Therapeutic Peptides, Proteins and their Nanostructures for Drug Delivery and Precision Medicine.

Peptide and protein nanostructures with tunable structural features, multifunctionality, biocompatibility and biomolecular recognition capacity enable development of efficient targeted drug delivery tools for precision medicine applications. In this review article, we present various techniques employed for the synthesis and self-assembly of peptides and proteins into nanostructures. We discuss design strategies utilized to enhance their stability, drug-loading capacity, and controlled release properties, in addition to the mechanisms by which peptide nanostructures interact with target cells, including receptor-mediated endocytosis and cell-penetrating capabilities. We also explore the potential of peptide and protein nanostructures for precision medicine, focusing on applications in personalized therapies and disease-specific targeting for diagnostics and therapeutics in diseases such as cancer.

Embryonic atrazine exposure and later in life behavioral and brain transcriptomic, epigenetic, and pathological alterations in adult male zebrafish.

Atrazine (ATZ), a commonly used pesticide linked to endocrine disruption, cancer, and altered neurochemistry, frequently contaminates water sources at levels above the US Environmental Protection Agency's 3 parts per billion (ppb; µg/L) maximum contaminant level. Adult male zebrafish behavior, brain transcriptome, brain methylation status, and neuropathology were examined to test the hypothesis that embryonic ATZ exposure causes delayed neurotoxicity, according to the developmental origins of health and disease paradigm. Zebrafish (Danio rerio) embryos were exposed to 0 ppb, 0.3 ppb, 3 ppb, or 30 ppb ATZ during embryogenesis (1-72 h post fertilization (hpf)), then rinsed and raised to maturity. At 9 months post fertilization (mpf), males had decreased locomotor parameters during a battery of behavioral tests. Transcriptomic analysis identified altered gene expression in organismal development, cancer, and nervous and reproductive system development and function pathways and networks. The brain was evaluated histopathologically for morphometric differences, and decreased numbers of cells were identified in raphe populations. Global methylation levels were evaluated at 12 mpf, and the body length, body weight, and brain weight were measured at 14 mpf to evaluate effects of ATZ on mature brain size. No significant difference in genome methylation or brain size was observed. The results demonstrate that developmental exposure to ATZ does affect neurodevelopment and neural function in adult male zebrafish and raises concern for possible health effects in humans due to ATZ's environmental presence and persistence. Graphical abstract.

Pulmonary neuroendocrine cells: crucial players in respiratory function and airway-nerve communication.

Pulmonary neuroendocrine cells (PNECs) are unique airway epithelial cells that blend neuronal and endocrine functions, acting as key sensors in the lung. They respond to environmental stimuli like allergens by releasing neuropeptides and neurotransmitters. PNECs stand out as the only lung epithelial cells innervated by neurons, suggesting a significant role in airway-nerve communication via direct neural pathways and hormone release. Pathological conditions such as asthma are linked to increased PNECs counts and elevated calcitonin gene-related peptide (CGRP) production, which may affect neuroprotection and brain function. CGRP is also associated with neurodegenerative diseases, including Parkinson's and Alzheimer's, potentially due to its influence on inflammation and cholinergic activity. Despite their low numbers, PNECs are crucial for a wide range of functions, highlighting the importance of further research. Advances in technology for producing and culturing human PNECs enable the exploration of new mechanisms and cell-specific responses to targeted therapies for PNEC-focused treatments.

Anxiety-related behavior and associated brain transcriptome and epigenome alterations in adult female zebrafish exposed to atrazine during embryogenesis.

Atrazine often contaminates drinking water sources, exceeding the maximum contaminant level established by the US Environmental Protection Agency at 3 parts per billion (ppb; µg/L). Atrazine is linked to endocrine disruption, neurotoxicity, and cancer, with delayed health effects observed after developmental exposure in line with the developmental origins of health and disease (DOHaD) hypothesis. To test the hypothesis that embryonic atrazine exposure induces delayed neurotoxicity in adult female zebrafish (Danio rerio), embryos were exposed to 0, 0.3, 3, or 30 ppb atrazine during embryogenesis (1-72 h post fertilization (hpf)) and raised to adults with no additional atrazine exposure. Behavioral outcomes were tested through a novel tank test, light-dark box, and open field test and indicated female zebrafish had more anxious phenotypes at 9 months post fertilization (mpf). Female brain transcriptomic analysis at 9 mpf found altered gene expression pathways related to organismal injury and cancer with beta-estradiol and estrogen receptor as top upstream regulators. These results were compared to 9 mpf male and 6 mpf female groups with the same atrazine embryonic exposures and showed differences in specific genes that were altered, but similarities in top molecular pathways. Molecular pathways associated with behavior were observed only in the 6 mpf transcriptomic profiles, suggesting prediction of observed behavioral outcomes at 9 mpf. The expression of genes associated with serotonin neurotransmission was also evaluated at 14 mpf to determine persistence; however, no significant changes were observed. Brain global methylation in 12 mpf zebrafish observed an increased percent 5 mC in females with embryonic 0.3 ppb atrazine exposure. Finally, the body length, body weight, and brain weight were determined at 14 mpf and were altered in all treatment groups. These results indicate that embryonic atrazine exposure does cause delayed neurotoxicity within the DOHaD framework, which is significant given atrazine's presence and persistence in the environment.