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PubMed2002

Evidence for synergy between alpha(2)-adrenergic and nonadrenergic mechanisms in central blood pressure regulation.

BACKGROUND: Both alpha(2)-adrenergic and non--alpha(2)-adrenergic mechanisms seem to be involved in the hypotensive effect of imidazoline-like drugs. This study aimed at investigating how these 2 mechanisms work together to modify blood pressure (BP). METHODS AND RESULTS: LNP 509, which appeared in this study to be devoid of alpha(2A)-adrenergic activity, was administered to anesthetized rabbits and wild-type (WT) mice into the cisterna magna and into the fourth ventricle, respectively. Mean arterial pressure decreased by a maximum of 46 +/- 4% and 16 +/- 2%, respectively. In D79N mice, which lack functional alpha(2A)-adrenergic receptors, LNP 509 also reduced mean arterial pressure by 17 +/- 2%. The hypotension induced by LNP 509 (100 microg/kg intracisternally) was prevented by S23757 (1 mg/kg intracisternally), an antagonist highly selective for I(1)-imidazoline binding sites (I(1)BS). A synergy between LNP 509 and the alpha(2)-adrenergic agonist alpha-methylnoradrenaline (alpha-MNA) was observed in rabbits (cisterna magna injection) and in WT mice (fourth ventricle injection) but not, as expected, in D79N mice. Similar to LNP 509 alone, rilmenidine (fourth ventricle injection), which binds both to alpha(2)-adrenergic receptors and to I(1)BS, decreased BP in D79N mice. In WT animals, rilmenidine had a significantly greater effect. Microinjections performed in rabbits showed that the synergism occurred at least in part in the nucleus reticularis lateralis of the brain stem. CONCLUSIONS: These results demonstrate that a central imidazoline-sensitive, but non--alpha(2)-adrenergic, mechanism can modify BP by itself. This mechanism, which may involve I(1)BS, interacts synergistically with an alpha(2)-adrenergic mechanism to decrease BP.

Adrenergic Agonists↗

PubMed1986

Changes in the subepithelial mesenchymal cell process meshwork in developing facial prominences in mouse embryos.

We examined temporal and spatial changes in the subepithelial mesenchymal cell process meshwork (CPM) in normally developing medial (MNP) and lateral nasal prominences (LNP) in mouse embryos by light and scanning electron microscopy. Marked changes were found only in the MNP during the fusion of the MNP and LNP. The CPM density in the prospective fusion area of the MNP gradually increased as the epithelial surfaces approached each other, attained its maximum just before contact, and decreased after contact. The CPM density in the prospective fusion area of the LNP changed only slightly even when the epithelial surfaces approached each other. The increase in CPM density paralleled that in the density of mesenchymal cell bodies. The LNP grew more actively toward the line of fusion than did the MNP during the progressive fusion of the two prominences. A larger number of fusion-associated epithelial morphological changes--the appearance of superficial protruding cells and cell degeneration--occurred in the MNP than in the LNP. These findings suggest that the increased CPM density is closely related to the growth of the facial prominences and the fusion-associated epithelial morphology and that the CPM plays an important role in the epithelial-mesenchymal interaction during the formation of the upper lip and primary palate.

Animals↗

PubMed2026

Ligand-Mediated Reprogramming Redirects Liver-Tropic Ionizable Lipid Nanoparticles for Lung-Selective mRNA Delivery.

