RESUMEN
The nanodrug delivery system-based nasal spray (NDDS-NS) can bypass the blood-brain barrier and deliver drugs directly to the brain, offering unparalleled advantages in the treatment of central nervous system (CNS) diseases. However, the current design of NNDS-NS is excessively focused on mucosal absorption while neglecting the impact of nasal deposition on nose-to-brain drug delivery, resulting in an unsatisfactory nose-to-brain delivery efficiency. In this study, the effect of the dispersion medium viscosity on nasal drug deposition and nose-to-brain delivery in NDDS-NS was elucidated. The optimized formulation F5 (39.36 mPa·s) demonstrated significantly higher olfactory deposition fraction (ODF) of 23.58%, and a strong correlation between ODF and intracerebral drug delivery (R2 = 0.7755) was observed. Building upon this understanding, a borneol-modified lipid nanoparticle nasal spray (BLNP-NS) that combined both nasal deposition and mucosal absorption was designed for efficient nose-to-brain delivery. BLNP-NS exhibited an accelerated onset of action and enhanced brain targeting efficiency, which could be attributed to borneol modification facilitating the opening of tight junction channels. Furthermore, BLNP-NS showed superiority in a chronic migraine rat model. It not only provided rapid relief of migraine symptoms but also reversed neuroinflammation-induced hyperalgesia. The results revealed that borneol modification could induce the polarization of microglia, regulate the neuroinflammatory microenvironment, and repair the neuronal damage caused by neuroinflammation. This study highlights the impact of dispersion medium viscosity on the nose-to-brain delivery process of NDDS-NS and serves as a bridge between the formulation development and clinical transformation of NDDS-NS for the treatment of CNS diseases.
Asunto(s)
Encéfalo , Canfanos , Lípidos , Nanopartículas , Rociadores Nasales , Ratas Sprague-Dawley , Animales , Nanopartículas/química , Ratas , Lípidos/química , Encéfalo/metabolismo , Canfanos/química , Canfanos/administración & dosificación , Canfanos/farmacología , Masculino , Administración Intranasal , Sistemas de Liberación de Medicamentos , Enfermedades del Sistema Nervioso Central/tratamiento farmacológico , Mucosa Nasal/metabolismo , Mucosa Nasal/efectos de los fármacos , Tamaño de la PartículaRESUMEN
Crocetin (CCT), a natural bioactive compound extracted and purified from the traditional Chinese medicinal herb saffron, has been shown to play a role in neurodegenerative diseases, particularly depression. However, due to challenges with solubility, targeting, and bioavailability, formulation development and clinical use of CCT are severely limited. In this study, we used the emulsification-reverse volatilization method to prepare CCT-loaded nanoliposomes (CN). We further developed a borneol (Bor) and lactoferrin (Lf) dual-modified CCT-loaded nanoliposome (BLCN) for brain-targeted delivery of CCT. The results of transmission electron microscope (TEM) and particle size analysis indicated that the size of BLCN (â¼140 nm) was suitable for transcellular transport across olfactory axons (â¼200 nm), potentially paving a direct path to the brain. Studies on lipid solubility, micropolarity, and hydrophobicity showed that BLCN had a relatively high Lf grafting rate (81.11 ± 1.33 %) and CCT entrapment efficiency (83.60 ± 1.04 %) compared to other liposomes, likely due to Bor improving the lipid solubility of Lf, and the combination promoting the orderly arrangement of liposome membrane molecules. Microplate reader and fluorescence microscopy analysis showed that BLCN efficiently promoted the endocytosis of fluorescent coumarin 6 into HT22 cells with a maximal fluorescence intensity of (13.48 ± 0.80 %), which was significantly higher than that of CCT (5.73 ± 1.17 %) and CN (12.13 ± 1.01 %). BLCN also exhibited sustained function, remaining effective for more than 12 h after reaching a peak at 1 h in cells, while CN showed a significant decrease after 4 h. The uptake mechanisms of BLCN in HT22 cells mainly involve energy-dependent, caveolae-mediated, and microtubule-mediated endocytosis, as well as micropinocytosis. Furthermore, BLCN displayed a significant neuroprotective effect on HT22 cells in glutamate-, corticosterone-, and H2O2-induced models. Tissue fluorescence image analysis of mice showed that BLCN exhibited substantial retention of fluorescent DiR in the brain after nasal administration for 12 h. These findings suggest that CCT has the potential for cellular uptake, neuroprotection, and targeted delivery to the brain following intranasal administration when encapsulated in Bor and Lf dual-modified nanoliposomes.
