An expert consensus statement on biomarkers of ageing for use in intervention studies.

Biomarkers of ageing serve as important outcome measures in longevity-promoting interventions. However, there is limited consensus on which specific biomarkers are most appropriate for human intervention studies. This work aimed to address this need by establishing an expert consensus on biomarkers of ageing for use in intervention studies via the Delphi method.

AI Promoted Virtual Screening, Structure-Based Hit Optimization, and Synthesis of Novel COVID-19 S-RBD Domain Inhibitors.

Coronavirus disease 2019 (COVID-19) is caused by a new, highly pathogenic severe-acute-respiratory syndrome coronavirus 2 (SARS-CoV-2) that infects human cells through its transmembrane spike (S) glycoprotein. The receptor-binding domain (RBD) of the S protein interacts with the angiotensin-converting enzyme II (ACE2) receptor of the host cells. Therefore, pharmacological targeting of this interaction might prevent infection or spread of the virus.

Comprehensive characterization of the neurogenic and neuroprotective action of a novel TrkB agonist using mouse and human stem cell models of Alzheimer's disease.

Background: Neural stem cell (NSC) proliferation and differentiation in the mammalian brain decreases to minimal levels postnatally. Nevertheless, neurogenic niches persist in the adult cortex and hippocampus in rodents, primates and humans, with adult NSC differentiation sharing key regulatory mechanisms with development. Adult neurogenesis impairments have been linked to Alzheimer's disease (AD) pathology.

Natural Compounds for Bone Remodeling: A Computational and Experimental Approach Targeting Bone Metabolism-Related Proteins.

Osteoporosis, characterized by reduced bone density and increased fracture risk, affects over 200 million people worldwide, predominantly older adults and postmenopausal women. The disruption of the balance between bone-forming osteoblasts and bone-resorbing osteoclasts underlies osteoporosis pathophysiology. Standard treatment includes lifestyle modifications, calcium and vitamin D supplementation and specific drugs that either inhibit osteoclasts or stimulate osteoblasts.

Clinical implementation of preemptive pharmacogenomics in psychiatry.

Background: Pharmacogenomics (PGx) holds promise to revolutionize modern healthcare. Although there are several prospective clinical studies in oncology and cardiology, demonstrating a beneficial effect of PGx-guided treatment in reducing adverse drug reactions, there are very few such studies in psychiatry, none of which spans across all main psychiatric indications, namely schizophrenia, major depressive disorder and bipolar disorder. In this study we aim to investigate the clinical effectiveness of PGx-guided treatment (occurrence of adverse drug reactions, hospitalisations and re-admissions, polypharmacy) and perform a cost analysis of the intervention.

A quest for the stereo-electronic requirements for selective agonism for the neurotrophin receptors TrkA and TrkB in 17-spirocyclic-dehydroepiandrosterone derivatives.

Introduction: The neurotrophin system plays a pivotal role in the development, morphology, and survival of the nervous system, and its dysregulation has been manifested in numerous neurodegenerative and neuroinflammatory diseases. Neurotrophins NGF and BDNF are major growth factors that prevent neuronal death and synaptic loss through binding with high affinity to their specific tropomyosin-related kinase receptors namely, TrkA and TrkB, respectively. The poor pharmacokinetic properties prohibit the use of neurotrophins as therapeutic agents.

A Robust Machine Learning Framework Built Upon Molecular Representations Predicts CYP450 Inhibition: Toward Precision in Drug Repurposing.

Human cytochrome P450 (CYP450) enzymes play a crucial role in drug metabolism and pharmacokinetics. CYP450 inhibition can lead to toxicity, in particular when drugs are co-administered with other drugs and xenobiotics or in the case of polypharmacy. Predicting CYP450 inhibition is also important for rational drug discovery and development, and precision in drug repurposing.

Bioenergetic Profiling in Glioblastoma Multiforme Patients with Different Clinical Outcomes.

The accumulation of cell biomass is associated with dramatically increased bioenergetic and biosynthetic demand. Metabolic reprogramming, once thought as an epiphenomenon, currently relates to disease progression, also in response to extracellular fate-decisive signals. Glioblastoma multiforme patients often suffer misdiagnosis, short survival time, low quality of life, and poor disease management options.