Systemic delivery of messenger RNA (mRNA) to target tissues and cells using lipid nanoparticles (LNPs) holds transformative potential for gene therapy. However, most clinically validated LNP exhibit strong liver tropism, and redirecting their organ specificity without redesigning entirely new chemistries remains challenging. Here we present a ligand-mediated lipid reprogramming approach that repurposes chemically defined, liver-tropic, ionizable lipids (lipidoids) for mRNA delivery beyond the liver. From a library of 90 degradable lipidoids, we identified 2-t6b as a potent liver-targeting platform. By site-specific displaying of small molecule ligands onto 2-t6b headgroup, we engineered a series of reconfigured lipidoids that achieve lung-specific targeting while retaining the parent delivery scaffold. Ligand7-2-t6b-lipid-functionalized LNP achieved over 200-fold higher mRNA translation in the lungs compared to the parent liver-tropic LNP. Proteomics and molecular docking analysis revealed enhanced binding of the modified lipid to vitronectin, a serum glycoprotein that improves integrin binding and thus promotes cellular uptake and translation efficiency. Ligand-mediated 2-t6b/ligand7 LNPs achieved outperformed efficacy and therapeutic potential in lung-specific genome editing relative to SORT-constructed 2-t6b LNP system. Our modular reprogramming strategy provides a generalizable framework to upgrade existing liver-biased LNPs into lung-selective mRNA carriers, advancing next-generation tissue-specific mRNA therapies for gene editing, protein replacement therapy, and regenerative medicine.

RNA, Messenger↗

PubMed2004

Laparoscopic navigation pointer for three-dimensional image-guided surgery.

BACKGROUND: The main drawback with the laparoscopic approach is that the surgeon is unable to palpate vessels, tumors, and organs during surgery. Furthermore, the laparoscope provides only surface view of organs. There is a need for more advanced visualizations that can enhance the view to include information below the surface of the organs for planning of the procedure and for control and guidance during treatment. METHODS: We propose three-dimensional (3D) navigation technology based on preoperatively acquired magnetic resonance or computed tomography data used in combination with a laparoscopic navigation pointer (LNP). The LNP has an attached position tracker that allows the surgeon to control the display of images interactively before and during surgery. This study evaluated the patient registration accuracy, the feasibility of image-based navigation and, qualitatively, the navigation precision in the retroperitoneum during laparoscopic surgery. RESULTS: This technology was used during the treatment of six patients (involving adrenalectomies and a neuroma protruding into the pelvis). An average patient registration accuracy of 6.90 mm was achieved. The precision during navigation in the retroperitoneum was, in some cases, better than the patient registration accuracy suggested. The technology helped the surgeons to understand better the anatomy and to locate blood vessels. CONCLUSIONS: In the reported cases, the LNP was a useful tool for image guidance in laparoscopic surgery, both for planning the surgical approach in detail and for guidance. The authors believe that adominal 3D image guidance using an LNP has a large potential for improving laparoscopic surgery, especially when vessels and anatomic relations may be difficult to identify using only a laparoscope. Accordingly, they believe this new technology could increase safety and make it easier for the surgeon to perform successful laparoscopic surgery.

Adenoma↗

PubMed2005

The IGF-system is not affected by a twofold change in protein intake in patients with type 1 diabetes.

OBJECTIVE: In type 1 diabetes the circulating IGF-system is altered with low IGF-I and changes in levels of IGF-binding proteins (IGFBPs) which may be of importance for the development of diabetes complications. Our aim was to study if IGF-I, as supported by experimental data in animals, can be affected by dietary protein intake. DESIGN AND METHODS: Twelve patients with type 1 diabetes, age 37.5+/-10.0 years (mean+/-SD), diabetes duration 20.1+/-9.3 years and HbA1c 6.3+/-0.6% were allocated to isocaloric diets with either low normal protein content (LNP), (10 E%; 0.9 g protein/kg body weight) or high normal protein content (HNP) (20 E%; 1.8 g protein/kg body weight) in an open randomised cross-over study. Each diet was taken for 10 days with a wash-out period of 11 days in between. Circulating levels of total and free IGF-I and -II, IGFBP-1, -2 and -3 and GH-binding protein (GHBP) as well as ghrelin were measured with validated in-house immunoassays. RESULTS: At day 10, urinary urea excretion was 320+/-75 mmol/24h during LNP diet compared with 654+/-159 mmol/24h during HNP diet (p<0.001). There were no changes in body weight or glycaemic control between the diets. Fasting levels of total IGF-I were 121+/-33 microg/L after LNP and 117+/-28 microg/L after HNP diet (ns) and the corresponding concentrations of IGFBP-1 were 142(141) and 132(157)mug/L [median (IQR)] (ns). There were no differences in plasma concentrations of total IGF-II, free IGF-I and -II, IGFBP-3, GHBP and ghrelin, whereas a small difference was found for IGFBP-2 (302+/-97 vs. 263+/-66 microg/L; LNP vs. HNP; p<0.04). CONCLUSIONS: A twofold change of the dietary protein intake does not influence the altered circulating IGF-system in type 1 diabetes. In order to affect the IGF-system other interventions must be used.

