TMPRSS2 is a functional receptor for human coronavirus HKU1

Nature, Journal Year: 2023, Volume and Issue: 624(7990), P. 207 - 214

Published: Oct. 25, 2023

Language: Английский

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Targeted approach to determine the impact of cancer-associated protease variants

Science Advances, Journal Year: 2025, Volume and Issue: 11(7)

Published: Feb. 12, 2025

Several steps of cancer progression, from tumor onset to metastasis, critically involve proteolytic activity. To elucidate the role proteases in cancer, it is particularly important consider single-nucleotide variants (SNVs) that affect active site proteases, thereby influencing cleavage specificity, substrate processing, and thus cell behavior. facilitate systematic studies, we here present a targeted approach determine impact cancer-associated protease (TACAP). Starting with semiautomated identification potential specificity-modulating SNVs, our workflow comprises mass spectrometry–based specificity profiling identification, localization, inhibitor followed by functional analyses investigating properties. demonstrate feasibility TACAP, analyzed meprin β R238Q variant. This amino acid exchange leads loss β’s characteristic preference for acidic acids at P1′ position, accompanied changes pool affinity compared wild type.

Language: Английский

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Machine learning models for predicting prostate cancer recurrence and identifying potential molecular biomarkers

Frontiers in Oncology, Journal Year: 2025, Volume and Issue: 15

Published: Feb. 17, 2025

Prostate cancer (PCa) recurrence affects between 20% and 40% of patients, being a significant challenge for predicting clinical outcomes increasing survival rates. Although serum PSA levels, Gleason score, tumor staging are sensitive detecting recurrence, they present low specificity. This study compared the performance three supervised machine learning models, Naive Bayes (NB), Support Vector Machine (SVM), Artificial Neural Network (ANN) classifying PCa events using dataset 489 patients from The Cancer Genome Atlas (TCGA). Besides comparing models performance, we searched analyzing whether incorporation specific genes expression in predictor set would enhance prediction then suggesting these as potential biomarkers patient prognosis. showed accuracy above 60% sensitivity 65% all combinations. ANN were more consistent their across different sets. Notably, SVM strong results precision specificity, particularly considering inclusion selected by feature selection ( NETO2 , AR HPN KLK3 ), without compromising sensitivity. However, relatively high standard deviations observed some metrics indicate variability simulations, gap additional studies via datasets. These findings suggest that dataset, representing promising approach early prognosis even before main treatment.

Language: Английский

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Relationship between REI and PSA in patients with obstructive sleep apnea: a prospective case-control study

Sleep And Breathing, Journal Year: 2025, Volume and Issue: 29(1)

Published: Jan. 3, 2025

Language: Английский

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Deciphering the molecular interaction between Vitamin D3 and pepsin by in vitro and in silico perspectives

Spectrochimica Acta Part A Molecular and Biomolecular Spectroscopy, Journal Year: 2025, Volume and Issue: 334, P. 125956 - 125956

Published: Feb. 27, 2025

Language: Английский

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Cell Progression and Survival Functions of Enzymes Secreted in Extracellular Vesicles Associated with Breast and Prostate Cancers

Cells, Journal Year: 2025, Volume and Issue: 14(7), P. 468 - 468

Published: March 21, 2025

Extracellular vesicles (EVs) are membrane-bound cargoes secreted by normal and pathological cells. Through their protein, nucleic acid, lipid cargoes, EVs mediate several cellular processes, such as cell–cell communication, cell development, immune response, tissue repair. Most importantly, through enzyme cargo, pathophysiological including the pathogenesis of cancer. In this review, we enumerate enzymes in (EV cargo) from cells patient clinical samples breast prostate cancers detail contributions to progression survival both cancers. Findings review reveal that EV cargo could exert functions via adhesion, proliferation, migration, invasion, metastasis. The might also influence chemoresistance, radioresistance, angiogenesis, death inhibition, colony formation, evasion. While current literature provides evidence possible mechanisms cancers, future studies required validate these effects modified provide insights into applications

Language: Английский

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Investigating the Genetic Links Between Immune Cell Profiles and Bladder Cancer: A Multidisciplinary Bioinformatics Approach

