RESUMEN
The development of nontoxic antifouling coatings in static marine environments is urgent. Herein, the successful synthesis of sulfobetaine borneol fluorinated polymers (PEASBF) by a free radical polymerization method is reported. The PEASBF coatings exhibit outstanding antifouling activity, which effectively resists the adhesion of Bovine serum albumin (FITC-BSA adhesion rate: 0.5%), Pseudomonas sp. (Biofilm: 1.3 absorbance) and Navicula sp. (Diatom attachment rate: 33%). More importantly, the PEASBF coatings display outstanding fouling release properties, achieving a release rate of 98% for Navicula sp., and the absorbance of the Pseudomonas sp. biofilm is only 0.2 under 10 Pa shear stress. XPS and MD studies showed that the fluorinated/isobornyl groups induce more sulfobetaine groups to migrate toward polymer surfaces for intensify antifouling. Additionally, the chiral stereochemical structure of borneol enhances antifouling and fouling release ability of amphiphilic polymers. Therefore, the PEASBF has the potential for static marine antifouling applications.
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Incrustaciones Biológicas , Canfanos , Polímeros , Incrustaciones Biológicas/prevención & control , Canfanos/química , Canfanos/farmacología , Polímeros/química , Polímeros/farmacología , Biopelículas/efectos de los fármacos , Animales , Pseudomonas/efectos de los fármacos , Betaína/química , Betaína/análogos & derivados , Betaína/farmacología , Albúmina Sérica Bovina/química , Diatomeas/efectos de los fármacos , Diatomeas/química , Tensoactivos/química , Tensoactivos/farmacología , Tensoactivos/síntesis química , Halogenación , Propiedades de SuperficieRESUMEN
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.
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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
Transdermal drug delivery (TDD) has attracted widespread attention because of the advantage of its non-invasive nature, easy self-administration, and low side effects. The key to this pathway of drug delivery is how to overcome the barrier of the lipid matrix in the stratum corneum (SC). In this work, molecular dynamics (MD) were employed to investigate the adsorption of thyrotropin-releasing hormone (TRH) on the SC, and the effects of three different chemical permeation enhancers (ethanol (ETOH), carveol (CAV), and borneol (BOR)) on the SC were analyzed. The results showed that ETOH hardly altered the order of lipids in the SC, while CAV and BOR disrupted the morphology of the SC. The primary target of CAV was the CHOL in SC, which not only disrupted the ordered arrangement of CHOL, but also "extracted" CHOL from SC. The thickness distribution of SC became more inhomogeneous in the presence of CAV and BOR, which facilitated the penetration of drug molecules. Compared to no chemical permeation enhancers, the free energy of permeation in the presence of chemical permeation enhancers was less than 4-10â¯kcalâ¯mol-1, which suggested that chemical permeation enhancers were more favorable for the permeation of drugs from viewpoints of thermodynamics. All the results provided theoretical insights into the effect of chemical permeation enhancers on the transdermal permeation of drugs.
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Administración Cutánea , Sistemas de Liberación de Medicamentos , Absorción Cutánea , Adsorción , Absorción Cutánea/efectos de los fármacos , Simulación de Dinámica Molecular , Permeabilidad , Etanol/química , Canfanos/química , Canfanos/farmacología , Piel/metabolismo , Piel/efectos de los fármacosRESUMEN
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
BACKGROUND: Borneol, a highly lipid-soluble bicyclic terpene mainly extracted from plants, is representative of monoterpenoids. Modern medicine has established that borneol exhibits a range of pharmacological activities and used in the treatment of many diseases, particularly Cardio-cerebrovascular diseases (CVDs). The crucial role in enhancing drug delivery and improving bioavailability has attracted much attention. In addition, borneol is also widely utilized in food, daily chemicals, fragrances, and flavors industries. PURPOSE: This review systematically summarized the sources, pharmacological activities and mechanisms, clinical