Adult↗

PubMed2005

Thermal analysis of the crystallization and melting behavior of lipid matrices and lipid nanoparticles containing high amounts of lecithin.

Lipid nanoparticles (LNP) based on triglycerides containing high amounts of the amphiphilic lipid lecithin have been proposed as a promising alternative drug delivery system with regard to drug loading capacity. Aim of the present study is to evaluate the influence of lecithin within the lipid matrix (LM) on the crystallization behavior by thermoanalysis and wide angle X-ray diffraction (WAXD). The crystallinity of LM and LNP is mainly determined by the triglyceride content. However, lecithin influences the crystallization behavior significantly. WAXD shows an accelerated polymorphic transition of the LM to the beta-modification upon storage with increasing lecithin content. Both, the melting point and the crystallization temperature are not affected by the lecithin concentration and are comparable to recrystallized triglyceride bulk. However, the crystallinity indices (CI) of LM show a general decrease by 10% suggesting an incomplete crystallization. For the formation of LNP at least 10% lecithin is necessary and all systems are present in the stable beta-modification. In comparison to the undispersed LM, the crystallization temperature of LNP is significantly decreased by about 20 degrees C whereas the melting point is reduced by about 5 degrees C only. Melting enthalpy is comparable to the untreated triglyceride bulk and elevated in comparison to the undispersed LM. Isothermal heat-conduction microcalorimetry (IMC) enables the determination of crystallization kinetics after fitting of the heat flow volume according to the Avrami equation.

Calorimetry, Differential Scanning↗

PubMed2026

Efficient prime editing in vivo and in vitro using lipid nanoparticles.

Prime editing is a versatile clinical genome editing method that enables precise substitutions, small insertions and deletions at specified locations in the genomes of living systems including human cells. Although non-viral lipid nanoparticle (LNP) delivery of RNA in vivo has become a preferred method for gene editing in animals and patients, its application to complex, three-component prime editing systems has yielded low editing efficiencies. Here we developed a systematic prime editing LNP (PE-LNP) optimization platform that addresses key bottlenecks in cargo design that limit editing efficiency. This generalizable workflow yielded PE-LNPs that can achieve 49% average in vivo prime editing in the bulk mouse liver with a single dose of 2 mg kg-1. We applied our workflow to the correction of PAH R408W, a cause of phenylketonuria, in a mouse model and achieved prime editing efficiencies and serum phenylalanine levels anticipated to be curative. We also show that PE-LNPs minimize off-target editing compared with DNA delivery methods, induce only transient elevation of liver enzymes and can be dosed repeatedly to improve editing efficiencies. These PE-LNP systems provide an attractive alternative to viral delivery by offering transient expression that minimizes off-target editing, no observed long-term toxicity and high levels of non-viral in vivo liver prime editing.

Animals↗

PubMed2004

Finding coexpressed genes in counts-based data: an improved measure with validation experiments.

MOTIVATION: Expressed sequence tag (EST) data reflects variation in gene expression, but previous methods for finding coexpressed genes in EST data are subject to bias and vastly overstate the statistical significance of putatively coexpressed genes. RESULTS: We introduce a new method (LNP) that reports reasonable p-values and also detects more biological relationships in human dbEST than do previous methods. In simulations with human dbEST library sizes, previous methods report p-values as low as 10(-30) on 1/1000 uncorrelated pairs, while LNP reports significance correctly. We validate the analysis on real human genes by comparing coexpressed pairs to gene ontology annotations and find that LNP is more sensitive than the three previous methods. We also find a small but statistically significant level of coexpression between interacting proteins relative to randomized controls. The LNP method is based on a log-normal prior on the distribution of expression levels.