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Encéfalo , Canfanos , Carotenoides , Lactoferrina , Liposomas , Nanopartículas , Fármacos Neuroprotectores , Vitamina A , Animales , Vitamina A/química , Vitamina A/administración & dosificación , Vitamina A/análogos & derivados , Liposomas/química , Carotenoides/química , Carotenoides/farmacología , Ratones , Encéfalo/metabolismo , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/administración & dosificación , Canfanos/química , Canfanos/farmacología , Lactoferrina/química , Lactoferrina/farmacología , Lactoferrina/administración & dosificación , Nanopartículas/química , Línea Celular , Tamaño de la Partícula , Masculino , Estructura Molecular , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Relación Estructura-Actividad , Neuroprotección/efectos de los fármacosRESUMEN
Biofilm-associated infections remain a tremendous obstacle to the treatment of microbial infections globally. However, the poor penetrability to a dense extracellular polymeric substance matrix of traditional antibacterial agents limits their antibiofilm activity. Here, we show that nanoaggregates formed by self-assembly of amphiphilic borneol-guanidine-based cationic polymers (BGNx-n) possess strong antibacterial activity and can eliminate mature Staphylococcus aureus (S. aureus) biofilms. The introduction of the guanidine moiety improves the hydrophilicity and membrane penetrability of BGNx-n. The self-assembled nanoaggregates with highly localized positive charges are expected to enhance their interaction with negatively charged bacteria and biofilms. Furthermore, nanoaggregates dissociate on the surface of biofilms into smaller BGNx-n polymers, which enhances their ability to penetrate biofilms. BGNx-n nanoaggregates that exhibit superior antibacterial activity have the minimum inhibitory concentration (MIC) of 62.5 µg·mL-1 against S. aureus and eradicate mature biofilms at 4 × MIC with negligible hemolysis. Taken together, this size-variable self-assembly system offers a promising strategy for the development of effective antibiofilm agents.
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Antibacterianos , Biopelículas , Canfanos , Guanidina , Pruebas de Sensibilidad Microbiana , Polímeros , Staphylococcus aureus , Biopelículas/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Guanidina/química , Guanidina/farmacología , Canfanos/química , Canfanos/farmacología , Polímeros/química , Polímeros/farmacología , Tensoactivos/química , Tensoactivos/farmacología , Humanos , Interacciones Hidrofóbicas e HidrofílicasRESUMEN
In plant secondary metabolite biosynthesis, acylation is a diverse physiological process, with BAHD acyltransferases playing an essential role. Borneol acetyltransferase (BAT) is an alcohol acetyltransferase, which catalyzes borneol and acetyl-CoA to synthesize bornyl acetate (BA). However, the enzymes involved in the biosynthesis of BA have so far only been characterized in Wurfbainia villosa, the studies on the WvBATs have only been conducted in vitro, and the catalytic activity was relatively low. In this research, three genes (WlBAT1, WlBAT2, and WlBAT3) have been identified to encode BATs that are capable of acetylating borneol to synthesize BA in vitro. We also determined that WlBAT1 has the highest catalytic efficiency for borneol-type substrates, including (+)-borneol, (-)-borneol, and isoborneol. Furthermore, we found that BATs could catalyze a wide range of substrate types in vitro, but in vivo, they exclusively catalyzed borneol-type substrates. Through molecular simulations and site-directed mutagenesis, it was revealed that residues D32, N36, H168, N297, N355, and H384 are crucial for the catalytic activity of WlBAT1, while the R382I-D385R double mutant of WlBAT1 exhibited an increasing acylation efficiency for borneol-type substrates in vitro and in vivo. These findings offer key genetic elements for the metabolic engineering of plants and synthetic biology to produce BA.
