Pursuing Polypharmacology: Benzothiopyranoindoles as G-Quadruplex Stabilizers and Topoisomerase I Inhibitors for Effective Anticancer Strategies.

Here, we explored the benzothiopyranoindole scaffold to develop antiproliferative agents with a polypharmacological profile targeting both G-quadruplex (G4)-structures and Topoisomerase (Topo) I enzyme. In a preliminary optimization phase, compound was selected from an in-house collection as a suitable lead for the rational development of a small library of analogs (-). When assayed in NIH's NCI-60 Human Cancer Cell Line In Vitro Screen Program, compound and its demethylated analogue showed significant antiproliferative/cytotoxic activity.

Discovery of -substituted-2-oxoindolin benzoylhydrazines as c-MET/SMO modulators in EGFRi-resistant non-small cell lung cancer.

Non-small cell lung cancer (NSCLC), the leading cause of cancer-related mortality worldwide, poses a formidable challenge due to its heterogeneity and the emergence of resistance to targeted therapies. While initially effective, first- and third-generation EGFR-tyrosine kinase inhibitors (TKIs) often fail to control disease progression, leaving patients with limited treatment options. To address this unmet medical need, we explored the therapeutic potential of multitargeting agents that simultaneously inhibit two key signalling pathways, the mesenchymal-epithelial transition factor (c-MET) and the G protein-coupled receptor Smoothened (SMO), frequently dysregulated in NSCLC.

Comprehensive structural investigation of a potent and selective CXCR4 antagonist via crosslink modification.

Macrocyclization presents a valuable strategy for enhancing the pharmacokinetic and pharmacodynamic profiles of short bioactive peptides. The exploration of various macrocyclic characteristics, such as crosslinking tethers, ring size, and orientation, is generally conducted during the early stages of development. Herein, starting from a potent and selective C-X-C chemokine receptor 4 (CXCR4) cyclic heptapeptide antagonist mimicking the N-terminal region of CXCL12, we demonstrated that the disulfide bridge could be successfully replaced with a side-chain to side-chain lactam bond, which is commonly not enlisted among the conventional disulfide mimetics.

Discovering Dually Active Anti-cancer Compounds with a Hybrid AI-structure-based Approach.

Cancer's persistent growth often relies on its ability to maintain telomere length and tolerate the accumulation of DNA damage. This study explores a computational approach to identify compounds that can simultaneously target both G-quadruplex (G4) structures and poly(ADP-ribose) polymerase (PARP)1 enzyme, offering a potential multipronged attack on cancer cells. We employed a hybrid virtual screening (VS) protocol, combining the power of machine learning with traditional structure-based methods.

Characterizing placental pericytes: Hypoxia and proangiogenic signalling.

Introduction: Pericytes wrap microvessels and interact with endothelial cells to regulate vascular growth. Though pericyte dropout has been reported in pathological human placentae and mouse models of placental pathology, there has been limited investigation of the role and function of placental pericytes in vascular health and pathology. This study aimed to investigate the angiogenic potential of human placental pericytes relative to other villous cell populations.

Disulfide bond replacement with non-reducible side chain to tail macrolactamization for the development of potent and selective CXCR4 peptide antagonists endowed with flanking binding sites.

The present study describes a small library of peptides derived from a potent and selective CXCR4 antagonist (3), wherein the native disulfide bond is replaced using a side-chain to tail macrolactamization technique to vary ring size and amino acid composition. The peptides were preliminary assessed for their ability to interfere with the interaction between the receptor and anti-CXCR4 PE-conjugated antibody clone 12G5. Two promising candidates (13 and 17) were identified and further evaluated in aI-CXCL12 competition binding assay, exhibiting IC in the low-nanomolar range.

Historical Structural Racism in the Built Environment and Physical Health among Residents of Allegheny County, Pennsylvania.