Algorithms↗

PubMed2004

A time-dependent analysis of intensive care unit pneumonia in trauma patients.

BACKGROUND: Appropriate and timely antibiotic therapy to treat pneumonia in trauma patients is extremely important. We evaluated the incidence and microbiology of pneumonia stratified by days postadmission and risk factors. METHODS: Prospective data were collected on 714 trauma patients admitted to the intensive care unit over a 1-year period. Pneumonia was classified as community acquired (CAP) (< or = 3 days), early nosocomial (ENP) (4-6 days), or late nosocomial (LNP) (> or = 7 days). In addition, pneumonia was classified as CAP only, nosocomial only (NI), or combination (CAP and NI, or ENP and LNP) pneumonia. Strict institutional guidelines were followed for diagnosis. RESULTS: One hundred eighty-two patients (25%) were diagnosed with 204 pneumonias over the study period. One hundred twenty-five (61%) of these pneumonias were ventilator associated. Staphylococcus aureus and Haemophilus influenzae were the most common pathogens isolated. Twenty-one percent of patients with CAP acquired an LNP (p < 0.025), in which Pseudomonas was the most common organism. Haemophilus caused LNP in 12% of patients. Cancer (p < 0.01), liver failure (p < 0.05), and age (p < 0.01) were predictive of nontypical pathogens in patients with CAP and ENP (p < 0.05). Obesity was most predictive of increased ventilator days (p < 0.001) and intensive care unit length of stay (p < 0.001). Increased age, alcohol abuse, and field airway were most predictive of mortality. CONCLUSION: Unanticipated pathogens were isolated in each class of pneumonia. The clinician must be aware of significant risk factors that may predispose patients to pathogens that are not ordinarily covered with standard antibiotic therapy.

Adult↗

PubMed1995

Salivary secretion in cat submandibular gland mediated by chorda tympani afferents.

The aim of the present study was to investigate whether the afferent traffic from the tongue mediated only via the chorda tympani nerve (CTN) can still elicit reflex salivary and vasodilator responses in the cat submandibular gland (SMG) after section of the lingual nerve proper (LNP). Electrical stimulation of the chorda lingual nerve (CLN) at a site approximately 5 mm distal to the intersection of the CLN and the SMG duct elicited salivary and vasodilator responses in the SMG in sympathectomized cats. Both responses were unaffected by section of the LNP. The optimal frequency of CLN stimulation for submandibular salivation and vasodilation was 20 Hz, regardless of whether the LNP had been cut. Prior treatment with the autonomic ganglion blocker hexamethonium (10 mg/kg iv) virtually abolished the salivation and the blood flow increase in SMG. Prior treatment with scopolamine (0.1 mg/kg iv) almost abolished the salivary secretions but had no effect on the vasodilator responses in the SMG elicited by CLN stimulation after LNP section. The mechanism underlying the reflex submandibular salivation mediated by chorda tympani afferents appears to involve parasympathetic muscarinic receptors, but the mechanism for the vasodilator response has yet to be established. These results indicate that afferent traffic passing through the CTN on CLN stimulation is importantly involved in the parasympathetic reflex secretory and vasodilator responses in the cat SMG.

Adrenergic Antagonists↗

PubMed2001

Assessment of the cytotoxic and clastogenic activities of the sesquiterpene lactone lynchnopholide in mammalian cells in vitro and in vivo.

Lychnopholide (LNP), a sesquiterpene lactone with antitumor, trypanocidal, and antimicrobial activities, was isolated from Vanillosmopsis erythropappa. The present study was carried out to assess the cytotoxic and clastogenic potential of this new agent in human cultured lymphocytes and Swiss bone marrow cells before the agent was used in medicine. The mitotic index, chromosomal aberrations (CAs), sister chromatid exchanges (SCEs), and proliferation index were investigated. There was no alteration in the number of CAs and SCEs in the continuous in vitro treatment. However, the highest concentration (0.2 microg/ml) of LNP was cytotoxic. LNP (0.1, 0.2, and 0.4 microg/ml) induced a significant increase in CA frequency at the G2 phase in all treated cultures. Only the highest concentration (26.67 mg/kg) caused a significant increase in the total number of CAs in the in vivo investigation. On the basis of these results, LNP had a clastogenic effect on both test systems and a cytotoxic effect in vitro.

