Placenta-tropic VEGF mRNA lipid nanoparticles ameliorate murine pre-eclampsia.

Pre-eclampsia is a placental disorder that affects 3-5% of all pregnancies and is a leading cause of maternal and fetal morbidity worldwide. With no drug available to slow disease progression, engineering ionizable lipid nanoparticles (LNPs) for extrahepatic messenger RNA (mRNA) delivery to the placenta is an attractive therapeutic option for pre-eclampsia. Here we use high-throughput screening to evaluate a library of 98 LNP formulations in vivo and identify a placenta-tropic LNP (LNP 55) that mediates more than 100-fold greater mRNA delivery to the placenta in pregnant mice than a formulation based on the Food and Drug Administration-approved Onpattro LNP (DLin-MC3-DMA).

EGFR-targeted ionizable lipid nanoparticles enhance in vivo mRNA delivery to the placenta.

The full potential of ionizable lipid nanoparticles (LNPs) as an in vivo nucleic acid delivery platform has not yet been realized given that LNPs primarily accumulate in the liver following systemic administration, limiting their success to liver-centric conditions. The engineering of LNPs with antibody targeting moieties can enable extrahepatic tropism by facilitating site-specific LNP tethering and driving preferential LNP uptake into receptor-expressing cell types via receptor-mediated endocytosis. Obstetric conditions stemming from placental dysfunction, such as preeclampsia, are characterized by overexpression of cellular receptors, including the epidermal growth factor receptor (EGFR), making targeted LNP platforms an exciting potential treatment strategy for placental dysfunction during pregnancy.

Precision treatment of viral pneumonia through macrophage-targeted lipid nanoparticle delivery.

Macrophages are integral components of the innate immune system, playing a dual role in host defense during infection and pathophysiological states. Macrophages contribute to immune responses and aid in combatting various infections, yet their production of abundant proinflammatory cytokines can lead to uncontrolled inflammation and worsened tissue damage. Therefore, reducing macrophage-derived proinflammatory cytokine release represents a promising approach for treating various acute and chronic inflammatory disorders.

Orthogonal Design of Experiments for Engineering of Lipid Nanoparticles for mRNA Delivery to the Placenta.

During healthy pregnancy, the placenta develops to allow for exchange of nutrients and oxygen between the mother and the fetus. However, placental dysregulation can lead to several pregnancy disorders, such as preeclampsia and fetal growth restriction. Recently, lipid nanoparticle (LNP)-mediated delivery of messenger RNA (mRNA) has been explored as a promising approach to treat these disorders.

Rational Design of Nanomedicine for Placental Disorders: Birthing a New Era in Women's Reproductive Health.

The placenta is a transient organ that forms during pregnancy and acts as a biological barrier, mediating exchange between maternal and fetal circulation. Placental disorders, such as preeclampsia, fetal growth restriction, placenta accreta spectrum, and gestational trophoblastic disease, originate in dysfunctional placental development during pregnancy and can lead to severe complications for both the mother and fetus. Unfortunately, treatment options for these disorders are severely lacking.

Ionizable Lipid Nanoparticles for mRNA Delivery to the Placenta during Pregnancy.

Ionizable lipid nanoparticles (LNPs) are the most clinically advanced nonviral platform for mRNA delivery. While they have been explored for applications including vaccines and gene editing, LNPs have not been investigated for placental insufficiency during pregnancy. Placental insufficiency is caused by inadequate blood flow in the placenta, which results in increased maternal blood pressure and restricted fetal growth.

Arene Variation of Highly Cytotoxic Tridentate Naphthoquinone-Based Ruthenium(II) Complexes and In-Depth In Vitro Studies.

The main purpose of this study was to synthesize a new set of naphthoquinone-based ruthenium(II) arene complexes and to develop an understanding of their mode of action. This study systematically reviews the steps of synthesis, aiming to provide a simplified approach using microwave irradiation. The chemical structures and the physicochemical properties of this novel group of compounds were examined by H-NMR and C-NMR spectroscopy, X-ray diffractometry, HPLC-MS and supporting DFT calculations.

Systematic Study on the Cytotoxic Potency of Commonly Used Dimeric Metal Precursors in Human Cancer Cell Lines.