trial, pharmacokinetics, toxicity, and application of borneol. In addition, this review describes the pharmacological effects of borneol ester and the combination of borneol with nanomaterial. This review will provide a valuable resource for those pursuing researches on borneol inspiring the pharmacological applications in the medicine, food and daily chemical products, and developing of new drugs containing borneol or its derivatives. METHODS: This review searched the keywords ("borneol" or "bornyl esters") and ("pharmacology" or "Traditional Chinese medicine" or "Cardio-cerebrovascular diseases" or "blood-brain barrier" or "ischemic stroke" or "nanomaterials" or "neurodegenerative diseases" or "diabetes" or "toxicity") in Web of Science, PubMed, Google Scholar and China National Knowledge Infrastructure (CNKI) from January 1990 to May 2024. The search was limited to articles published in English and Chinese. RESULTS: Borneol exhibits extensive pharmacological activities including anti-inflammatory effects, analgesia, antioxidation, and has the property of crossing biological barriers and treating CVDs. The intrinsic molecular mechanisms are involved in multiple components, such as regulation of various key factors (including Tumor necrosis factor-α, Nuclear factor kappa-B, Interleukin-1ß, Malondialdehyde), inhibiting transporter protein function, regulating biochemical levels, and altering physical structural changes. In addition, this review describes the pharmacological effects of borneol ester and the combination of borneol with nanomaterial. CONCLUSION: The pharmacological properties and applications of borneol are promising, including anti-inflammatory, analgesic, antimicrobial, and antioxidant properties, as well as enhancing drug delivery and treating CVDs. However, its clinical application is hindered by the limited research on safety, efficacy, and pharmacokinetics. Therefore, this review systemically summarized the advances on pharmacological activities and mechanisms of the borneol. Standardized clinical trials and exploration of synergistic effects with other drugs were also are outlined.
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Canfanos , Canfanos/farmacología , Humanos , Animales , Antiinflamatorios/farmacologíaRESUMEN
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
OBJECTIVE: The long-term use of trastuzumab (TRZ), a therapeutic agent for human epidermal growth factor receptor 2 (HER2)+ breast cancer subtype (HER2+ BC), induces resistance. Borneol (BOR) exerts anticancer effects on various types of cancer. However, its anticancer effect on HER2+ BC remains unknown. This study aimed to determine the potential target genes of BOR and its effect on overcoming the resistance of HER2+ BC to TRZ. METHODS: The hub gene of BOR's potential target on HER2+ BC cells was determined via a bioinformatics approach. Resistant HCC1954 cells (HCC1954-TR) were obtained through repeated inducement of HCC1954 cancer cells with TRZ. The cells were then subjected to cytotoxic tests involving single compounds and their combinations. Then, the hub gene expression was determined using quantitative reverse-transcription polymerase chain reaction. The interaction between BOR and selected proteins was measured through molecular docking. RESULTS: Hub genes IL6, TNF, ESR1, IL1B, CYP19A1, AR, NR3C1, RELA, CYP17A1, and GPT were obtained via a bioinformatics approach. HCC1954-TR cells were successfully established. The TRZ-BOR combination treatment of parental HCC1954 (400 µg/mL and 25 µM) and HCC1954-TR (800 µg/mL and 100 µM) yielded considerably better results compared with BOR or TRZ alone. The expressions of AR, GPT, and ESR1 under the TRZ-BOR combination were notably different compared with those under single exposure. The molecular docking study of CYP19A1, CYP17A1, NR3C1, and IL-1ß highlighted the potential interaction between BOR and such proteins. CONCLUSION: BOR improved the cytotoxic effects of TRZ on HCC1954 and HCC1954-TR cell lines, where it specifically targets AR, ESR1, and GPT genes. In addition, the BOR effect, which counteracted the resistance of HCC1954-TR cells to TRZ, was mediated by genes CYP19A1, CYP17A1, NR3C1, IL-1, and RELA. However, additional research is required to validate their role in BOR activity to circumvent the resistance of HER2+ BC to TRZ.