Adult↗

PubMed1994

[Late declaration of pregnancy: an indicator of psychosocial vulnerability of the family].

Social, economical and family characteristics were studied in 90 women who notified their pregnancy beyond the French legal recommended limit of 3 months (LNP). The development of the children born from these pregnancies was also studied. A group of women notifying their pregnancy within the legal limit of 3 months served as a control. The data were collected at home by nurses from the Service de Protection Maternelle et Infantile visiting the family at the time of notification of the pregnancy and at ages 4, 12 and 36 months. The results showed frequent psychological, economical and social disabilities of women with LNP, presenting high rates of unemployment, low income, unusual ages of pregnancy (44% before 20 years and after 35 years), absence of father, consideration of voluntary interruption of pregnancy. Their offspring had a frequent unfavourable family environment, but their development did not show significant differences at 3 years of age as compared with children of the control group: however they presented signs suggesting a greater vulnerability, and especially frequent language and behaviour disturbances. From these data LNP appears as an indicator of psycho-social vulnerability of the family. Therefore LNP should lead to a systematic visit of the family at home by a social worker in order to assess its degree of psycho-social vulnerability and to provide, when necessary, preventive action directed towards the protection of the child development.

Child↗

PubMed1997

[Locked nail plate: a new treatment for unstable pertrochanteric fractures].

PURPOSE OF THE STUDY: This work is the outcome of a preliminary study on pertrochanteric fractures which showed that impaction with simple nail plates (SNP) was lead by hypercorrection in valgus demineralization and malposition of the nail in the femoral neck. To improve anchoring of the nail in the cervico-cephalic part, the authors propose to use a locked nail-plate (LNP), an innovative device based on the addition to the normal nail plate, of a screw securing neck and nail. MECHANICAL STUDY: Mechanical flexion and compression tests carried out on 8 pairs of femurs of fresh cadavers showed comparable rigidity for the two mounting, SNP and LNP. The difference became apparent at an equivalent load through a perforation in the SNP across the femoral head and by separation of the head from the LNP without any perforation. CLINICAL STUDY: 56 patients operated on between June 1994 and June 1996 were included 30 cases could be followed. There was only one complication: one dismantling of the plate from the diaphysis. The other 29 cases consolidated within an average of 8 weeks without any complications. Locking of the nail was effective and there was never cutting out the head by the nail nor any impaction in the focus of the fracture site. This was despite the fact that, in 12 cases there was advanced demineralization, in 8 cases hypercorrection in valgus, and in 13 cases of misalignment of the nail in the neck, all three of these being recognized as causes of articular deterioration. DISCUSSION: Pertrochanteric fractures currently represent a serious public health problem for which costs are definitely going to grow in the near future. We need a method for solid osteosynthesis simple and relatively inexpensive, but which also avoids the common mechanical complications. The LNP seems to correct SNP problems. This modification represents an improvement and should be used for any unstable pertrochanteric fracture.

Biomechanical Phenomena↗

PubMed1999

A Nod factor-binding lectin is a member of a distinct class of apyrases that may be unique to the legumes.

Recent studies from our laboratory have found that a root lectin from the legume Dolichos hifloris is present on the root surface, binds rhizobial Nod factor and has apyrase activity. To assess the broader significance of this lectin/nucleotide phosphohydrolase (Db-LNP), we have cloned a second related cDNA (Db-apyrase-2) from D. hiflorus, as well as related cDNAs from the legumes Lotus japonicus and Medicago sativa, and from Arabidopsis thaliana, a non-legume. The deduced amino acid sequences of these apyrases were aligned with one another and with the sequences of other apyrases from plants, animals, yeast and protozoa. Phylogenetic analysis shows that Db-LNP has closely related orthologs only in other legumes, while Db-apyrase-2 is more closely related to apyrase sequences from non-leguminous plants. We also show that the orthologs of Db-LNP from M. sativa and Pisum sativum have carbohydrate binding activity. The results suggest that legume LNPs may represent a special class of apyrases that arose by gene duplication and subsequent specialization.