The cytotoxicities of seven dimeric metal species of the general formula [M(arene)Cl ] , commonly used as precursors for complex synthesis and deemed biologically inactive, are investigated in seven commonly employed human cancer cell lines. Four of these complexes featured a ruthenium(II) core, where p-cymene, toluene, benzene and indane were used as arenes. Furthermore, the osmium(II) p-cymene dimer, as well as the Cp* dimers of rhodium(III) and its heavier analogue iridium(III) were included in this work (Cp*=1,2,3,4,5-pentamethylcyclopentadienide).

Tridentate 3-Substituted Naphthoquinone Ruthenium Arene Complexes: Synthesis, Characterization, Aqueous Behavior, and Theoretical and Biological Studies.

A series of nine Ru arene complexes bearing tridentate naphthoquinone-based ,,-ligands was synthesized and characterized. Aqueous stability and their hydrolysis mechanism were investigated via UV/vis photometry, HPLC-MS, and density functional theory calculations. Substituents with a positive inductive effect improved their stability at physiological pH (7.

Investigations on the Anticancer Potential of Benzothiazole-Based Metallacycles.

A series of 2-phenylbenzothiazole derivatives and their corresponding organometallic ruthenium(II) and osmium(II) complexes were synthesized, designed to exploit both, the attributes of the half-sandwich transition metal scaffold and the bioactivity spectrum of the applied 2-phenylbenzothiazoles. All synthesized compounds were characterized via standard analytical methods. The obtained organometallics showed antiproliferative activity in the low μM range and are thus at least an order of magnitude more potent than the free ligands.

Novel phthiocol-based organometallics with tridentate coordination motif and their unexpected cytotoxic behaviour.

Novel phthiocol-based organometallics with in situ formed tridentate N,O,O-coordination motif were established via three-component microwave assisted one-pot reaction. These complexes exhibited enhanced stability in aqueous solution compared to the parental compound KP2048 and showed unexpected cytotoxic behaviour and selectivity in 2D and 3D cell cultures.

BDNF-Live-Exon-Visualization (BLEV) Allows Differential Detection of BDNF Transcripts and .

exon-IV and exon-VI transcripts are driven by neuronal activity and are involved in pathologies related to sleep, fear or memory disorders. However, how their differential transcription translates activity changes into long-lasting network changes is elusive. Aiming to trace specifically the network controlled by exon-IV and -VI derived BDNF during activity-dependent plasticity changes, we generated a transgenic reporter mouse for - - ), in which expression of exon-IV and -VI can be visualized by co-expression of CFP and YFP.

Visualizing BDNF Transcript Usage During Sound-Induced Memory Linked Plasticity.

Activity-dependent BDNF (brain-derived neurotrophic factor) expression is hypothesized to be a cue for the context-specificity of memory formation. So far, activity-dependent BDNF cannot be explicitly monitored independently of basal BDNF levels. We used the BLEV ( DNF- - ) reporter mouse to specifically detect activity-dependent usage of exon-IV and -VI promoters through bi-cistronic co-expression of CFP and YFP, respectively.

Skeletal muscle O-GlcNAc transferase is important for muscle energy homeostasis and whole-body insulin sensitivity.

Objective: Given that cellular O-GlcNAcylation levels are thought to be real-time measures of cellular nutrient status and dysregulated O-GlcNAc signaling is associated with insulin resistance, we evaluated the role of O-GlcNAc transferase (OGT), the enzyme that mediates O-GlcNAcylation, in skeletal muscle.

Methods: We assessed O-GlcNAcylation levels in skeletal muscle from obese, type 2 diabetic people, and we characterized muscle-specific OGT knockout (mKO) mice in metabolic cages and measured energy expenditure and substrate utilization pattern using indirect calorimetry. Whole body insulin sensitivity was assessed using the hyperinsulinemic euglycemic clamp technique and tissue-specific glucose uptake was subsequently evaluated.

NO-Sensitive Guanylate Cyclase Isoforms NO-GC1 and NO-GC2 Contribute to Noise-Induced Inner Hair Cell Synaptopathy.

Nitric oxide (NO) activates the NO-sensitive soluble guanylate cyclase (NO-GC, sGC) and triggers intracellular signaling pathways involving cGMP. For survival of cochlear hair cells and preservation of hearing, NO-mediated cascades have both protective and detrimental potential. Here we examine the cochlear function of mice lacking one of the two NO-sensitive guanylate cyclase isoforms [NO-GC1 knockout (KO) or NO-GC2 KO].