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Neoplasias de la Mama , Canfanos , Biología Computacional , Resistencia a Antineoplásicos , Receptor ErbB-2 , Trastuzumab , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Trastuzumab/farmacología , Femenino , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Biología Computacional/métodos , Canfanos/farmacología , Simulación del Acoplamiento Molecular , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Antineoplásicos Inmunológicos/farmacología , Células Tumorales Cultivadas , Línea Celular TumoralRESUMEN
BACKGROUND: Meningeal lymphatic vessels (mLVs) have great potential to be the therapeutic target for ß Amyloid protein (Aß) clearing in Alzheimer's disease (AD), but the regulatory methods of the mLVs are limited. The lymphatic valve, marked by FOXC2, is the fundamental structure for maintaining stable lymphatic drainage function. Preliminary evidence suggested that borneol (BO) as the classical phytochemicals could enhance the expression of FOXC2 in the mLVs of healthy mice. PURPOSE: This study aims to explore the regulatory ability of BO on lymphatic valves of mLVs in the AD model mice. STUDY DESIGN: We used the intracerebroventricular injection of Aß42 oligomers to construct the AD-like symptoms model induced by toxic protein deposition. We administered BO nano micelles(BO-Ms) orally before and after to simulate the AD prevention and treatment strategy. METHODS: Herein, this study characterized the efficacy and pathways of BO-Ms for regulating mLVs in AD model by Rt-PCR, WB and confocal microscopy, and determined the effects of BO-Ms on Aß clearance, behavior and safety of AD mice. RESULTS: The AD modeling process severely impaired the expression of lymphatic valves. However, after oral administering BO-Ms for prevention and treatment, an increase in the lymphatic valves of the transverse sinus was observed, which derived from the up-regulation of the transcription factor (FOXC2 and Akt) and the down-regulation of the transcription inhibitors (FOXO1 and PRDM1). Furthermore, the effects of BO-Ms on the lymphatic valves could enhance the lymphatic drainage of the mLVs in AD-like mice, promoting the clearance of toxicity aggregates, protecting neurons, and alleviating AD-like symptoms. Simultaneously, continuous oral BO-Ms for 30 days didn't show any significant organ toxicity. The most important thing was that the preventive effect of BO administration was superior to therapeutic administration in all data. CONCLUSION: In summary, our research indicated that BO is a promoter of lymphatic valve formation in the mLVs, and could prevent or repair damage caused by toxic Aß42. BO was the only bioactive natural product with the ability to regulate mLVs valves. Thus, BO has the potential to become phytochemicals for alleviating AD symptoms by enhancing the drainage function of mLVs.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Canfanos , Modelos Animales de Enfermedad , Factores de Transcripción Forkhead , Animales , Péptidos beta-Amiloides/metabolismo , Enfermedad de Alzheimer/prevención & control , Enfermedad de Alzheimer/tratamiento farmacológico , Ratones , Canfanos/farmacología , Factores de Transcripción Forkhead/metabolismo , Masculino , Vasos Linfáticos/efectos de los fármacos , Meninges/efectos de los fármacos , Ratones Endogámicos C57BLRESUMEN
Considerable research efforts have been directed toward the symptom relief of Parkinson's disease (PD) by attenuating dopamine (DA) depletion. One common feature of these existing therapies is their unavailability of preventing the neurodegenerative process of dopaminergic neurons. (+)-Borneol, a natural highly lipid-soluble bicyclic monoterpene, has been reported to regulate the levels of monoamine neurotransmitters in the central nervous system and exhibit neuroprotective effects. However, the effect of (+)-borneol on the dopaminergic neuronal loss of methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice is not defined. Herein, we first report that 30 mg/kg (+)-borneol significantly attenuated the motor deficits of PD mice, which benefits from markedly increasing the level of DA and decreasing the metabolic rate of DA in the striatum of conscious and freely moving mouse detected by ultraperformance liquid chromatography tandem mass spectrometry online combined with in vivo brain microdialysis sampling. It is worth noting that the enhanced level of DA by (+)-borneol was enabled by the reduction in loss of tyrosine hydroxylase-immunoreactive dopaminergic neurons in the substantia nigra and striatum and promotion of reserpine- or nomifensine-induced DA release in PD mice. Interestingly, (+)-borneol evidently inhibited the decreased expression levels of DA transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) on the MPTP mouse model of PD. Moreover, (+)-borneol suppressed the neuroinflammation by inhibiting the production of IL-1ß, IL-6, and TNF-α and attenuated oxidative stress by decreasing the level of MDA and increasing the activities of SOD and GSH-px in PD mice. These findings demonstrate that (+)-borneol protects DA neurons by inhibiting neuroinflammation and oxidative stress. Further research work for the neuroprotection mechanism of (+)-borneol will focus on reactive oxygen species-mediated apoptosis. Therefore, (+)-borneol is a potential therapeutic candidate for retarding the neurodegenerative process of PD.