Asunto(s)
Acetiltransferasas , Canfanos , Proteínas de Plantas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Proteínas de Plantas/química , Acetiltransferasas/genética , Acetiltransferasas/metabolismo , Acetiltransferasas/química , Canfanos/metabolismo , Canfanos/química , Biocatálisis , Especificidad por Sustrato , Cinética , Mutagénesis Sitio-DirigidaRESUMEN
Sustainable retinal codelivery poses significant challenges technically, although it is imperative for synergistic treatment of wet age-related macular degeneration (wAMD). Here, a microemulsion-doped hydrogel (Bor/PT-M@TRG) is engineered as an intravitreal depot composing of temperature-responsive hydrogel (TRG) and borneol-decorated paeoniflorin (PF) & tetramethylpyrazine (TMP)-coloaded microemulsions (Bor/PT-M). Bor/PT-M@TRG, functioning as the "ammunition depot", resides in the vitreous and continuously releases Bor/PT-M as the therapeutic "bullet", enabling deep penetration into the retina for 21 days. A single intravitreal injection of Bor/PT-M@TRG yields substantial reductions in choroidal neovascularization (CNV, a hallmark feature of wAMD) progression and mitigates oxidative stress-induced damage in vivo. Combinational PF&TMP regulates the "reactive oxygen species/nuclear factor erythroid-2-related factor 2/heme oxygenase-1" pathway and blocks the "hypoxia inducible factor-1α/vascular endothelial growth factor" signaling in retina, synergistically cutting off the loop of CNV formation. Utilizing fluorescence resonance energy transfer and liquid chromatography-mass spectrometry techniques, they present compelling multifaceted evidence of sustainable retinal codelivery spanning formulations, ARPE-19 cells, in vivo eye balls, and ex vivo section/retina-choroid complex cell levels. Such codelivery approach is elucidated as the key driving force behind the exceptional therapeutic outcomes of Bor/PT-M@TRG. These findings highlight the significance of sustainable retinal drug codelivery and rational combination for effective treatment of wAMD.
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Pirazinas , Animales , Pirazinas/química , Pirazinas/administración & dosificación , Pirazinas/farmacología , Pirazinas/farmacocinética , Retina/efectos de los fármacos , Retina/metabolismo , Degeneración Macular/tratamiento farmacológico , Sistemas de Liberación de Medicamentos/métodos , Humanos , Neovascularización Coroidal/tratamiento farmacológico , Neovascularización Coroidal/metabolismo , Neovascularización Coroidal/patología , Ratones , Hidrogeles/química , Hidrogeles/farmacología , Estrés Oxidativo/efectos de los fármacos , Canfanos/química , Canfanos/farmacología , Ratones Endogámicos C57BL , Especies Reactivas de Oxígeno/metabolismoRESUMEN
2-Methylisoborneol is a widespread musty odourant that is produced by many bacteria including actinomycetes, cyanobacteria and myxobacteria. Two 2-methylisoborneol synthases (MIBS) that are phylogenetically distant to the known enzyme from Streptomyces coelicolor were found to be highly active for 2-methylisoborneol biosynthesis. Based on the enzyme structure and on an amino acid sequence alignment, the MIBS from S. coelicolor was extensively studied through site-directed mutagenesis.
Asunto(s)
Streptomyces coelicolor , Secuencia de Aminoácidos , Streptomyces coelicolor/genética , Streptomyces coelicolor/metabolismo , Canfanos/química , Canfanos/metabolismo , Mutagénesis Sitio-DirigidaRESUMEN
Fenchone is a bicyclic monoterpene found in a variety of aromatic plants, including Foeniculum vulgare and Peumus boldus, and is used in the management of airways disorders. This study aimed to explore the bronchodilator effect of fenchone using guinea pig tracheal muscles as an ex vivo model and in silico studies. A concentration-mediated tracheal relaxant effect of fenchone was evaluated using isolated guinea pig trachea mounted in an organ bath provided with physiological conditions. Sustained contractions were achieved using low K+ (25 mM), high K+ (80 mM), and carbamylcholine (CCh; 1 µM), and fenchone inhibitory concentration-response curves (CRCs) were obtained against these contractions. Fenchone selectively inhibited with higher potency contractions evoked by low K+ compared to high K+ with resultant EC50 values of 0.62 mg/mL (0.58-0.72; n = 5) and 6.44 mg/mL (5.86-7.32; n = 5), respectively. Verapamil (VRP) inhibited both low and high K+ contractions at similar concentrations. Pre-incubation of the tracheal tissues with K+ channel blockers such as glibenclamide (Gb), 4-aminopyridine (4-AP), and tetraethylammonium (TEA) significantly shifted the inhibitory CRCs of fenchone to the right towards higher doses. Fenchone also inhibited CCh-mediated contractions at comparable potency to its effect against high K+ [6.28 mg/mL (5.88-6.42, n = 4); CCh] and [6.44 mg/mL (5.86-7.32; n = 5); high K+]. A similar pattern was obtained with papaverine (PPV), a phosphodiesterase (PDE), and Ca2+ inhibitor which inhibited both CCh and high K+ at similar concentrations [10.46 µM (9.82-11.22, n = 4); CCh] and [10.28 µM (9.18-11.36; n = 5); high K+]. However, verapamil, a standard Ca2+ channel blocker, showed selectively higher potency against high K+ compared to CCh-mediated contractions with respective EC50 values of 0.84 mg/mL (0.82-0.96; n = 5) 14.46 mg/mL (12.24-16.38, n = 4). The PDE-inhibitory action of fenchone was further confirmed when its pre-incubation at 3 and 5 mg/mL potentiated and shifted the isoprenaline inhibitory CRCs towards the left, similar to papaverine, whereas the Ca2+ inhibitory-like action of fenchone pretreated tracheal tissues were authenticated by the rightward shift of Ca2+ CRCs with suppression of maximum response, similar to verapamil, a standard Ca2+ channel blocker. Fenchone showed a spasmolytic effect in isolated trachea mediated predominantly by K+ channel activation followed by dual inhibition of PDE and Ca2+ channels. Further in silico molecular docking studies provided the insight for binding of fenchone with Ca2+ channel (-5.3 kcal/mol) and K+ channel (-5.7), which also endorsed the idea of dual inhibition.
