge, this is the first study where the nitrogen optimisation was investigated to improve the synthesis of biosurfactants and power generation in a bioelectrochemical system.
PubMed: 38908152
DOI: 10.1016/j.jenvman.2024.121514 -
Current Opinion in Cell Biology Jun 2024Dysfunction in mitochondrial maintenance and trafficking is commonly correlated with the development of neurodegenerative disorders such as Parkinson's disease and... (Review)
Review
Dysfunction in mitochondrial maintenance and trafficking is commonly correlated with the development of neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. Thus, biomedical research has been dedicated to understanding how architecturally complex neurons maintain and transport their mitochondria. However, the systems that coordinate mitochondrial QC (quality control) dynamics and trafficking in response to neuronal activity and stress are less understood. Additionally, the degree of integration between the processes of mitochondrial trafficking and QC is unclear. Recent work indicates that mitochondrial motility modulators (i.e., anchors and tethers) help coordinate mitochondrial health by mediating distinct, stress-level-appropriate QC pathways following mitochondrial damage. This review summarizes current evidence supporting the role of two mitochondrial motility modulators, Syntaphilin and Mitofusin 2, in coordinating mitochondrial QC to promote neuronal health. Exploring motility modulators' intricate regulatory molecular landscape may reveal new therapeutic targets for delaying disease progression and enhancing neuronal survival post-insult.
PubMed: 38908094
DOI: 10.1016/j.ceb.2024.102383 -
Redox Biology May 2024Ferroptosis is a pervasive non-apoptotic form of cell death highly relevant in various degenerative diseases and malignancies. The hallmark of ferroptosis is... (Review)
Review
Ferroptosis is a pervasive non-apoptotic form of cell death highly relevant in various degenerative diseases and malignancies. The hallmark of ferroptosis is uncontrolled and overwhelming peroxidation of polyunsaturated fatty acids contained in membrane phospholipids, which eventually leads to rupture of the plasma membrane. Ferroptosis is unique in that it is essentially a spontaneous, uncatalyzed chemical process based on perturbed iron and redox homeostasis contributing to the cell death process, but that it is nonetheless modulated by many metabolic nodes that impinge on the cells' susceptibility to ferroptosis. Among the various nodes affecting ferroptosis sensitivity, several have emerged as promising candidates for pharmacological intervention, rendering ferroptosis-related proteins attractive targets for the treatment of numerous currently incurable diseases. Herein, the current members of a Germany-wide research consortium focusing on ferroptosis research, as well as key external experts in ferroptosis who have made seminal contributions to this rapidly growing and exciting field of research, have gathered to provide a comprehensive, state-of-the-art review on ferroptosis. Specific topics include: basic mechanisms, in vivo relevance, specialized methodologies, chemical and pharmacological tools, and the potential contribution of ferroptosis to disease etiopathology and progression. We hope that this article will not only provide established scientists and newcomers to the field with an overview of the multiple facets of ferroptosis, but also encourage additional efforts to characterize further molecular pathways modulating ferroptosis, with the ultimate goal to develop novel pharmacotherapies to tackle the various diseases associated with - or caused by - ferroptosis.
PubMed: 38908072
DOI: 10.1016/j.redox.2024.103211 -
Cell Communication and Signaling : CCS Jun 2024Mechanical unloading of the knee articular cartilage results in cartilage matrix atrophy, signifying the osteoarthritic-inductive potential of mechanical unloading. In...
BACKGROUND
Mechanical unloading of the knee articular cartilage results in cartilage matrix atrophy, signifying the osteoarthritic-inductive potential of mechanical unloading. In contrast, mechanical loading stimulates cartilage matrix production. However, little is known about the response of meniscal fibrocartilage, a major mechanical load-bearing tissue of the knee joint, and its functional matrix-forming fibrochondrocytes to mechanical unloading events.
METHODS
In this study, primary meniscus fibrochondrocytes isolated from the inner avascular region of human menisci from both male and female donors were seeded into porous collagen scaffolds to generate 3D meniscus models. These models were subjected to both normal gravity and mechanical unloading via simulated microgravity (SMG) for 7 days, with samples collected at various time points during the culture.
RESULTS
RNA sequencing unveiled significant transcriptome changes during the 7-day SMG culture, including the notable upregulation of key osteoarthritis markers such as COL10A1, MMP13, and SPP1, along with pathways related to inflammation and calcification. Crucially, sex-specific variations in transcriptional responses were observed. Meniscus models derived from female donors exhibited heightened cell proliferation activities, with the JUN protein involved in several potentially osteoarthritis-related signaling pathways. In contrast, meniscus models from male donors primarily regulated extracellular matrix components and matrix remodeling enzymes.