Biomedicines, Journal Year: 2025, Volume and Issue: 13(5), P. 1203 - 1203

Published: May 15, 2025

Background: Bladder cancer (BC) is a common malignancy in the urinary system, with an increasing incidence rate. Immune cell infiltration within tumor microenvironment (TME) plays crucial role BC progression and treatment response. However, immune composition of TME presents significant challenge to effectiveness current therapeutic strategies. Methods: We performed bidirectional Mendelian randomization (MR) analysis investigate impact cells on risk. Single nucleotide polymorphisms (SNPs) related were annotated, candidate genes associated risk identified. Differential expression identified immune-related differentially expressed (iDEGs), protein–protein interaction (PPI) network along functional enrichment conducted explore their roles development. Machine learning-based feature selection was applied identify potential biomarkers targets. Results: MR revealed eight subtypes significantly BC. Using SNPs linked these cells, 129 through SNPense tool cross-referenced BC, resulting identification 28 iDEGs. learning five diagnostic (COLEC12, TMCC1, CEP55, KLK3, COL4A1) AUC 0.903, which are implicated modulation progression. Conclusions: This study provides new insights into mechanisms identifies promising for early diagnosis intervention.

Language: Английский

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Secretome Analysis: Reading Cellular Sign Language to Understand Intercellular Communication

Molecular & Cellular Proteomics, Journal Year: 2023, Volume and Issue: 23(1), P. 100692 - 100692