Amino Acid Sequence↗

PubMed2005

Theoretical study of structure, pKa, lipophilicity, solubility, absorption, and polar surface area of some centrally acting antihypertensives.

The methods of theoretical chemistry have been used to elucidate the molecular properties of the substituted imidazoline and oxazoline structures, a class of potent agonists and antagonists of imidazoline receptors. The geometries of various tautomers and isomers of 2-[2,6-dichlorophenylimino]imidazolidine (clonidine), 1-(N-dicyclopropylmethyl)amino-2-oxazoline (rilmenidine), 4-chloro-N-(4,5-dihydro-1H-imidazol-2yl)-6-methoxy-2-methyl-5-pyrimidinamine (moxonidine), N-(dicyclopropylmethyl)-4,5-dihydro-1H-pyrrol-2-amine (aminopyrroline), N-dicyclopropylmethyl-4,5-dihydrothiazol-2-amine (aminothiazoline), 4,5-dihydro-2-(2-methoxyphenyl)-1H-imidazole (compound_6), 4,5-dihydro-2-(3-methylthiophen-2-yl)-1H-imidazole (compound_7), N-(2-chloro-4-iodophenyl)-4,5-dihydro-5-methyl-3H-pyrrol-2-amine (LNP_911), N-amidino-3,5-diamino-6-chloropyrazine-carboxamide (amiloride), 2-(1,4-benzodioxan-2-yl)-2-imidazoline (idazoxan), (+/-)-2-(2-ethyl-2,3-dihydro-2-benzofuranyl)-2-imidazoline (efaroxan), (4-aminobutyl)guaninine (agmatine), and 1-methyl-9H-pyrido[3,4-b]indole (harmane) have been studied using Becke3LYP/6-31+G(d,p) and BP86/TZ2P DFT methods. The optimized geometries indicate that these molecules show a distinctly nonplanar configuration of the imidazoline and oxazoline moieties. In the gas-phase, rilmenidine and aminothiazoline exist in two forms (amino and imino), the amino tautomers being more stable by about 6 kJ/mol. The calculations showed, in agreement with experiments, that clonidine, moxonidine, and LNP_911 exist in a more stable imino tautomer. The tautomer containing the amino group is by about 30 kJ/mol less stable. Computations that include the effect of solvation indicated that also in water the relative stability order of individual tautomers (amino and imino forms) is preserved. The computed pKa values varied between 6.7 and 9.0, and correlate well with the available experimental pKa's found in the literature. Among the clinically useful antihypertensives moxonidine exhibits the lowest basicity in water. At pH = 7.4 only about 50% of this drug exists in ionized form. The available experimental partition coefficients of compounds investigated are best reproduced by the CLOGP method. The computed partition coefficients varied between -1.80 (agmatine) and 5.35 (LNP_911) (CLOGP). Clonidine, moxonidine, and rilmenidine are moderately lipophilic compounds with lipophilicities between these two extreme values. The computed solubilities (about 0.1-4 g/L) show that the imidazoline and oxazoline derivatives studied have very low water solubility. The analysis of molecular descriptors defined by Lipinski has shown that most of the compounds studied obey 'rule of five'. Amiloride and agmatine 'outlets' exhibit also the lowest absorption. Therefore, in the early stages of the design of ligands acting on imidazoline binding sites, it is becoming more important to determine the pKa, lipophilicity, water solubility, polar surface area, absorption, and other physicochemical properties associated with a drug, before synthetic work is undertaken, with the aim of avoiding the synthesis of compounds that are predicted to have poor biopharmaceutical characteristics.