Detection of Excitatory and Inhibitory Synapses in the Auditory System Using Fluorescence Immunohistochemistry and High-Resolution Fluorescence Microscopy.

In sensory systems, a balanced excitatory and inhibitory circuit along the ascending pathway is not only important for the establishment of topographically ordered connections from the periphery to the cortex but also for temporal precision of signal processing. The accomplishment of spatial and temporal cortical resolution in the central nervous system is a process that is likely initiated by the first sensory experiences that drive a period of increased intracortical inhibition. In the auditory system, the time of first sensory experience is also the period in which a reorganization of cochlear efferent and afferent fibers occurs leading to the mature innervation of inner and outer hair cells.

BDNF in Lower Brain Parts Modifies Auditory Fiber Activity to Gain Fidelity but Increases the Risk for Generation of Central Noise After Injury.

For all sensory organs, the establishment of spatial and temporal cortical resolution is assumed to be initiated by the first sensory experience and a BDNF-dependent increase in intracortical inhibition. To address the potential of cortical BDNF for sound processing, we used mice with a conditional deletion of BDNF in which Cre expression was under the control of the Pax2 or TrkC promoter. BDNF deletion profiles between these mice differ in the organ of Corti (BDNF (Pax2) -KO) versus the auditory cortex and hippocampus (BDNF (TrkC) -KO).

Neuromagnetic hand and foot motor sources recruited during action verb processing.

The current study investigated sensorimotor involvement in the processing of verbs describing actions performed with the hands, feet, or no body part. Actual movements were used to identify neuromagnetic sources for hand and foot actions. These sources constrained the analysis of verb processing.

Networks of lexical borrowing and lateral gene transfer in language and genome evolution.

Like biological species, languages change over time. As noted by Darwin, there are many parallels between language evolution and biological evolution. Insights into these parallels have also undergone change in the past 150 years.

L-type CaV1.2 deletion in the cochlea but not in the brainstem reduces noise vulnerability: implication for CaV1.2-mediated control of cochlear BDNF expression.

Voltage-gated L-type Ca(2+) channels (L-VGCCs) like CaV1.2 are assumed to play a crucial role for controlling release of trophic peptides including brain-derived neurotrophic factor (BDNF). In the inner ear of the adult mouse, besides the well-described L-VGCC CaV1.

The Geisler method: tracing activity-dependent cGMP plasticity changes upon double detection of mRNA and protein on brain slices.

We recently demonstrated that an increase of guanosine 3',5'-cyclic monophosphate (cGMP) signaling could protect the inner ear from noise-induced hair cell damage. Noise exposure not only damages hair cells but also alters the central responsiveness to sound leading to plasticity changes. cGMP signaling has long been known to play a crucial role for plasticity changes and long-term potentiation (LTP).

Noise-induced inner hair cell ribbon loss disturbs central arc mobilization: a novel molecular paradigm for understanding tinnitus.

Increasing evidence shows that hearing loss is a risk factor for tinnitus and hyperacusis. Although both often coincide, a causal relationship between tinnitus and hyperacusis has not been shown. Currently, tinnitus and hyperacusis are assumed to be caused by elevated responsiveness in subcortical circuits.

Lack of brain-derived neurotrophic factor hampers inner hair cell synapse physiology, but protects against noise-induced hearing loss.

The precision of sound information transmitted to the brain depends on the transfer characteristics of the inner hair cell (IHC) ribbon synapse and its multiple contacting auditory fibers. We found that brain derived neurotrophic factor (BDNF) differentially influences IHC characteristics in the intact and injured cochlea. Using conditional knock-out mice (BDNF(Pax2) KO) we found that resting membrane potentials, membrane capacitance and resting linear leak conductance of adult BDNF(Pax2) KO IHCs showed a normal maturation.

cGMP-Prkg1 signaling and Pde5 inhibition shelter cochlear hair cells and hearing function.

Noise-induced hearing loss (NIHL) is a global health hazard with considerable pathophysiological and social consequences that has no effective treatment. In the heart, lung and other organs, cyclic guanosine monophosphate (cGMP) facilitates protective processes in response to traumatic events. We therefore analyzed NIHL in mice with a genetic deletion of the gene encoding cGMP-dependent protein kinase type I (Prkg1) and found a greater vulnerability to and markedly less recovery from NIHL in these mice as compared to mice without the deletion.