Published: Dec. 10, 2023

•Cell type-specific and proximity biotin labeling enables secretome characterization.•Glycan-mediated analysis requires carefully controlled interpretation.•Recent trends to perform in vivo.•Computational methods are critical interpret cellular organismal secretion. A significant portion of mammalian proteomes is secreted the extracellular space fulfill crucial roles cell-to-cell communication. To best recapitulate intricate multi-faceted crosstalk between cells a live organism, there an ever-increasing need for study protein secretion model systems that include multiple cell types. In addition, posttranslational modifications further expand complexity versatility This review aims summarize recent strategies employ coculture, chemical biology tools, enrichment, proteomic characterize composition function secretomes. all geared towards gaining better understanding vivo mediated by secretory signaling. The term was first used year 2000 designate processes bacteria Bacillus subtilis (1Tjalsma H. Bolhuis A. Jongbloed J.D. Bron S. van Dijl J.M. Signal peptide-dependent transport subtilis: genome-based survey secretome.Microbiol. Mol. Biol. Rev. 2000; 64: 515-547Google Scholar) has since become generally describe global group proteins secreted, released, or shed into environment cell, tissue, organ, organism at any given time. It been estimated proteome encompasses nearly 3000 >2000 localized plasma membrane, collectively representing some 25% (2Uhlen M. Fagerberg L. Hallstrom B.M. Lindskog C. Oksvold P. Mardinoglu et al.Proteomics. Tissue-based map human proteome.Science. 2015; 3471260419Google Scholar, 3Uhlen Karlsson M.J. Hober Svensson A.S. Scheffel J. Kotol D. al.The secretome.Sci. Signal. 2019; 12eaaz0274Google Scholar). trafficking these through pathway energetically expensive process, involve >250 needed after completion synthesis translocate endoplasmic reticulum (ER) Golgi, while assembling disulfide bonds adding N- O-linked glycans (4Gutierrez Feizi Li Kallehauge T.B. Hefzi Grav L.M. al.Genome-scale reconstructions predict metabolic costs limitations secretion.Nat. Commun. 2020; 11: 68Google expenditure warranted fact range important functions key proper functioning its niche, eventually entire organism. Specifically, comprises large variety bioactive molecules such as enzymes, hormones, antibodies, matrix (ECM) provide scaffolding ECM play regulating cell–cell cell–ECM interactions (3Uhlen 5Sainio Jarvelainen Extracellular matrix-cell interactions: focus on therapeutic applications.Cell 66109487Google 6Naba Ten years proteomics: accomplishments, challenges, future perspectives.Mol. Cell Proteomics. 2023; 22100528Google class constituted growth factors cytokines signal recipient induce specific response. not only required maintain tissue homeostasis healthy (as stipulated below) but also diseases like cancer where constitute organizing principle among cells, stroma, immune tumor microenvironment (7Propper D.J. Balkwill F.R. Harnessing chemokines therapy.Nat. Clin. Oncol. 2022; 19: 237-253Google 8Padgaonkar Shendre Chatterjee Banerjee Cancer secretome: finding out hidden messages secretions.Clin. Transl. 25: 1145-1155Google 9Robinson J.L. Uhlen Nielsen systematic investigation malignant diagnostic potential secretome.Cell Rep. 26: 2622-26235.e5Google Knowing sustain mutual therefore provides insight fundamental aspects maintenance onset disease may clues intervention interfering this network 10Cox T.R. cancer.Nat. Cancer. 2021; 21: 217-238Google Furthermore, it worth noting body fluids blood cerebrospinal fluid organs throughout body, putting center stage biomarker discovery. aim overview have emerged recently enrichment characterization proteins, including their modifications. we discuss application recapitulation systemic vivo. Secretory can either autocrine paracrine fashion host essential homeostasis, development, response stress. signaling, produces soluble mediator binds receptor same thereby completing self-sufficient form auto-regulation. For instance, production transforming factor-beta (TGFβ) well-studied yet intriguing case bi-phasic self-regulation (Fig. 1, Left). early stages cancer, TGFβ tumor-inhibitory suppressing cycle progression promoting apoptosis. However, late stages, turns increase invasiveness metastasis (11Massague TGFbeta cancer.Cell. 2008; 134: 215-230Google Paracrine signaling produced one acting another within diffusion radius enable outcome dependent population allows more complex fine-regulated with regulatory points. interferon-gamma (IFNγ) most well-understood mediators Right). While specialized IFNγ restricted almost other types receptors receive react (12Gocher A.M. Workman C.J. Vignali D.A.A. Interferon-gamma: teammate opponent tumour microenvironment?.Nat. Immunol. 22: 158-172Google ensures effectively modify successful elimination threats body. An extensively studied repair. Since repertoire documented promote proliferation migration, congruent secretions stimulate wound healing skin regeneration (13Gwam Mohammed N. Ma X. Stem secretome, regeneration, clinical translation: narrative review.Ann. Med. 9: 70Google On hand, preconditioning mesenchymal stromal shown produce different secretomes, be use (14Ferreira J.R. Teixeira G.Q. Santos S.G. Barbosa M.A. Almeida-Porada G. Goncalves R.M. Mesenchymal influencing pre-conditioning.Front. 