CONCLUSION
These findings advance our understanding of sex disparities in knee osteoarthritis by developing a novel in vitro model using cell-seeded meniscus constructs and simulated microgravity, revealing significant sex-specific molecular mechanisms and therapeutic targets.
Topics: Humans; Meniscus; Male; Female; Weightlessness Simulation; Cells, Cultured; Middle Aged; Cell Proliferation; Chondrocytes; Adult; Transcriptome
PubMed: 38907358
DOI: 10.1186/s12964-024-01684-w -
Acta Neuropathologica Communications Jun 2024Neurofibromatosis Type 1 (NF1) is caused by loss of function variants in the NF1 gene. Most patients with NF1 develop skin lesions called cutaneous neurofibromas (cNFs)....
snRNA-seq of human cutaneous neurofibromas before and after selumetinib treatment implicates role of altered Schwann cell states, inter-cellular signaling, and extracellular matrix in treatment response.
Neurofibromatosis Type 1 (NF1) is caused by loss of function variants in the NF1 gene. Most patients with NF1 develop skin lesions called cutaneous neurofibromas (cNFs). Currently the only approved therapeutic for NF1 is selumetinib, a mitogen -activated protein kinase (MEK) inhibitor. The purpose of this study was to analyze the transcriptome of cNF tumors before and on selumetinib treatment to understand both tumor composition and response. We obtained biopsy sets of tumors both pre- and on- selumetinib treatment from the same individuals and were able to collect sets from four separate individuals. We sequenced mRNA from 5844 nuclei and identified 30,442 genes in the untreated group and sequenced 5701 nuclei and identified 30,127 genes in the selumetinib treated group. We identified and quantified distinct populations of cells (Schwann cells, fibroblasts, pericytes, myeloid cells, melanocytes, keratinocytes, and two populations of endothelial cells). While we anticipated that cell proportions might change with treatment, we did not identify any one cell population that changed significantly, likely due to an inherent level of variability between tumors. We also evaluated differential gene expression based on drug treatment in each cell type. Ingenuity pathway analysis (IPA) was also used to identify pathways that differ on treatment. As anticipated, we identified a significant decrease in ERK/MAPK signaling in cells including Schwann cells but most specifically in myeloid cells. Interestingly, there is a significant decrease in opioid signaling in myeloid and endothelial cells; this downward trend is also observed in Schwann cells and fibroblasts. Cell communication was assessed by RNA velocity, Scriabin, and CellChat analyses which indicated that Schwann cells and fibroblasts have dramatically altered cell states defined by specific gene expression signatures following treatment (RNA velocity). There are dramatic changes in receptor-ligand pairs following treatment (Scriabin), and robust intercellular signaling between virtually all cell types associated with extracellular matrix (ECM) pathways (Collagen, Laminin, Fibronectin, and Nectin) is downregulated after treatment. These response specific gene signatures and interaction pathways could provide clues for understanding treatment outcomes or inform future therapies.
Topics: Humans; Schwann Cells; Skin Neoplasms; Benzimidazoles; Extracellular Matrix; Signal Transduction; Neurofibroma; Female; Male; RNA-Seq; Middle Aged; Adult; Neurofibromatosis 1; Protein Kinase Inhibitors; Transcriptome
PubMed: 38907342
DOI: 10.1186/s40478-024-01821-z -
Journal of Cheminformatics Jun 2024Temperature-responsive liquid chromatography (TRLC) offers a promising alternative to reversed-phase liquid chromatography (RPLC) for environmentally friendly analytical...
Temperature-responsive liquid chromatography (TRLC) offers a promising alternative to reversed-phase liquid chromatography (RPLC) for environmentally friendly analytical techniques by utilizing pure water as a mobile phase, eliminating the need for harmful organic solvents. TRLC columns, packed with temperature-responsive polymers coupled to silica particles, exhibit a unique retention mechanism influenced by temperature-induced polymer hydration. An investigation of the physicochemical parameters driving separation at high and low temperatures is crucial for better column manufacturing and selectivity control. Assessment of predictability using a dataset of 139 molecules analyzed at different temperatures elucidated the molecular descriptors (MDs) relevant to retention mechanisms. Linear regression, support vector regression (SVR), and tree-based ensemble models were evaluated, with no standout performer. The precision, accuracy, and robustness of models were validated through metrics, such as r and mean absolute error (MAE), and statistical analysis. At , logP predominantly influenced retention, akin to reversed-phase columns, while at , complex interactions with lipophilic and negative MDs, along with specific functional groups, dictated retention. These findings provide deeper insights into TRLC mechanisms, facilitating method development and maximizing column potential.
