A human lung alveolus-on-a-chip model of acute radiation-induced lung injury

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Oct. 16, 2023

Acute exposure to high-dose gamma radiation due radiological disasters or cancer radiotherapy can result in radiation-induced lung injury (RILI), characterized by acute pneumonitis and subsequent fibrosis. A microfluidic organ-on-a-chip lined human alveolar epithelium interfaced with pulmonary endothelium (Lung Alveolus Chip) is used model RILI vitro. Both exhibit DNA damage, cellular hypertrophy, upregulation of inflammatory cytokines, loss barrier function within 6 h exposure, although greater damage observed the endothelium. The dose sensitivity on-chip more like than animal preclinical models. Chip also evaluate potential ability two drugs - lovastatin prednisolone suppress effects RILI. These data demonstrate that Lung provides a relevant alternative for studying molecular basis may be useful evaluation new countermeasure therapeutics.

Language: Английский

---

Intestinal organ chips for disease modelling and personalized medicine

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2024, Volume and Issue: 21(11), P. 751 - 773

Published: Aug. 27, 2024

Language: Английский

---

Drug-Gene Network Signature Modeling Predicts Breast Cancer Patient Response to Neoadjuvant Chemotherapy

Published: March 18, 2025

Neoadjuvant chemotherapy (NAC) has been a staple treatment for breast cancer (BRCA) patients regardless of the tumor histological type. While this can be effective on population level, pathologic complete response (pCR) rate post-NAC individual varies widely throughout various clinical demographic groups and not dramatically changed in practice. Improving stratification methods therapeutic interventions could avoid physical side effects as well psychological stress undergoing NAC if patient is unlikely to respond [1, 2]. Given rapid advancements sequencing technologies availability RNA expression data, medical solutions based transcriptomics data are becoming increasingly prevalent [3]. Here, we present novel method stratify prognosis therapy using from pre-treatment biopsies by relying network biology interactions rather than gene panels. We processed datasets through BioNAV™ pipeline generate signatures (BioNAV™ NS) combined with random forest machine learning model incorporating other metadata, including race, specific drugs used treatment, subtyping. These offer insights into gene-gene drug-gene occurring within each patient’s biopsy. This study demonstrates capability NS help guide BRCA prognoses comprehensive, network-level view data. Using NS, were able accurately predict mean area under receiver operator characteristic (AUROC) 82.4%. The addition receptor type further increased performance high an AUROC 93.7% who progesterone positive (PR+). Additionally, classifier was maintained when combining multiple studies platforms heterogeneous preprocessing steps prior processing. Stratification subgroups enhanced predictive accuracy BioNAV™, outperforming two leading models recent literature 18.6% 12.9%, respectively. significantly enhances value transcriptomic determine NAC. approach offers integration biological metadata layers improve outcome prediction, highlighting potentially mechanisms that have hidden inside population. A transition towards personalized plans adjuvant treatments may enhance efficacy reduce adverse events.

Language: Английский

---

Donepezil Nanoemulsion Induces a Torpor-like State with Reduced Toxicity in Nonhibernating Xenopus laevis Tadpoles

ACS Nano, Journal Year: 2024, Volume and Issue: 18(35), P. 23991 - 24003

Published: Aug. 21, 2024

Achieving a reversible decrease of metabolism and other physiological processes in the whole organism, as occurs animals that experience torpor or hibernation, could contribute to increased survival after serious injury. Using Bayesian network tool with transcriptomic data chemical structure similarity assessments, we predicted Alzheimer's disease drug donepezil (DNP) be promising candidate for small molecule might induce torpor-like state. This was confirmed screening study Xenopus laevis tadpoles, nonhibernator animal model. To improve therapeutic performance minimize its toxicity, encapsulated DNP nanoemulsion formulated low-toxicity materials. formulation is composed emulsified droplets <200 nm diameter contain 1.250 mM DNP, representing ≥95% encapsulation efficiency. The induced comparable effects those produced by free indicated reduced swimming motion, cardiac beating frequency, oxygen consumption, but an improved biodistribution. Use resulted more controlled increase concentration organism compared higher brain, which toxicity enabled induction longer state fully reversible. These studies also demonstrate potential use tadpoles high-throughput vivo screen assess efficacy, biodistribution, drug-loaded nanocarriers.

Language: Английский

---

Genetic and Protein Network Underlying the Convergence of Rett-Syndrome-like (RTT-L) Phenotype in Neurodevelopmental Disorders

Cells, Journal Year: 2023, Volume and Issue: 12(10), P. 1437 - 1437

Published: May 21, 2023

Mutations of the X-linked gene encoding methyl-CpG-binding protein 2 (MECP2) cause classical forms Rett syndrome (RTT) in girls. A subset patients who are recognized to have an overlapping neurological phenotype with RTT but lacking a mutation that causes or atypical can be described as having ‘Rett-syndrome-like (RTT-L). Here, we report eight from our cohort diagnosed RTT-L carry mutations genes unrelated RTT. We annotated list associated patient cohort, considered them light peer-reviewed articles on genetics RTT-L, and constructed integrated protein–protein interaction network (PPIN) consisting 2871 interactions connecting 2192 neighboring proteins among RTT- RTT-L-associated genes. Functional enrichment analysis identified number intuitive biological processes. also transcription factors (TFs) whose binding sites common across set appear important regulatory motifs for them. Investigation most significant over-represented pathway suggests HDAC1 CHD4 likely play central role interactome between