2018; 2837Google Scholar), alluding possibility using secretomes under certain stimuli treat diseases. Particularly repair desirable naturally inefficient, utility heavily investigated. stem explored therapies trauma, stroke, neurodegenerative conditions spinal cord traumatic brain injuries, ischemic Parkinson's (15Pinho A.G. Cibrao Silva N.A. Monteiro Salgado A.J. basic insights opportunities CNS disorders.Pharmaceuticals (Basel). 13: 31Google Skeletal muscles secrete sets depending state physical exercise, during myogenesis, dystrophin deficiency, muscle atrophy, insulin stimulation (16Florin Lambert Sanchez Zappia Durieux Tieppo skeletal cells: review.Osteoarthr. Cartil. Open. 2100019Google Moreover, tested tendon ligament treatment (17Rhatomy Prasetyo T.E. Setyawan R. Soekarno N.R. Romaniyanto F. Sedjati A.P. al.Prospect conditioned medium (secretome) healing: review.Stem Cells 895-902Google Collectively, examples demonstrate rich source therapeutics regenerative therapy. Not do support healing, regulate organization remodeling. myocardial diseases, FGF2, VEGF, IL-11 critically cardiac remodeling (18Segers V.F.M. De Keulenaer G.W. Autocrine remodeling: targets.J. Am. Heart Assoc. 10e019169Google Dysregulation manifest pathophysiological mechanisms hypertrophy, fibrosis, inflammation. mammary gland development organization, which dysregulated breast (19Rosen Roarty K. development: what learn about intratumoral heterogeneity?.Breast Res. 2014; 16: 202Google pancreas endocrine alpha-cells beta-cells thought take mutually exclusive glucagon production. Yet, histological proximity, alpha engage indirectly beta-cell (20Holter M.M. Saikia Cummings B.P. Alpha-cell regulation secretion.Front. Endocrinol. (Lausanne). 13934775Google Such developmental very prevalent animals. fact, long time, limited animals, whereas species exclusively rely quorum sensing communicate. Recent studies unified two similar genetic circuits control many quorum-sensing essentially extreme ends common spectrum (21Doganer B.A. Yan L.K.Q. Youk sensing: spectrum.Trends 2016; 262-271Google Secreted they players pathological processes. notably includes constitutes niche closely interact releasing various cytokines, chemokines, decisive role survival tumors (22Hanahan Hallmarks cancer: new dimensions.Cancer Discov. 12: 31-46Google 23Hinshaw D.C. Shevde L.A. innately modulates progression.Cancer 79: 4557-4566Google Additionally, exploit release proteases protein-modifying enzymes affect stiffness, turn drive transformation growth, enhance epithelial-to-mesenchymal transition metastasis, drug resistance (24Winkler Abisoye-Ogunniyan Metcalf K.J. Werb Z. Concepts remodelling metastasis.Nat. 5120Google Immune components microenvironment, mounting evidence indicates both innate adaptive (25Ren Zhang Y. Siemers Insights gained from single-cell microenvironment.Annu. 39: 583-609Google cell-secreted will pave way improved approaches target simultaneously, increasing likelihood design effective interventions patients (26Berraondo Sanmamed M.F. Ochoa M.C. Etxeberria I. Aznar Perez-Gracia al.Cytokines immunotherapy.Br. 120: 6-15Google 27Roma-Rodrigues Mendes Baptista P.V. Fernandes A.R. Targeting therapy.Int. Sci. 20: 840Google 28Jiang Wang Deng Xiong Ge Xiang B. al.Role PD-L1/PD-1-mediated escape.Mol. 18: 10Google As if secretion-mediated enough, functionally different, dictated interactions, substrates present uniquely space. moonlighting adds layer mystery understand intercellular (29Cohen Chirico W.J. Lipke P.N. Through back door: unconventional secretion.Cell Surf. 6100045Google Protein exterior distinguished proceed classical non-classical ways. Classically directed peptides (30Coleman Inukai Inouye Dual peptide transfer across membrane.Cell. 1985; 43: 351-360Google These typically short sequences 16 30 amino acids N terminus shuttle newly synthesized polypeptide chains path. usually consists positively charged n-region, hydrophobic h-region, peptidase recognition site (31Inouye Soberon Franceschini T. Nakamura Itakura Role positive charge amino-terminal region membrane.Proc. Natl. Acad. U. 1982; 3438-3441Google 32Guo Sun Shu al.Positive n-region contributes efficient post-translational translocation small preproteins.J. Chem. 293: 1899-1907Google destined cleaved membrane fusion exterior. steers nascent ER subsequently Golgi apparatus, cleavage functionalization occur. During transit, glycosylations added, processed, trimmed endow boost stability harsh (33Benham reticulum.Cold Spring Harb. Perspect. 2012; 4a012872Google fully modified glycosylated bud off trans-Golgi vesicles, COPII Rab then direct vesicle membranes proteinaceous contents vesicles released (34Ramazanov B.R. Tran M.L. von Blume Sending TGN.Curr. Opin. 71: 55-62Google Although majority follow pathway, much 40% contain identifiable bypass (35Grieve Rabouille bypass: skirting around heart secretion.Cold 2011; 3: a005298Google 36Dimou E. Nickel W. Unconventional eukaryotic secretion.Curr. 28: R406-R410Google 37Rabouille Pathways secretion.Trends 2017; 27: 230-240Google Non-classical modes 'Golgi bypass' increasingly reported emerging so previously anticipated (38Villarreal Mendez O. Salvans Gregori Baselga Villanueva major contributor line secretomes.Mol. 2013; 1046-1060Google ectodomain shedding, process domain fate membrane-resident proteolytic (39Lichtenthaler S.F. Lemberg M.K. Fluhrer Proteolytic shedding mammals-hardware, concepts, developments.EMBO 37: e99456Google mechanistically example γ-secretase amyloid precursor ectodomains results accumulation plagues Alzheimer's (40Zhou Yang Guo Zhou Q. Lei Shi Recognition gamma-secretase.Science. 