PubMed: 38907264
DOI: 10.1186/s13321-024-00873-6 -
Diagnostic Pathology Jun 2024Human pulmonary dirofilariasis (HPD) is rare in Hungary, and it stems from Dirofilaria immitis, mainly transmitted through mosquito bites, with dogs as primary hosts....
BACKGROUND
Human pulmonary dirofilariasis (HPD) is rare in Hungary, and it stems from Dirofilaria immitis, mainly transmitted through mosquito bites, with dogs as primary hosts. Despite its prevalence in veterinary settings, human cases are infrequent. Historically, Mediterranean countries report most HPD cases, but sporadic cases occur in temperate European regions. Radiologically, HPD often manifests in a non-specific manner, resembling pulmonary neoplasms, leading to unnecessary surgery and patient distress.
METHODS
This study presents a notable case series from Hungary, encompassing a 12-year period, documenting 5 instances of HPD with the aim to provide baseline estimate of occurrence for future comparison.
RESULTS
Among the patients studied, all were of middle age (median: 52 years, range: 37-69) and exhibited tumor-like lesions, primarily localized to the right lung, necessitating lobectomy or wedge resection. Histological examination consistently revealed a necrotizing granulomatous response characterized by remnants of helminths, without the presence of ovules. Furthermore, rigorous diagnostic procedures excluded other potential infectious agents through specialized staining techniques. Polymerase chain reaction analysis definitively confirmed the diagnosis of HPD in each case.
CONCLUSIONS
This case series highlights HPD as a seldom zoonosis, with a probable escalation in its occurrence within temperate regions. Therefore, clinicians should maintain a heightened awareness of HPD in the differential diagnosis of pulmonary coin lesions. Early recognition and diagnosis are paramount for appropriate management and prevention of potential complications associated with this increasingly recognized infectious entity.
Topics: Humans; Dirofilariasis; Hungary; Middle Aged; Male; Adult; Female; Animals; Aged; Lung Diseases, Parasitic; Dirofilaria immitis; Lung
PubMed: 38907257
DOI: 10.1186/s13000-024-01507-z -
Diagnostic Pathology Jun 2024Catenin (Cadherin-Associated Protein), Beta 1 (CTNNB1) genomic alterations are rare in prostate cancer (PCa). Gain-of-function mutations lead to overexpression of...
BACKGROUND
Catenin (Cadherin-Associated Protein), Beta 1 (CTNNB1) genomic alterations are rare in prostate cancer (PCa). Gain-of-function mutations lead to overexpression of β-catenin, with consequent hyperactivation of the Wnt/β-catenin signaling pathway, implicated in PCa progression and treatment resistance. To date, successful targeted treatment options for Wnt/β-catenin - driven PCa are lacking.
METHODS
We report a rare histologic transformation of a CTNNB1 (β-catenin) mutated metastatic castration resistant prostate cancer (mCRPC), clinically characterized by highly aggressive disease course. We histologically and molecularly characterized the liver metastatic tumor samples, as well as successfully generated patient-derived organoids (PDOs) and patient-derived xenograft (PDX) from a liver metastasis. We used the generated cell models for further molecular characterization and drug response assays.
RESULTS
Immunohistochemistry of liver metastatic biopsies and PDX tumor showed lack of expression of typical PCa (e.g., AR, PSA, PSAP, ERG) or neuroendocrine markers (synaptophysin), compatible with double-negative CRPC, but was positive for nuclear β-catenin expression, keratin 7 and 34βE12. ERG rearrangement was confirmed by fluorescent in situ hybridization (FISH). Drug response assays confirmed, in line with the clinical disease course, lack of sensitivity to common drugs used in mCRPC (e.g., enzalutamide, docetaxel). The casein kinase 1 (CK1) inhibitor IC261 and the tankyrase 1/2 inhibitor G700-LK showed modest activity. Moreover, despite harbouring a CTNNB1 mutation, PDOs were largely insensitive to SMARCA2/4- targeting PROTAC degraders and inhibitor.
CONCLUSIONS
The reported CTNNB1-mutated mCRPC case highlights the potential challenges of double-negative CRPC diagnosis and underlines the relevance of further translational research to enable successful targeted treatment of rare molecular subtypes of mCRPC.
Topics: Humans; Male; beta Catenin; Mutation; Prostatic Neoplasms, Castration-Resistant; Liver Neoplasms; Animals; Biomarkers, Tumor; Aged; Disease Progression
PubMed: 38907236
DOI: 10.1186/s13000-024-01511-3 -
The EMBO Journal Jun 2024
PubMed: 38907035
DOI: 10.1038/s44318-024-00152-y