Asunto(s)
Canfanos/química , Canfanos/farmacología , Norbornanos/química , Norbornanos/farmacología , Parasimpatolíticos/química , Parasimpatolíticos/farmacología , Tráquea/efectos de los fármacos , Animales , Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/farmacología , Fenómenos Químicos , Relación Dosis-Respuesta a Droga , Cobayas , Técnicas In Vitro , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Estructura Molecular , Inhibidores de Fosfodiesterasa/química , Inhibidores de Fosfodiesterasa/farmacología , Canales de Potasio/agonistas , Canales de Potasio/química , Relación Estructura-ActividadRESUMEN
A series of novel cannabinoid-type derivatives were synthesized by the coupling of (1S,4R)-(+) and (1R,4S)-(-)-fenchones with various resorcinols/phenols. The fenchone-resorcinol derivatives were fluorinated using Selectfluor and demethylated using sodium ethanethiolate in dimethylformamide (DMF). The absolute configurations of four compounds were determined by X-ray single crystal diffraction. The fenchone-resorcinol analogs possessed high affinity and selectivity for the CB2 cannabinoid receptor. One of the analogues synthesized, 2-(2',6'-dimethoxy-4'-(2â³-methyloctan-2â³-yl)phenyl)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-ol (1d), had a high affinity (Ki = 3.51 nM) and selectivity for the human CB2 receptor (hCB2). In the [35S]GTPγS binding assay, our lead compound was found to be a highly potent and efficacious hCB2 receptor agonist (EC50 = 2.59 nM, E(max) = 89.6%). Two of the fenchone derivatives were found to possess anti-inflammatory and analgesic properties. Molecular-modeling studies elucidated the binding interactions of 1d within the CB2 binding site.
Asunto(s)
Canfanos/química , Canfanos/farmacología , Agonistas de Receptores de Cannabinoides/química , Agonistas de Receptores de Cannabinoides/farmacología , Diseño de Fármacos , Norbornanos/química , Norbornanos/farmacología , Receptor Cannabinoide CB2/química , Canfanos/síntesis química , Agonistas de Receptores de Cannabinoides/síntesis química , Técnicas de Química Sintética , Relación Dosis-Respuesta a Droga , Humanos , Ligandos , Modelos Moleculares , Estructura Molecular , Norbornanos/síntesis química , Unión Proteica , Receptor Cannabinoide CB2/agonistas , Análisis Espectral , Relación Estructura-ActividadRESUMEN
OBJECTIVES: Natural borneol and synthetic borneol were commonly used to treat ischaemic stroke in clinical practice. This study evaluated their different neuroprotective effects on the remodelling and repair of the neurovascular unit (NVU) after cerebral ischaemia. METHODS: We evaluated the different effects of borneol through neurological test and staining methods in cerebral ischaemia injury. Western blot, immunohistochemistry and transmission electron microscopy were used to evaluate the reparative effects of borneol on NVU. KEY FINDINGS: The prevention and treatment of borneol could prolong recovery time, reduce body temperature and cerebral infarction rate and improve pathological conditions. Further investigations revealed that borneol could inhibit the expression of DII4, Hes1, Hes5 and p65 and increase the Nissl body number and microvessel density. They also inhibited the activation of the microglia. It was also observed through an ultramicroelectron microscope that the structural stability of the NVU has also been repaired. Moreover, natural borneol shows better results in most indicators when compared with synthetic borneol. CONCLUSIONS: Natural borneol showed a stronger effectiveness and had better regulation and neuroprotection on the NVU when compared with synthetic borneol, indicating that it may be better to use natural borneol in the prescription of Chinese patent medicine in clinical practice.
Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Canfanos/farmacología , Fármacos Neuroprotectores/farmacología , Animales , Temperatura Corporal/efectos de los fármacos , Isquemia Encefálica/patología , Canfanos/química , Modelos Animales de Enfermedad , Masculino , Microglía/efectos de los fármacos , Microscopía Electrónica de Transmisión , Fármacos Neuroprotectores/química , Ratas , Ratas Sprague-DawleyRESUMEN
Microorganisms use a complex array of chemical compounds to interact with their surroundings. They produce and process different molecules in response to changes in the environment or in their metabolism. One of the most well-known volatile organic compounds produced by microorganisms is the C11-terpenoid 2-methylisoborneol (2-MIB), which has received attention because of the off-flavor it confers to fresh and reservoir water as well as to cultured fish. Cleaning water supplies of the off-flavor 2-MIB has been of interest for the scientific community for years, with the use of techniques that are either expensive, e. g., activated carbon, or create toxic byproducts, e. g., ozonation. In the present study, soil samples from nature were collected from a forest and the volatile organic compounds produced by microbes were extracted and analyzed with focus on non-canonical terpenoid structures. HS-SPME-GC/MS analysis of soil samples revealed 1-methylcamphene (1-MC), 2-methylenebornane (2-MB) and 2-MIB as C11-terpenoids. Due to the high 1-MC/2-MIB ratio compared to previous reports, it was hypothesized that microbial degradation of 2-MIB was in place. Addition of synthetic 2-MIB to biologically active soil revealed complete degradation of the pollutant to 2-MB, 1-MC and 2-methyl-2-bornene (2-M2B). The results suggest the potential of using respective natural microorganisms for biodegradation of 2-MIB, with applications in water treatment, fishery and soil ecology.
Asunto(s)
Naftoles , Suelo , Animales , Canfanos/química , BosquesAsunto(s)
Acrilatos/efectos adversos , Automonitorización de la Glucosa Sanguínea/instrumentación , Canfanos/efectos adversos , Reacciones Cruzadas , Dermatitis Alérgica por Contacto/inmunología , Lactonas/efectos adversos , Sesquiterpenos/efectos adversos , Acrilatos/química , Canfanos/química , Dermatitis Alérgica por Contacto/diagnóstico , Dermatitis Alérgica por Contacto/etiología , Diabetes Mellitus Tipo 1/sangre , Humanos , Lactonas/química , Masculino , Estructura Molecular , Pruebas del Parche , Sesquiterpenos/química , Adulto JovenRESUMEN
Cinnamomum camphora chvar. Borneol essential oil (BEO, 18.2% v/v borneol) is a by-product of steam distillation to produce natural crystalline borneol (NCB, 98.4% v/v borneol). Given the known medicinal properties of borneol, the analgesic function and safety were studied. Horn's method and the Draize test revealed a gender difference in mice regarding acute oral LD50, i.e., low-toxicity to female mice (2749 mg/kg), but practically nontoxic to male mice (5081 mg/kg). There was no acute and skin or eye irritation when BEO was applied directly, if the BEO concentration was less than 50%. The analgesic effect of BEO was evaluated by the glacial acetic acid-induced writhing pain model. Continuous topical application of BEO to the abdomen of mice for 6 d, significantly reduced observed writhing in mice (p < 0.001) with a strong dose-response relationship (r = -0.9006). Concomitantly, the levels of the serum pain-related mediators, prostaglandin E2 (PGE2) and transient receptor potential melastatin-8 (TRPM8) were significantly reduced (p < 0.001), and the latter showed a strong dose-response relationship (r = -0.9427). Therefore, BEO had similar analgesic functions to borneol and was demonstrated to be safe for medicinal use.