Historical structural racism in the built environment contributes to health inequities, yet to date, research has almost exclusively focused on racist policy of redlining. We expand upon this conceptualization of historical structural racism by examining the potential associations of probable blockbusting, urban renewal, and proximity to displacement from freeway construction, along with redlining, to multiple contemporary health measures. Analyses linked historical structural racism, measured continuously at the census-tract level using archival data sources, to present-day residents' physical health measures drawn from publicly accessible records for Allegheny County, Pennsylvania.

Identification of Dual Inhibitors Targeting Main Protease (M) and Cathepsin L as Potential Anti-SARS-CoV-2 Agents.

In this structure-activity relationship (SAR) study, we report the development of dual inhibitors with antiviral properties targeting the SARS-CoV-2 main protease (M) and human cathepsin L (hCatL). The novel molecules differ in the aliphatic amino acids at the P2 site and the fluorine position on the phenyl ring at the P3 site. The identified dual inhibitors showed values within 1.

Development of Novel Peptidyl Nitriles Targeting Rhodesain and Falcipain-2 for the Treatment of Sleeping Sickness and Malaria.

In recent decades, neglected tropical diseases and poverty-related diseases have become a serious health problem worldwide. Among these pathologies, human African trypanosomiasis, and malaria present therapeutic problems due to the onset of resistance, toxicity problems and the limited spectrum of action. In this drug discovery process, rhodesain and falcipain-2, of and , are currently considered the most promising targets for the development of novel antitrypanosomal and antiplasmodial agents, respectively.

Sex-specific associations between childhood trauma and adult systemic inflammation in daily life.

Objective: Childhood trauma may contribute to lifelong health through chronic systemic inflammation. However, associations between childhood trauma and inflammation are mixed, indicating that distinct types of childhood trauma may relate to inflammation differently. Moreover, most studies use a single assessment of inflammatory markers that may not reliably estimate stable interindividual differences.

Childhood trauma and hair cortisol response over the year following onset of a chronic life event stressor.

Objective: Childhood trauma may contribute to poor lifelong health in part through programming of the HPA-axis response to future life stressors. To date, empirical evidence shows an association of childhood trauma with dysregulation of the HPA-axis and blunted cortisol reactivity to acute stressors. Here, we conduct an initial examination of childhood trauma as a moderator of changes over time in perceived stress levels and HPA-axis response to a major chronic stressor in adulthood.

Cannabidiol Exposure During Rat Pregnancy Leads to Labyrinth-Specific Vascular Defects in the Placenta and Reduced Fetal Growth.

Cannabis use is increasing among pregnant people, and cannabidiol (CBD), a constituent of cannabis, is often perceived as "natural" and "safe" as it is non-intoxicating. , cannabis exposure is associated with negative health outcomes, including fetal growth restriction (FGR). The placenta supplies oxygen and nutrients to the fetus, and alterations in placental development can lead to FGR.

Investigating the effects of valproic acid on placental epigenetic modifications and development in the CD-1 mouse model.

Gestational exposure to the anticonvulsant drug valproic acid (VPA) is associated with congenital malformations and neurodevelopmental disorders through its action as a histone deacetylase inhibitor. VPA can elicit placental toxicity and affect placental growth and development. The objective of this study was to evaluate the impact of maternal exposure to VPA on the mouse placenta following exposure on gestational day (GD) 13 since previous studies have shown that mice exposed at this time during gestation give birth to offspring with an autism spectrum disorder-like phenotype.

Extracellular Matrix Influences Gene Expression and Differentiation of Mouse Trophoblast Stem Cells.

Trophoblast stem (TS) cells were first isolated from the mouse placenta; however, little is known about their maintenance and niche in vivo. TS cells, like other stem cells, have a unique microenvironment in which the extracellular matrix (ECM) is a component. Placental pathology is associated with ECM change.

Duration of Breastfeeding and Supportive Paternal Caregiving in Early Childhood and the Potential Mediating Function of Maternal Caregiving.