363: eaaw0930Google last decade, (EVs) garnered lot attention, excellent biomarkers liquid biopsies explain organotropic distribution (41Hoshino Costa-Silva Shen T.L. Rodrigues Hashimoto Tesic Mark al.Tumour exosome integrins determine metastasis.Nature. 527: 329-335Google EVs membrane-bound point clearly distinct mechanism secretion, compared Golgi-independent free instead (42Filaquier Marin Parmentier Villeneuve Roads hubs 75102072Google 2). note due biogenesis path EVs, retain relatively encapsulated still protect even outside (43Zhang Liu Lin al.A vesicle-mediated secretion.Cell. 181: 637-652.e15Google EV templated sequence highly state, fitness, external poorly predictable. Thus, changes extremely dynamic states molecular triggers. three discussed above, consider flux whether constitutive inducible. Most basal level biological likely environment. Inducible involves triggered presynthesized loads observed neuronal transduction neurotransmitters (44White K.A. Kim B.N. Quantifying neurotransmitter single-vesicle resolution high-density complementary metal-oxide-semiconductor electrode array.Nat. 431Google entero- neuro-endocrine (45Xie Jones K.L. Rayner C.K. Wu Enteroendocrine hormone control: importance gut stimulation.Pharmaceutics. 790Google 46Yoo E.S. Yu Sohn J.W. Neuroendocrine appetite metabolism.Exp. 53: 505-516Google broadly controls behavior coordinating motor movements, language affective behavior, trigger system respond necessitate immunological neuroendocrine enteroendocrine together diet metabolism, energy balance homeostasis. evident prompted 3). cannot done directly because organ involving types, culture vitro useful mono-culture or, increasingly, coculture systems. introduced enrich analytical depth, exploiting affinity handle designing sophisticated tools labeling. Finally, when combined engineering, starting We here salient literature 3), highlighting methodological merits, questions, indicating challenges future. long-standing identify despite general shortcoming 2D simplified representation bottleneck experiments presence bovine serum constituents media. quantitative perspective, reach concentration 0.05 0.1 μg/μl without stimulation, divided over hundreds thousands species. Full 10% concentrations 5-6 μg/μl, >95% top 10 abundant proteins. drastic imbalance abundance creates problem low abundance–secreted masked high artefacts, hampering detection identification mass spectrometry. partially circumvented omitting serum; however starvation create stress condition distorts (47Shin Rhim Kwon Choi S.Y. Shin Ha C.W. al.Comparative differentially serum-free serum-containing media BONCAT pulsed SILAC.Sci. 3096Google 48Eichelbaum Winter Berriel Diaz Herzig Krijgsveld Selective analysis.Nat. Biotechnol. 30: 984-990Google Use SILAC-labeled distinguish residual employed, example, investigate beta-secretase 2 (BACE2) melanoma (49Matafora V. Farris Restuccia Tamburri Martano Bernardelli al.Amyloid aggregates accumulate modulating YAP activity.EMBO 21e50446Google show pattern (SILAC-labeled) astrocytes altered few hours, type (unlabeled) neurons were added classical, unconventional, (50Stiess Wegehingel Nguyen Bradke Cambridge S.B. dual SILAC strategy quantifying cell-cell induced secretion.J. Proteome 14: 3229-3238Google circumvent negative effects extended periods starvation, approach decouple (exposure cytokines) depletion, removing h before harvest (51Knecht Eberl H.C. Bantscheff Interval-based secretomics unravels acute-phase hepatocyte systems.Mol. 21100241Google way, authors could profiles cytokine-induced 72 period. Even eliminating serum, trace amounts remnant identified sensitive LC-MS/MS. cases, consensus field search data against database experimental (i.e., human, mouse, etc) concatenated sequences, hit removed. caveat procedure share similarity eliminated, calling caution. Compared altogether, powerful alternative devised selectively originating cultured serum. display significantly enhanced coverage depth. concept, intrinsic biosynthetic machinery incorporate non-natural via clickable reactive groups (i.e. azides alkynes), bioorthogonal non-canonical acid tagging (BONCAT) (52Dieterich Link Graumann Tirrell D.A. Schuman E.M. noncanonical (BONCAT).Proc. 2006; 103: 9482-9487Google Methionine azido-homoalanine (AHA) immensely specifically capture quantities (48Eichelbaum 53Eichelbaum Combining click-chemistry analysis.Methods 1174: 101-114Google Alkyne-containing homo-propargylglycine compatible BONCAT. Minimal AHA ensure incorporation initiator codon, average 3 methionines, good accessibility on-bead trypsin digestion, followed LC-MS/MS identification. attractive feature click chemistry coupling azide-bearing alkyne beads selective covalent bond stringent washing remove non-labeled background contaminants. Alternatively, occur alkyne-biotin subsequent azide-modified pool avidin purification. Pulse applied macrophages, quantify upon macrophage activation Moreov

