Biochemical pharmacology最新文献

The insular cortex is a multifunctional and richly connected region of the cerebral cortex, critical in the neural integration of external stimuli and internal signals. Well-served for this role by a large network of afferent and efferent connections, the mouse insula can be simplified into an anterior, medial and posterior portion. Here we focus on the medial subregion, a once over-looked area that has gained recent attention for its involvement in an array of behaviours. Although the connections of medial insular cortex neurons have been previously identified, their precise glutamatergic phenotype remains undefined (typically defined by the presence of the subtype of vesicular glutamate transporters). Hence, we combined Cre knock-in mouse lines and adeno-associated viral tracing to distinguish between the expression of the two major vesicular glutamate transporters, type 1 (vGlut1) and 2 (vGlut2), in the subregion's neuronal inputs and outputs. Our results determined that the medial insula has extensive glutamatergic efferents expressing both vGlut1 and vGlut2 throughout the neuraxis. In contrast, a more conservative number of glutamatergic inputs were observed, with exclusively vGlut2+ projections received from hypothalamic and thalamic regions. Taken together, we demonstrate that vGlut1- and vGlut2-expressing networks of this insular subdivision have distinct connectivity patterns, including a greater abundance of vGlut1+ fibres innervating hypothalamic regions and the extended amygdala. These findings provide insight into the distinct chemo-architecture of this region, which may facilitate further investigation into the role of the medial insula in complex behaviour.

Parkinson's disease (PD) is characterized by the accumulation of misfolded α-synuclein (α-syn). Promoting the degradation of misfolded proteins has been shown to be an effective approach to alleviate PD. This review highlights the roles of specific heat shock proteins (HSPs) in modulating α-syn aggregation and neuronal survival. HSP27 prevents glycosylation-induced α-syn aggregation, disrupts copper ion interactions, inhibits mitochondrial apoptosis, and prevents dopaminergic neuronal cell death. HSP70 alleviates dopaminergic neuronal damage by promoting mitophagy and preventing neuronal apoptosis. HSC70 plays a critical role in chaperone-mediated autophagy and facilitates lysosomal degradation. GRP78 mitigates abnormal protein aggregation. The HSP70-HSP40-HSP110 system is capable of degrading α-syn amyloid fibers. Inhibition of HSP90 expression protects neurons. Further research should prioritize developing regulators of HSPs as treatments for PD. While HSPs offer promise in PD management, their complex roles necessitate cautious therapeutic development to harness their potential. Understanding the specific roles of different HSPs will be essential to developing effective therapies for α-syn clearance.

Innate immune cells in the tumor microenvironment (TME) play an important role in breast cancer (BC) metastatic spread and influence patient survival. Macrophages differentiate along a proinflammatory M1 to protumorigenic M2 phenotype spectrum which affects distinct functions, like angiogenesis and cytokine production, and modulates BC aggressiveness and affects patient survival. Mast cells (MCs) are myeloid derived cells that serve as the first line of innate immune defense but their role in the TME of BC is not well understood. In this study, we have identified a subpopulation of innate immune cells that shows strong immunopositivity for the least studied adipokine CTRP8. Using a new and highly specific polyclonal antiserum on patient BC tissues, we identify a subset of tryptase + MCs and CD68 + macrophages co-expressing immunoreactive CTRP8. In M1 polarized THP-1 myeloid cells, this adipokine stimulated increased secretion of pro-inflammatory cytokines and elevated expression of the relaxin/ CTRP8 receptor RXFP1. Comparative analysis of secreted cytokine profiles in THP-1 M1 macrophages exposed to either CTRP8, relaxin-2 (RLN2), or the small molecule RXFP1 agonist ML-290 revealed ligand-specific cytokine signatures. Our study identified novel subsets of CTRP8 + myeloid derived innate immune cells and links this adipokine to pro-inflammatory events in the TME of BC.

The therapeutic interest of renin-angiotensin system (RAS) drugs for the treatment of neuroinflammation has been recently acknowledged. Nevertheless, most RAS drugs display limited passage across the blood-brain barrier (BBB). Therefore, this study investigated the potential of intranasal (IN) delivery of six RAS drugs to circumvent the BBB and attain the brain, envisioning its future use in central nervous system (CNS) neuroinflammatory diseases, such as Alzheimer's disease (AD). Captopril, enalaprilat, irbesartan, lisinopril, losartan and valsartan were firstly screened based on their impact on the viability of nasal, lung, and neuronal cell lines and their apparent permeability (Papp) across porcine olfactory mucosa. Irbesartan, identified as the one with the best safety and permeability balance, was selected for pharmacokinetic characterization following single and multidose IN administration to CD-1 mice. The results were compared to those obtained by intravenous (IV) injection to assess direct nose-to-brain drug delivery. Olfactory toxicity and anxiety were also evaluated after multidose IN treatment. Irbesartan IN administration significantly enhanced brain targeting, with a 3-fold increase in the maximum concentration (C_max) and a 2.5-fold increase in the area under the curve (AUC_t) in the brain compared to IV route. The drug exhibited a t_max of 15 min post-IN administration and achieved a brain targeting efficiency of 239.56%, with a significant direct transport percentage of 58.26%. Multidose administration indicated no systemic or tissue accumulation, with accumulation ratio (R_ac) values below 1.0, and no significant olfactory toxicity. Overall, the study highlights the potential of IN delivery of irbesartan as a promising strategy to improve brain targeting and therapeutic outcomes in CNS diseases such as AD, providing an effective approach to bypass BBB limitations.