Language: Английский

---

Identification of pharmacological inducers of a reversible hypometabolic state for whole organ preservation

eLife, Journal Year: 2024, Volume and Issue: 13

Published: Feb. 6, 2024

Drugs that induce reversible slowing of metabolic and physiological processes would have great value for organ preservation, especially organs with high susceptibility to hypoxia-reperfusion injury, such as the heart. Using whole-organism screening metabolism, mobility, development in Xenopus, we identified an existing drug, SNC80, rapidly reversibly slows biochemical activities while preserving cell tissue viability. Although SNC80 was developed a delta opioid receptor activator, discovered its ability slow metabolism is independent modulating activity novel analog (WB3) almost 1000 times less binding equally active. Metabolic suppression also achieved using microfluidic human organs-on-chips, well explanted whole porcine hearts limbs, demonstrating cross-species relevance this approach potential clinical surgical transplantation. Pharmacological induction combination perfusion transport systems may offer new therapeutic preservation transplantation, trauma management, enhancing patient survival remote low-resource locations.

Language: Английский

---

Identification of pharmacological inducers of a reversible hypometabolic state for whole organ preservation

Published: Feb. 6, 2024

Drugs that induce reversible slowing of metabolic and physiological processes would have great value for organ preservation, especially organs with high susceptibility to hypoxia-reperfusion injury, such as the heart. Using whole-organism screening metabolism, mobility, development in Xenopus , we identified an existing drug, SNC80, rapidly reversibly slows biochemical activities while preserving cell tissue viability. Although SNC80 was developed a delta opioid receptor activator, discovered its ability slow metabolism is independent modulating activity novel analog (WB3) almost 1,000 times less binding equally active. Metabolic suppression also achieved using microfluidic human organs-on-chips, well explanted whole porcine hearts limbs, demonstrating cross-species relevance this approach potential clinical surgical transplantation. Pharmacological induction combination perfusion transport systems may offer new therapeutic preservation transplantation, trauma management, enhancing patient survival remote low-resource locations.

Language: Английский

---

IRSF 2023 - Rett Syndrome Scientific Meeting Report

Translational Science of Rare Diseases, Journal Year: 2023, Volume and Issue: 6(4), P. 137 - 150

Published: Sept. 1, 2023

Language: Английский

---

Target-agnostic drug prediction integrated with medical record analysis uncovers differential associations of statins with increased survival in COVID-19 patients

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: April 13, 2022

Drug repurposing requires distinguishing established drug class targets from novel molecule-specific mechanisms and rapidly derisking their therapeutic potential in a time-critical manner, particularly pandemic scenario. In response to the challenge identify treatment options for COVID-19, several studies reported that statins, as class, reduce mortality these patients. However, it is unknown if different statins exhibit consistent function or may have varying benefit.To test differ ability exert protective effects based on molecular computational predictions electronic medical record analysis.A Bayesian network tool was used predict drugs shift host transcriptomic SARS-CoV-2 infection towards healthy state. Drugs were predicted using 14 RNA-sequencing datasets 72 autopsy tissues 465 COVID-19 patient samples cultured human cells organoids infected with SARS-CoV-2, total of 2,436 investigated. Top included which then assessed records containing over 4,000 patients determine risk prescribed specific versus untreated matched controls. The same tested Vero E6 endothelial related OC43 coronavirus.Simvastatin among most highly compounds (14/14 datasets) five other including atorvastatin, be active > 50% analyses. Analysis clinical database revealed reduced only observed subset simvastatin atorvastatin. vitro testing potent direct inhibitor whereas less effective. Simvastatin also inhibited cytokine production cells.Different sustain lives despite having shared target lipid-modifying mechanism action. These findings highlight value target-agnostic prediction coupled databases clinically evaluate non-obvious derisk accelerate opportunities.

Language: Английский

---

Author response: Identification of pharmacological inducers of a reversible hypometabolic state for whole organ preservation

Published: Aug. 8, 2024

Drugs that induce reversible slowing of metabolic and physiological processes would have great value for organ preservation, especially organs with high susceptibility to hypoxia-reperfusion injury, such as the heart. Using whole-organism screening metabolism, mobility, development in Xenopus, we identified an existing drug, SNC80, rapidly reversibly slows biochemical activities while preserving cell tissue viability. Although SNC80 was developed a delta opioid receptor activator, discovered its ability slow metabolism is independent modulating activity novel analog (WB3) almost 1,000 times less binding equally active. Metabolic suppression also achieved using microfluidic human organs-on-chips, well explanted whole porcine hearts limbs, demonstrating cross-species relevance this approach potential clinical surgical transplantation. Pharmacological induction combination perfusion transport systems may offer new therapeutic preservation transplantation, trauma management, enhancing patient survival remote low-resource locations.

Language: Английский

---