Asunto(s)
Analgésicos/farmacología , Canfanos/farmacología , Cinnamomum camphora/química , Aceites Volátiles/farmacología , Administración Tópica , Analgésicos/efectos adversos , Analgésicos/química , Animales , Canfanos/química , Evaluación de Medicamentos , Femenino , Masculino , Ratones , Ratones Endogámicos ICR , Aceites Volátiles/químicaRESUMEN
Combinations of phytochemical(s) and engineered nanoparticles have attracted immense research interest due to their superior antimicrobial effects against contaminations. Herein, a Pickering emulsion is developed with capsulized phytochemicals including borneol and citral (BC-Cap) stabilized by hydrophilic amine-functionalized silica nanoparticles (SiO2 âNH2 NPs). The droplet sizes of Pickering emulsion were 5.2 ± 1.4 µm under the condition that the concentrations of SiO2 âNH2 NPs ranged from 0.6 to 1.2 wt.%, and the emulsion showed desirable stability during storage at 40°C for 365 days. In addition, the antibacterial and antibiofilm activities of the Pickering emulsion were investigated. The antibacterial effect of BC-Cap increased by two- to fourfold compared with citral or borneol alone. Treatment of BC/BC-Cap for 4 h eliminated the formation of biofilms generated by Listeria monocytogenes (at 5/1.25 mg/ml; 2 × MIC concentration) and Pseudomonas aeruginosa (at 5/2.5 mg/ml; 2 × MIC concentration). Further mechanistic studies revealed that the antibiofilm effects of BC-Cap were attributed to its ability to increase the porosity and lytic effects on the cell membrane of bacteria. Findings from the current study support the antibacterial and antibiofilm effects of BC-Cap Pickering emulsion as a promising food additive. PRACTICAL APPLICATION: The Pickering emulsion has potential applications as bacteriostatic agent in packaging materials and general surface disinfectant. The combination of borneol and citral is stabilized by hydrophilic amine-functionalized silica nanoparticles (SiO2 âNH2 NPs). With the synergistic effects of borneol and citral, the Pickering emulsion shows a promising elimination effect against the formation of biofilms produced by Listeria monocytogenes and Pseudomonas aeruginosa.
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Monoterpenos Acíclicos , Antibacterianos , Canfanos , Nanopartículas , Monoterpenos Acíclicos/química , Antibacterianos/farmacología , Canfanos/química , Emulsiones/química , Listeria monocytogenes/efectos de los fármacos , Nanopartículas/química , Tamaño de la Partícula , Pseudomonas aeruginosa/efectos de los fármacos , Dióxido de SilicioRESUMEN
The modern trend of research is highly focused on finding new bioactive molecules from medicinal plants. As a functional bicyclic monoterpene, Bornyl acetate (BA) has displayed antioxidant and anti-inflammatory properties in different types of cells and tissues. The purpose of this research was to evaluate the probable hypotensive effect of BA, an underlying mechanism(s) backboned by in-silico studies. Mean arterial pressure and heart rate were recorded via invasive blood pressure measuring technique in normotensive Sprague-Dawley rats following the administration of BA (1-80mg/kg). Docking studies were carried out with various targets involved in the pathophysiology of hypertension.RO5 and ADMET properties were also evaluated. In the current study dose-dependent reduction in systolic, diastolic and mean arterial pressure was observed. Pretreatment with atropine and captopril significantly (p<0.001) reduced the hypotensive effect produced by BA. On the other hand docking studies showed pronounced interactions with M2 mAch receptor in an agonistic way and ACE protein in an antagonistic way. BA justified all cut-off limits of RO5 and had an acceptable predicted computational toxicity profile. Results postulate that dose-dependent hypotensive effect of BA is mediated through the muscarinic pathway and ACE inhibitory activity corresponding well with findings of in-silico studies.
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Antihipertensivos/farmacología , Canfanos/farmacología , Monoterpenos/farmacología , Animales , Antihipertensivos/química , Presión Sanguínea/efectos de los fármacos , Canfanos/química , Simulación por Computador , Frecuencia Cardíaca/efectos de los fármacos , Simulación del Acoplamiento Molecular , Estructura Molecular , Monoterpenos/química , Ratas , Ratas Sprague-DawleyRESUMEN
Targeted treatment of cerebral ischemia/reperfusion injury (CIRI) remains a problem due to the difficulty in drug delivery across the blood-brain barrier (BBB). In this study, we developed Bo-TSA-NP, a novel tanshinone IIA (TSA) loaded nanoparticles modified by borneol, which has long been proved with the ability to enhance other drugs' transport across the BBB. The Bo-TSA-NP, with a particle size of about 160 nm, drug loading of 3.6%, showed sustained release and P-glycoprotein (P-gp) inhibition property. It demonstrated a significantly higher uptake by 16HBE cells in vitro through the clathrin/caveolae-mediated endocytosis and micropinocytosis. Following intranasal (IN) administration, Bo-TSA-NP significantly improved the preventive effect on a rat model of CIRI with improved neurological scores, decreased cerebral infarction areas and a reduced content of malondialdehyde (MDA) and increased activity of superoxide dismutase (SOD) in rat brain. In conclusion, these results indicate that Bo-TSA-NP is a promising nose-to-brain delivery system that can enhance the prevention effect of TSA on CIRI.