Language: Английский

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Trypsin, chymotrypsin and elastase in health and disease

Future Journal of Pharmaceutical Sciences, Journal Year: 2024, Volume and Issue: 10(1)

Published: Sept. 17, 2024

Abstract Background Serine proteases represent over 1% of all proteins in humans. This family is found on cell surfaces, subcellular organelles like lysosomes or mitochondria, within the nucleus and protoplasm. Main body abstract Among them, trypsin, chymotrypsin elastase have aroused great interest because their numerous functions pathophysiological processes. Altered expression these enzymes experimental animal models humans has been related to various pathologies, developmental defects, metabolic dysfunctions, cancer, peripheral vascular diseases infectious diseases. Trypsin chymotrypsin-like activate, less oftentimes inactivate, substrates, together with growth factors, receptors, adhesion molecules, angiogenic factors metalloproteases. a number them are key cancer progression, metastasis severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease. Elastin-degrading enzyme- elastase, slowly damages elastin lifetime an organism. The physiological processes triggered by leads progression different conditions such as syndrome, pulmonary emphysema, atherosclerosis, chronic obstructive These serine currently considered be targets for development new potent therapeutics. Short conclusion cumulative knowledge that outlined pathological implications proposed strategies regulate activities targeting therapeutic application validation selected disease states highlighted. should enhance our appreciation roles aetiology some well chemotherapeutic benefits inhibition modulation.

Language: Английский

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Impact of polyethylene microplastics exposure on kallikrein-3 levels, steroidal-thyroidal hormones, and antioxidant status in murine model: protective potentials of naringin

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Oct. 10, 2024

The widespread presence of microplastics in the environment has raised significant concerns regarding their potential impact on human and animal health. Among various microplastic types, polyethylene (PE-MPs) are particularly prevalent due to extensive use packaging consumer products. Exploring uncharted therapeutic potentials naringin, this study delves into its mitigating effects disruptions kallikrein-3 levels, steroidal-thyroidal hormone balance, antioxidant defense triggered by PE-MPs exposure, paving way for novel interventions environmental toxin-induced endocrine oxidative stress disorders. Male Wistar rats (n = 24) were randomly grouped four: Control, (1.5 mg/kg), + NAR mg/kg 100 NAR), (100 mg/kg). Hormonal parameters assessed after 28 days exposure. exposure caused a increase(p < 0.005) level (KLK-3) while it significantly reduces levels testosterone (TST), luteinizing hormone, thyroid stimulating (TSH) Free-triiodothyronine (fT3) Total cholesterol (TChol) concentration. also disrupted (p profile down-regulating activities glutathione-S-transferase, catalase (CAT), superoxide dismutase (SOD) reducing glutathione (GSH) ascorbic acid (AA) concentration malondialdehyde (MDA) increased relative control. However, naringin hormonal profiles demonstrated, as normalized KLK-3, steroid, concentration, enhanced defense. This suggests that is promising protective agent against damage induced contaminants such microplastics.

Language: Английский

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