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Canfanos , Dopamina , Neuronas Dopaminérgicas , Ratones Endogámicos C57BL , Microdiálisis , Fármacos Neuroprotectores , Animales , Dopamina/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Masculino , Ratones , Fármacos Neuroprotectores/farmacología , Microdiálisis/métodos , Canfanos/farmacología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Estrés Oxidativo/efectos de los fármacos , Modelos Animales de Enfermedad , Encéfalo/efectos de los fármacos , Encéfalo/metabolismoRESUMEN
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
Background: Gliomas are characterized by high mortality rates and resistance. Even with conventional chemotherapy the prognosis of glioblastoma remains poor. Many medications are not optimally effective due to limited bioavailability. The bioavailability of medicine can be enhanced by borneol, a monoterpenoid substance. In this study, we investigated the effect of borneol, a commonly used Chinese medicine, on chemosensitivity in C6 glioma and U251 human glioma cell lines and elucidated its therapeutic molecular targets. Methods: The chemosensitivity-inducing effects of borneol in C6 and U251 cells were examined using CCK8 and clonal formation assays. The mechanism underlying the effect of borneol was evaluated through immunohistochemistry and western blotting assays. Further, the number of autophagosomes was determined via transmission electron microscopy. Finally, the chemical sensitization effect of borneol was evaluated in SD rats after C6 orthotopic tumor transplantation. Results: Borneol increased cytotoxicity in C6 and U251 cells in response to temozolomide (TMZ). In addition, through transmission electron microscopy, western blotting, and immunohistochemical tests, we found that borneol combined with TMZ significantly increased the level of autophagy and that hypoxia inducible factor-1(HIF-1α) is a candidate target through which borneol enhances the cytotoxic effect of TMZ. Borneol's ability to enhance HIF-1α degradation was counteracted following the administration of autophagy inhibitors. In vivo, borneol treatment was found to enhance the anticancer effect of TMZ and delay tumor progression, and this effect was closely related to its ability to promote the autophagic degradation of HIF-1α. Conclusions: HIF-1α might be a valid therapeutic target of borneol, which can be potentially applied as a chemosensitizing drug used for glioma treatment.
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Canfanos , Glioma , Humanos , Animales , Ratas , Ratas Sprague-Dawley , Canfanos/farmacología , Glioma/tratamiento farmacológico , Autofagia , Temozolomida/farmacologíaRESUMEN
Hypertension is the main risk factor of cardiovascular and cerebrovascular diseases. In this paper, a novel compound known as 221s (2,9), which includes tanshinol, borneol and a mother nucleus of ACEI, was synthesized by condensation esterification, deprotection, amidation, deprotection, and amidation, with borneol as the initial raw material, using the strategy of combinatorial molecular chemistry. The structure of the compound was confirmed by 1H NMR, 13C NMR, and high-resolution mass spectrometry, with a purity of more than 99.5%. The compound 221s (2,9) can significantly reduce the systolic and diastolic blood pressure of SHR rats by about 50 mmHg and 35 mmHg after 4 weeks of administration. The antihypertensive effect of 221s (2,9) is equivalent to that of captopril. The use of 221s (2,9) can reduce the content of Ren, Ang II and ACE in the serum of SHR rats, inhibit the RAAS and enhance the vascular endothelial function by upregulating the level of NO. Pathological studies in this area have shown that high dosage of 221s (2,9) can notably protect myocardial fibrosis in rats and reduce the degeneration and necrosis of myocardial fibers, inflammatory cell infiltration, and proliferation of fibrous tissue in the heart of rat. Therefore, the existing work provided a foundation for preclinical research and follow-up clinical research of 221s (2,9) as a new drug.