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Abietanos/farmacología , Isquemia Encefálica/tratamiento farmacológico , Canfanos/química , Nanopartículas/química , Fármacos Neuroprotectores/farmacología , Daño por Reperfusión/prevención & control , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Adyuvantes Farmacéuticos , Administración Intranasal , Animales , Encéfalo/efectos de los fármacos , Química Farmacéutica , Preparaciones de Acción Retardada , Modelos Animales de Enfermedad , Portadores de Fármacos , Malondialdehído/antagonistas & inhibidores , Tamaño de la Partícula , Polietilenglicoles/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Ratas , Succinimidas/química , Superóxido Dismutasa/biosíntesisRESUMEN
A series of (-)-borneol derivatives containing 2-aryl-thiazole scaffold were designed, synthesized, and characterized by 1H NMR, 13C NMR, and HRMS. The fungicidal activities of these novel compounds against Fusarium oxysporum, Magnaporthe grisea, Botrytis cinerea, and Penicillium digitatum were evaluated. The results indicated that (1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl(Z)-4-oxo-4-(((2-phenylthiazol-4-yl)methyl)amino)but-2-enoate (6a) displayed potential fungicidal activities with broad spectrum. Especially, 6a exhibited an IC50 value of 48.5 mg/L against P. digitatum, which has higher fungicidal activity than commercial products hymexazol and amicarthiazol. Moreover, (1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl-4-oxo-4-(((2-phenylthiazol-4-yl)methyl)amino)butanoate (5a) possesses an IC50 value of 24.3 mg/L against B. cinerea, comparable to hymexazol and far superior to amicarthiazol. Furthermore, the superficial structure-activity relationship was discussed, which might be helpful for discovering novel fungicides.
Asunto(s)
Antifúngicos/farmacología , Canfanos/farmacología , Diseño de Fármacos , Fungicidas Industriales/farmacología , Penicillium/efectos de los fármacos , Tiazoles/farmacología , Antifúngicos/síntesis química , Antifúngicos/química , Canfanos/síntesis química , Canfanos/química , Relación Dosis-Respuesta a Droga , Fungicidas Industriales/síntesis química , Fungicidas Industriales/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-Actividad , Tiazoles/químicaRESUMEN
The development and application of natural antibacterial materials have always been the focus of biomedical research. Borneol as a natural antibacterial compound has received extensive attention. However, the hydrophobicity caused by its unique structure limits its application range to a certain extent. In this study, we combine zwitterionic 2-methacryloyloxyethyl phosphorylcholine (MPC) with a complex bicyclic monoterpene structure borneol compound and prepare an excellent antifouling and antibacterial surface via the Schiff-base bond. The prepared coating has excellent hydrophilicity verified by the contact angle (CA), and its polymer layer is confirmed by X-ray photoelectron spectroscopy (XPS). The zwitterion MPC and borneol moieties in the copolymer play a coordinating role, relying on super hydration and the special stereochemical structure to prevent protein adsorption and inhibit bacterial adhesion, respectively, which are demonstrated by bovine serum albumin (BSA) adsorption and antibacterial activity test. Moreover, the water-soluble borneol derivative as the antibacterial surfaces we designed here was biocompatible toward MRC-5 (lung fibroblasts), as showed by in vitro cytotoxicity assays. Such results indicate the potential application of the as-prepared hydrophilic surfaces in the biomedical materials.