Development and Comparative In Vitro and In Vivo Study of BNN27 Mucoadhesive Liposomes and Nanoemulsions for Nose-to-Brain Delivery.

Intranasal administration offers an alternative and promising approach for direct nose-to-brain delivery. Herein, we developed two chitosan (CHT)-coated (and uncoated) nanoformulations of BNN27 (a synthetic C-17-spiro-dehydroepiandrosterone analogue), liposomes (LIPs), and nanoemulsions (NEs), and compared their properties and brain disposition (in vitro and in vivo). LIPs were formulated by thin film hydration and coated with CHT by dropwise addition.

Development of a multigram synthesis of the bradykinin receptor 2 agonist FR-190997 and analogs thereof.

Using Fujisawa's B2R agonist FR-190997, we recently demonstrated for the first time that agonism at the bradykinin receptor type 2 (B2R) produces substantial antiproliferative effects. FR-190997 elicited an EC of 80 nM in the triple-negative breast cancer cell line MDA-MB-231, a much superior performance to that exhibited by most approved breast cancer drugs. Consequently, we initiated a program aiming primarily at synthesizing adequate quantities of FR-190997 to support further in vitro and in vivo studies toward its repurposing for various cancers and, in parallel, enable the generation of novel FR-190997 analogs for an SAR study.

Untargeted Metabolomics for Disease-Specific Signatures.

Human diseases account for complex traits that usually exhibit markedly diverse clinical manifestations coming from a series of pathogenic processes that shape heterogeneous phenotypes. Considering that correlation does not imply causation as well as population differences and/or inter-individual variability, disease-specific signatures are becoming critical for biomarker discovery. Untargeted metabolomics is deemed to be a powerful approach to delineate molecular pathways of prime interest.

Pharmacometabolomics-Based Translational Biomarkers: How to Navigate the Data Ocean.

Metabolome is the end point of the genome-environment interplay, and enables an important holistic overview of individual adaptability and host responses to environmental, ecological, as well as endogenous changes such as disease. Pharmacometabolomics is the application of metabolome knowledge to decipher the mechanisms of interindividual and intraindividual variations in drug efficacy and safety. Pharmacometabolomics also contributes to prediction of drug treatment outcomes on the basis of baseline (predose) and postdose metabotypes through mathematical modeling.

Radiotherapy in Metastatic Urothelial Carcinoma: Rationale and Clinical Applications.

Urothelial carcinoma is the most common type of bladder cancer including upper urinary tract urothelial cell carcinoma (renal pelvis and ureters) and urethral carcinoma. It exhibits high mortality and morbidity rates and is usually diagnosed at a late, incurable stage, carrying a poor prognosis. Local symptoms in patients with metastatic urothelial carcinoma (mUC) have an adverse impact on quality of life (QoL) and are associated with frequent hospitalizations.

Diagnostic and Therapeutic Challenges in a Patient with Ureteral Metastases from a Triple Negative Breast Cancer.

Metastatic ureteral tumors arising from a primary breast carcinoma are extremely rare. They present with hematuria and radiological findings compatible with obstructive ureteral phenomena. We present a case of an 87-year-old woman with a history of lymphoma and triple negative breast cancer (TNBC), during an emergency admission for peptic ulcer, developed macroscopic hematuria.

A 3-miRNA Signature Enables Risk Stratification in Glioblastoma Multiforme Patients with Different Clinical Outcomes.

Malignant gliomas constitute a complex disease phenotype that demands optimum decision-making as they are highly heterogeneous. Such inter-individual variability also renders optimum patient stratification extremely difficult. microRNA (hsa-miR-20a, hsa-miR-21, hsa-miR-21) expression levels were determined by RT-qPCR, upon FFPE tissue sample collection of glioblastoma multiforme patients (n = 37).

The clinical utility of polygenic risk scores in genomic medicine practices: a systematic review.

Genomic medicine aims to improve health using the individual genomic data of people to inform care. While clinical utility of genomic medicine in many monogenic, Mendelian disorders is amply demonstrated, clinical utility is less evident in polygenic traits, e.g.

ENT-A010, a Novel Steroid Derivative, Displays Neuroprotective Functions and Modulates Microglial Responses.