Adsorption↗

PubMed2026

Enhancing Lipid Nanoparticle-Mediated Circular RNA and mRNA Expression in the Placenta through Inhibition of IFNAR-JAK-STAT Signaling.

The placenta has emerged as a promising target for RNA lipid nanoparticle (LNP)-based therapies to treat obstetric complications, yet efficient extrahepatic RNA transfection remains a challenge. Here, we identify innate immune signaling as a regulator of placental RNA translation and demonstrate that inhibition of IFN-α/β receptor (IFNAR) and JAK-STAT signaling enhances LNP-mediated transgene expression in the placenta for both messenger RNA (mRNA) and circular RNA (circRNA). While a placenta-tropic LNP enabled robust and durable circRNA expression in trophoblasts in vitro, circRNA translation was substantially decreased in vivo compared to mRNA in pregnant mice. Inhibition of IFNAR-JAK-STAT signaling enhanced circRNA translation up to 12-fold in maternal organs and increased circRNA and mRNA translation in the placenta up to 17.5- and 4-fold, respectively. JAK-STAT inhibition also enhanced translation of therapeutically relevant VEGF-encoding circRNA and mRNA in pregnant mice, suggesting innate immune modulation as a broadly applicable strategy to improve RNA therapeutics during pregnancy.

Female↗

PubMed2003

Bmp4 gene is expressed at the putative site of fusion in the midfacial region.

The molecular mechanisms by which the primordia of the midface grow and fuse to form the primary palate portion of the craniofacial region are not well characterized. This is in spite of the fact that failure of growth and/or fusion of these primordia leads to the most common craniofacial birth defect in humans (i.e. clefts of the lip and/or palate). Bmp4 plays a critical role during early embryonic development and has previously been shown to play a role in epithelial-mesenchymal interactions in the craniofacial region of chicks. We analyze the expression of bmp4 in mouse as the midfacial processes undergo fusion to form the primary palate. We show that bmp4 is expressed in a very distinct manner in the three midfacial processes (lateral nasal, LNP, medial nasal, MNP, and maxillary processes, MxP) that ultimately fuse to form the midface. Prior to fusion of the midfacial processes, bmp4 is expressed in the ectoderm of the LNP, MNP, and MxP in a distinct spatial and temporal manner near and at the site of fusion of the midface. Bmp4 appears to demarcate the cells in the LNP and MNP that will eventually contact and fuse with each other. As fusion of the three prominences proceeds, some bmp4 expressing cells are trapped in the fusion line. Later, the expression of bmp4 switches to the mesenchyme of the midface underlying its initial expression in the ectoderm. The switch occurs soon after fusion of the three processes. The pattern of expression in the midfacial region implicates the important role of bmp4 in mediating the fusion process, possibly through apoptosis of cells in the putative site of fusion, during midfacial morphogenesis.

Animals↗

PubMed2024

Accelerating diabetic wound healing by ROS-scavenging lipid nanoparticle-mRNA formulation.

Current treatment options for diabetic wounds face challenges due to low efficacy, as well as potential side effects and the necessity for repetitive treatments. To address these issues, we report a formulation utilizing trisulfide-derived lipid nanoparticle (TS LNP)-mRNA therapy to accelerate diabetic wound healing by repairing and reprogramming the microenvironment of the wounds. A library of reactive oxygen species (ROS)-responsive TS LNPs was designed and developed to encapsulate interleukin-4 (IL4) mRNA. TS2-IL4 LNP-mRNA effectively scavenges excess ROS at the wound site and induces the expression of IL4 in macrophages, promoting the polarization from the proinflammatory M1 to the anti-inflammatory M2 phenotype at the wound site. In a diabetic wound model of db/db mice, treatment with this formulation significantly accelerates wound healing by enhancing the formation of an intact epidermis, angiogenesis, and myofibroblasts. Overall, this TS LNP-mRNA platform not only provides a safe, effective, and convenient therapeutic strategy for diabetic wound healing but also holds great potential for clinical translation in both acute and chronic wound care.

Wound Healing↗