Asunto(s)
Antibacterianos/farmacología , Incrustaciones Biológicas/prevención & control , Canfanos/farmacología , Materiales Biocompatibles Revestidos/farmacología , Metacrilatos/farmacología , Fosforilcolina/análogos & derivados , Polímeros/farmacología , Adsorción , Antibacterianos/síntesis química , Antibacterianos/química , Canfanos/química , Supervivencia Celular/efectos de los fármacos , Materiales Biocompatibles Revestidos/síntesis química , Materiales Biocompatibles Revestidos/química , Escherichia coli/efectos de los fármacos , Humanos , Metacrilatos/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Tamaño de la Partícula , Fosforilcolina/química , Fosforilcolina/farmacología , Polímeros/síntesis química , Polímeros/química , Bases de Schiff/síntesis química , Bases de Schiff/química , Bases de Schiff/farmacología , Albúmina Sérica Bovina/química , Staphylococcus aureus/efectos de los fármacos , Propiedades de SuperficieRESUMEN
Although the World Health Organisation had announced that smallpox was eradicated over 40 years ago, the disease and other related pathogenic poxviruses such as monkeypox remain potential bioterrorist weapons and could also re-emerge as natural infections. We have previously reported (+)-camphor and (-)-borneol derivatives with an antiviral activity against the vaccinia virus. This virus is similar to the variola virus (VARV), the causative agent of smallpox, but can be studied at BSL-2 facilities. In the present study, we evaluated the antiviral activity of the most potent compounds against VARV, cowpox virus, and ectromelia virus (ECTV). Among the compounds tested, 4-bromo-N'-((1R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)benzohydrazide 18 is the most effective compound against various orthopoxviruses, including VARV, with an EC50 value of 13.9 µM and a selectivity index of 206. Also, (+)-camphor thiosemicarbazone 9 was found to be active against VARV and ECTV.
Asunto(s)
Canfanos , Alcanfor , Isoindoles , Orthopoxvirus/efectos de los fármacos , Animales , Antivirales/síntesis química , Antivirales/química , Antivirales/farmacología , Canfanos/síntesis química , Canfanos/química , Canfanos/farmacología , Alcanfor/análogos & derivados , Alcanfor/química , Alcanfor/farmacología , Células Cultivadas , Humanos , Isoindoles/síntesis química , Isoindoles/química , Isoindoles/farmacología , Orthopoxvirus/clasificación , Orthopoxvirus/patogenicidad , Orthopoxvirus/fisiología , Infecciones por Poxviridae/tratamiento farmacológico , Infecciones por Poxviridae/virología , Tiosemicarbazonas/química , Tiosemicarbazonas/farmacologíaRESUMEN
Rotational microwave jet spectroscopy studies of the monoterpenol α-fenchol have so far failed to identify its second most stable torsional conformer, despite computational predictions that it is only very slightly higher in energy than the global minimum. Vibrational FTIR and Raman jet spectroscopy investigations reveal unusually complex OH and OD stretching spectra compared to other alcohols. Via modeling of the torsional states, observed spectral splittings are explained by delocalization of the hydroxy hydrogen atom through quantum tunneling between the two non-equivalent but accidentally near-degenerate conformers separated by a low and narrow barrier. The energy differences between the torsional states are determined to be only 16(1) and 7(1) cm-1hc for the protiated and deuterated alcohol, respectively, which further shrink to 9(1) and 3(1) cm-1hc upon OH or OD stretch excitation. Comparisons are made with the more strongly asymmetric monoterpenols borneol and isopinocampheol as well as with the symmetric, rapidly tunneling propargyl alcohol. In addition, the third-in contrast localized-torsional conformer and the most stable dimer are assigned for α-fenchol, as well as the two most stable dimers for propargyl alcohol.
Asunto(s)
Canfanos/química , Hidrógeno/química , Modelos Químicos , Modelos Moleculares , Norbornanos/química , AlgoritmosRESUMEN
Monoterpenes are non-polar secondary metabolites widely used by industry due to their excellent therapeutic, food-ingredient and cosmetic properties. However, their low solubility in water limits their use. In this sense, cyclodextrins (CDs) have been widely used to solve these technological challenges. Thus, this study aims to use (-)-borneol as a monoterpene model to prepare inclusion complexes between ß-CD and hydroxypropyl-ß-CD (HP-ß-CD) through different ways and characterize them in order to choose the best inclusion method to improve physicochemical properties of monoterpenes. To achieve this goal, the samples were prepared by physical mixture (PM), paste complex (PA) and freeze-drying complex (FD) and then, extensively characterized by thermal analysis, Fourier-transform infrared spectroscopy, scanning electron microscopy, size particle, X-ray diffraction and nuclear magnetic resonance. The physicochemical results showed that freeze-drying was more effective to form inclusion complexes between (-)-borneol with both CDs. This research highlights the importance of recognizing the best method to prepare inclusion complexes, including food additives as (-)-borneol, to achieve better results in food preparations.