Tackling neurodegeneration and neuroinflammation is particularly challenging due to the complexity of central nervous system (CNS) disorders, as well as the limited drug accessibility to the brain. The activation of tropomyosin-related kinase A (TRKA) receptor signaling by the nerve growth factor (NGF) or the neurosteroid dehydroepiandrosterone (DHEA) may combat neurodegeneration and regulate microglial function. In the present study, we synthesized a C-17-spiro-cyclopropyl DHEA derivative (ENT-A010), which was capable of activating TRKA.

Development and Biological Characterization of a Novel Selective TrkA Agonist with Neuroprotective Properties against Amyloid Toxicity.

Neurotrophins are growth factors that exert important neuroprotective effects by preventing neuronal death and synaptic loss. Nerve Growth Factor (NGF) acts through the activation of its high-affinity, pro-survival TrkA and low-affinity, pro-apoptotic p75 receptors. NGF has been shown to slow or prevent neurodegenerative signals in Alzheimer's Disease (AD) progression.

Three-Dimensional Cell Metabolomics Deciphers the Anti-Angiogenic Properties of the Radioprotectant Amifostine.

Aberrant angiogenesis is a hallmark for cancer and inflammation, a key notion in drug repurposing efforts. To delineate the anti-angiogenic properties of amifostine in a human adult angiogenesis model via 3D cell metabolomics and upon a stimulant-specific manner, a 3D cellular angiogenesis assay that recapitulates cell physiology and drug action was coupled to untargeted metabolomics by liquid chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy. The early events of angiogenesis upon its most prominent stimulants (vascular endothelial growth factor-A or deferoxamine) were addressed by cell sprouting measurements.

Exploiting the Role of Hypoxia-Inducible Factor 1 and Pseudohypoxia in the Myelodysplastic Syndrome Pathophysiology.

Myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal hematopoietic stem (HSCs) and/or progenitor cells disorders. The established dependence of MDS progenitors on the hypoxic bone marrow (BM) microenvironment turned scientific interests to the transcription factor hypoxia-inducible factor 1 (HIF-1). HIF-1 facilitates quiescence maintenance and regulates differentiation by manipulating HSCs metabolism, being thus an appealing research target.

Insights into intrauterine growth restriction based on maternal and umbilical cord blood metabolomics.

Intrauterine growth restriction (IUGR) is a fetal adverse condition, ascribed by limited oxygen and nutrient supply from the mother to the fetus. Management of IUGR is an ongoing challenge because of its connection with increased fetal mortality, preterm delivery and postnatal pathologies. Untargeted nuclear magnetic resonance (H NMR) metabolomics was applied in 84 umbilical cord blood and maternal blood samples obtained from 48 IUGR and 36 appropriate for gestational age (AGA) deliveries.

Bioenergetic Profiling of the Differentiating Human MDS Myeloid Lineage with Low and High Bone Marrow Blast Counts.

Myelodysplastic syndromes (MDS) encompass a very heterogeneous group of clonal hematopoietic stem cell differentiation disorders with malignant potential and an elusive pathobiology. Given the central role of metabolism in effective differentiation, we performed an untargeted metabolomic analysis of differentiating myeloid lineage cells from MDS bone marrow aspirates that exhibited <5% (G1) or ≥5% (G2) blasts, in order to delineate its role in MDS severity and malignant potential. Bone marrow aspirates were collected from 14 previously untreated MDS patients (G1, = 10 and G2, = 4) and age matched controls ( = 5).

The Role of microRNAs in Gliomas - Therapeutic Implications.

Background: Malignant gliomas constitute a complex disease phenotype that demands optimum decision-making. Despite being the most common type of primary brain tumors, gliomas are highly heterogeneous when their pathophysiology and response to treatment are considered. Such inter-individual variability also renders differential and early diagnosis extremely difficult.

Documentation of clinically relevant genomic biomarker allele frequencies in the next-generation FINDbase worldwide database.

FINDbase (http://www.findbase.org) is a comprehensive data resource recording the prevalence of clinically relevant genomic variants in various populations worldwide, such as pathogenic variants underlying genetic disorders as well as pharmacogenomic biomarkers that can guide drug treatment.