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Antihipertensivos , Hipertensión , Ratas , Animales , Antihipertensivos/uso terapéutico , Ratas Endogámicas SHR , Canfanos/farmacología , Presión Sanguínea , Miocitos CardíacosRESUMEN
Epilepsy is one common brain disorder, which is not well controlled by current pharmacotherapy. In this study we characterized the therapeutic potential of borneol, a plant-derived bicyclic monoterpene compound, in the treatment of epilepsy and elucidated the underlying mechanisms. The anti-seizure potency and properties of borneol were assessed in both acute and chronic mouse epilepsy models. Administration of (+)-borneol (10, 30, 100 mg/kg, i.p.) dose-dependently attenuated acute epileptic seizure in maximal-electroshock seizure (MES) and pentylenetetrazol (PTZ)-induced seizure models without obvious side-effect on motor function. Meanwhile, (+)-borneol administration retarded kindling-induced epileptogenesis and relieved fully kindled seizures. Importantly, (+)-borneol administration also showed therapeutic potential in kainic acid-induced chronic spontaneous seizure model, which was considered as a drug-resistant model. We compared the anti-seizure efficacy of 3 borneol enantiomers in the acute seizure models, and found (+)-borneol being the most satisfying one with long-term anti-seizure effect. In electrophysiological study conducted in mouse brain slices containing the subiculum region, we revealed that borneol enantiomers displayed different anti-seizure mechanisms, (+)-borneol (10 µM) markedly suppressed the high frequency burst firing of subicular neurons and decreased glutamatergic synaptic transmission. In vivo calcium fiber photometry analysis further verified that administration of (+)-borneol (100 mg/kg) inhibited the enhanced glutamatergic synaptic transmission in epilepsy mice. We conclude that (+)-borneol displays broad-spectrum anti-seizure potential in different experimental models via decreasing the glutamatergic synaptic transmission without obvious side-effect, suggesting (+)-borneol as a promising anti-seizure compound for pharmacotherapy in epilepsy.
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Epilepsia , Excitación Neurológica , Ratones , Animales , Anticonvulsivantes/farmacología , Anticonvulsivantes/uso terapéutico , Epilepsia/inducido químicamente , Epilepsia/tratamiento farmacológico , Canfanos/uso terapéutico , Canfanos/farmacología , Excitación Neurológica/fisiología , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológico , Modelos Animales de EnfermedadRESUMEN
Objectives Due to its high morbidity, high mortality, and high disability, stroke has been the first cause of death and the major cause of adult disability in China. Natural borneol has been widely utilized in Traditional Chinese Medicine to promote drug absorption. Formononetin is a natural isoflavonoid with potent neuroprotective activity but poor brain delivery. Methods This study aimed to screen the optimum proportion that natural borneol promotes formononetin entry into the brain, evaluate the anti-cerebral ischaemia efficacy of formononetin/natural borneol combination in middle cerebral artery occlusion/reperfusion model rats, and clarify the possible mechanism for natural borneol's promoting formononetin delivery in the brain. Key findings Our studies exhibited that natural borneol remarkably promoted formononetin entry into the brain when combined with formononetin in a 1 : 1 molar ratio and notably improved neuro-behavioural scores and reduced the infarct of middle cerebral artery occlusion/reperfusion model rats. This study further discovered that the enhanced anti-cerebral ischaemia effect resulted from natural borneol increasing the permeability of the blood-brain barrier to elevate formononetin concentration in the brain rather than the pharmacodynamic synergy or addition between formononetin and natural borneol. Conclusions The study provides a good strategy to screen drug combinations for the treatment of brain disease by combining natural borneol with other drugs.
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Isquemia Encefálica , Daño por Reperfusión , Animales , Ratas , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Canfanos/farmacología , Isquemia Encefálica/tratamiento farmacológico , Encéfalo , Daño por Reperfusión/tratamiento farmacológicoRESUMEN
BACKGROUND: The Asian tiger mosquito Aedes albopictus is a competent vector of several viral arboviruses including yellow fever, dengue fever, and chikungunya. Several vital mosquito behaviors (e.g., feeding, host-seeking, mating, and oviposition) are primarily dependent on the olfactory system for semiochemicals detection and discrimination. However, the limited number of studies hampers our understanding of the relationships between the Ae. albopictus olfactory system and the complex chemical world. METHODS: We performed RT-qPCR assay on antennae of Ae. albopictus mosquitoes of different sexes, ages and physiological states, and found odorant receptor 11 (AalbOr11) enriched in non-blood-fed female mosquitoes. Then, we examined the odorant preference with a panel of physiologically and behaviorally relevant odorants in Xenopus oocytes. RESULTS: The results indicated that AalbOr11 could be activated by ten aromatics, seven terpenes, six heterocyclics, and three alcohols. Furthermore, using post-RNA interference (RNAi) hand-in-cage assay, we found that reducing the transcript level of AalbOr11 affected the repellency activity mediated by (+)-fenchone at a lower concentration (0.01% v/v). CONCLUSIONS: Using in vitro functional characterization, we found that AalbOr11 was a broadly tuned receptor. Moreover, we found that AalbOr11 shared a conserved odorant reception profile with homologous Anopheles gambiae Or11. In addition, RNAi and bioassay suggested that AablOr11 might be one of the receptors mediating (+)-fenchone repellency activity. Our study attempted to link odor-induced behaviors to odorant reception and may lay the foundation for identifying active semiochemicals for monitoring or controlling mosquito populations.