Objective: Supportive paternal caregiving is influenced by contextual factors, including maternal caregiving behaviors. Although longer periods of breastfeeding have been found to be associated with higher levels of maternal supportive parenting, it remains unknown whether the benefits of breastfeeding also extend to fathers' supportive caregiving. This study tested the indirect relation between the duration of breastfeeding and paternal supportive parenting through maternal supportive parenting.

Cannabinoids and the placenta: Receptors, signaling and outcomes.

Cannabis use during pregnancy is increasing. The improvement of pregnancy-related symptoms including morning sickness and management of mood and stress are among the most reported reasons for its use. Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are the most abundant cannabinoids found within the cannabis flower.

A systematic review and meta-analysis of the stability of peripheral immune markers in healthy adults.

Peripheral immune markers are widely used to predict risk for inflammatory disease. However, whether single assessments of inflammatory biomarkers represent stable individual differences remains unclear. We reviewed 50 studies (N = 48,674; 57 % male; mean age 54 (range 13-79) years) that assessed markers of inflammation on >1 occasion, with time between measures ranging from 24 h to 7+ years.

Multi-analytical study of the medieval wall paintings from the rupestrian church at Lentini (eastern Sicily): new evidence of the use of woad ().

Unlabelled: This study presents the results of the examination and characterisation of the wall paintings that decorate the rupestrian church named , which is located in the territory of Lentini (eastern Sicily, few tens of kilometres from Catania and Syracuse). The earliest mural paintings in the church date back to the twelfth century AD. A multi-analytical approach was adopted for the characterisation of stone materials, secondary degradation products, and pigments.

Systemic Inflammation Contributes to the Association Between Childhood Socioeconomic Disadvantage and Midlife Cardiometabolic Risk.

Background: Childhood socioeconomic disadvantage is associated with increased risk for chronic inflammation and cardiometabolic disease at midlife.

Purpose: As it is presently unknown whether inflammation mediates the relationship between childhood socioeconomic status (SES) and adulthood cardiometabolic risk, we investigated associations between retrospectively reported childhood SES, circulating levels of inflammatory markers, and a latent construct of cardiometabolic risk in midlife adults.

Methods: Participants were 1,359 healthy adults aged 30-54 (Adult Health and Behavior Iⅈ 52% women, 17% Black) who retrospectively reported childhood SES (parental education, occupational grade).

Physical Activity and Healthy Eating Programming in Schools to Support Student's Health-Related Fitness: An Observational Study.

Centers for Disease Control (CDC) guidelines recommend schools use a coordinated health approach to support healthy eating and physical activity. This study examines whether the number of healthy eating and physical activity programs and activities used by schools and their perceived success relate to students' health-related fitness. This observational study used data from the Healthy Zone Schools Program.

Protein Phosphatase 2A Activation Via ApoER2 in Trophoblasts Drives Preeclampsia in a Mouse Model of the Antiphospholipid Syndrome.

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Keeping children healthy during and after COVID-19 pandemic: meeting youth physical activity needs.

Background: The purpose of this study was to: 1) examine the maintenance of Physical Education and physical activity during the distance learning time, 2) determine the resources educators are utilizing to deliver PE curricula, and 3) understand the challenges experienced by educators during distance learning.

Methods: A survey was sent to a cohort of school-based fitness assessment software users. Respondents were largely school-based individuals including PE teachers (n = 1789), school (n = 62) and district administrators (n = 64), nurses (n = 3), and "other" (n = 522).

Duration of Breastfeeding Mediates the Association Between Early Socioeconomic Risk and Child Vocabulary at Age 4.

Objective: Early-life socioeconomic disadvantage is associated with both obesity and lower cognitive abilities in childhood. One theorized underlying mechanism is breastfeeding duration because breast milk contains nutrients that can promote healthy adiposity profiles and stimulate brain development. However, studies have rarely examined these potential associations with child body mass index (BMI) in high-income Western countries, much less investigated breastfeeding duration as a mediator of the relationship between childhood socioeconomic status (SES) and later child vocabulary.