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Aedes/fisiología , Mosquitos Vectores/fisiología , Receptores Odorantes/fisiología , Aedes/clasificación , Aedes/genética , Animales , Canfanos/farmacología , Femenino , Repelentes de Insectos/farmacología , Masculino , Mosquitos Vectores/clasificación , Mosquitos Vectores/genética , Norbornanos/farmacología , Interferencia de ARN/fisiología , Receptores Odorantes/genética , Transcripción GenéticaRESUMEN
Borneol is a bicyclic monoterpene that has long been used in traditional Chinese medicine to increase blood-brain barrier permeability and has shown promising cardiovascular effects. The present study aimed to evaluate the effect of borneol on vascular tone, blood pressure, autonomic function, and baroreflex sensitivity in normotensive and hypertensive rats. A combination of in vitro and in vivo assays was performed in 2-kidneys-1-clip hypertensive rats (2K1C) and their controls (sham). We assessed the in vivo effect of oral treatment with borneol on blood pressure, heart rate, autonomic function, and baroreflex sensitivity in sham and 2K1C rats. Additionally, the vasorelaxant effect of borneol in the superior mesenteric artery isolated from rats and its mechanism of action were evaluated. Oral administration of borneol (125 mg/kg/day) reduced blood pressure, sympathetic vasomotor hyperactivity, and serum oxidative stress and improved baroreflex sensitivity in 2K1C rats. In vessel preparations, borneol induced endothelium-independent vasodilatation after precontraction with phenylephrine or KCl (60 mM). There was no difference in the vascular effect induced by borneol in either the 2K1C or the sham group. In addition, borneol antagonized the contractions induced by CaCl2 and reversed (S)-(-)-Bay K 8644-induced contraction. These data suggest that borneol presents antihypertensive effects in 2K1C rats, which is associated with its ability to improve autonomic impairment and baroreflex dysfunction. The borneol-induced relaxation in the superior mesenteric artery involves L-type Ca2+ channel blockade. This vascular action associated with the antioxidant effect induced by borneol may be responsible, at least in part, for the in vivo effects induced by this monoterpene.
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Hipertensión Renovascular , Hipertensión , Animales , Barorreflejo , Presión Sanguínea/fisiología , Canfanos/farmacología , Canfanos/uso terapéutico , Femenino , Humanos , Hipertensión Renovascular/tratamiento farmacológico , Masculino , RatasRESUMEN
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.
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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.
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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
Efficient delivery of brain-targeted drugs is highly important for the success of therapies in neurodegenerative diseases. Borneol has several biological activities, such as anti-inflammatory and cell penetration enhancing effect, and can regulate processes in the neurovascular unit (NVU), such as protein toxic stress, autophagosome/lysosomal system, oxidative stress, programmed cell death and neuroinflammation. However, the influence of borneol on NVU in neurodegenerative diseases has not been fully explained. This study searched the keywords 'borneol', 'neurovascular unit', 'endothelial cell', 'astrocyte', 'neuron', 'blood-brain barrier', 'neurodegenerative diseases' and 'brain disease' in PubMed, BioMed Central, China National Knowledge Infrastructure (CNKI) and Bing search engines to explore the influence of borneol on NVU. In addition to the principle and mechanism of penetration of borneol in the brain, this study also showed its multiple regulation effects on NVU. Borneol was able to penetrate the blood-brain barrier (BBB), affecting the signal transmission between BBB and the microenvironment of the brain, downregulating the expression of inflammatory and oxidative stress proteins in NVU, especially in microglia and astrocytes. In summary, borneol is a potential drug delivery agent for drugs against neurodegenerative diseases.
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Canfanos/administración & dosificación , Sistemas de Liberación de Medicamentos , Enfermedades Neurodegenerativas/tratamiento farmacológico , Animales , Astrocitos/metabolismo , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Encéfalo/fisiopatología , Canfanos/farmacocinética , Canfanos/farmacología , Humanos , Microglía/metabolismo , Distribución TisularRESUMEN
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.