RESUMEN

8-Prenylgenistein (8PG), a genistein derivative, is present in fermented soybeans (Glycine max), including cheonggukjang (CGJ), and exhibits osteoprotective, osteogenic, and antiadipogenic properties. However, the hepatoprotective effects of 8PG and its underlying molecular mechanisms remain largely unexplored. Here, we identified the high binding affinity of 8PG with AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1), which acts as a potent AMPK activator that counteracts hepatic steatosis. Notably, 8PG exhibited better pharmacokinetics with greater absorption and higher plasma binding than the positive controls for the target proteins. Moreover, 8PG exerted non-carcinogenic activity in rats and significantly increased AMPK phosphorylation. Compound C, an AMPK inhibitor, did not antagonize 8PG-activated AMPK in HepG2 cells. 8PG significantly attenuated palmitate-induced lipid accumulation and enhanced phosphorylated AMPK and its downstream target, acetyl-CoA carboxylase. Further, 8PG activated nuclear SIRT1 at the protein level, which promoted fatty acid oxidation in palmitate-treated HepG2 cells. Overall, 8PG acts as a potent AMPK activator, further attenuating hepatic steatosis via the SIRT1-mediated pathway and providing new avenues for dietary interventions to treat metabolic dysfunction-associated steatotic liver disease (MASLD).

Asunto(s)

Proteínas Quinasas Activadas por AMP , Isoflavonas , Sirtuina 1 , Sirtuina 1/metabolismo , Animales , Humanos , Proteínas Quinasas Activadas por AMP/metabolismo , Células Hep G2 , Ratas , Masculino , Isoflavonas/farmacología , Isoflavonas/uso terapéutico , Hígado Graso/tratamiento farmacológico , Hígado Graso/metabolismo , Transducción de Señal/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Fosforilación/efectos de los fármacos , Ratas Sprague-Dawley , Glycine max/química , Genisteína/farmacología

RESUMEN

The prevalence of obesity and related consequences, including insulin resistance and Alzheimer's-like neuropathology, has increased dramatically. Contributing to this prevalence is the shift in lifestyle preference away from wholesome foods and exercise to the Western-style diet and sedentarism. Despite advances in drug development, a healthy diet and regular exercise remain the most effective approaches to mitigating the unwanted sequelae of diet-induced obesity on brain health. In this study, we used the high-fat high-sugar (HFHS) mouse model of neurodegeneration to examine the effects of exercise training (HFHS+Ex), genistein treatment (HFHS+Gen), and combination treatment (HFHS+Ex+Gen) on proteins relating to neurodegeneration in the brain of male mice. After a period of 12 weeks, as expected, HFHS feeding increased body weight, adipose tissue weight, and systemic plasma inflammation (TNF-α) compared to lean mice fed a standard diet. HFHS feeding also increased protein expression of brain markers of insulin resistance (pGSK-3ß, p-IR), apoptosis (caspase 3), early neurofibrillary tangles (CP13), and amyloid-beta precursor (CT20). Compared to HFHS mice, Ex decreased body weight, plasma TNF-α, and expression of pGSK-3ß, caspase 3, CP13, amyloid-ß precursor (22c11), and ADAM10. Treatment with Gen was equally protective on these markers and decreased the expression of p-IR. Combination treatment with Ex and Gen afforded the greatest overall benefits, and this group exhibited the greatest reduction in body and adipose tissue weight and all brain markers, except for 22c11 and ADAM10, which were decreased compared to mice fed an HFHS diet. In addition, levels of 4G8, which detects protein levels of amyloid-ß, were decreased with combination treatment. Our results indicate that exercise training, genistein supplementation, or combination treatment provide varying degrees of neuroprotection from HFHS feeding-induced Alzheimer's pathology. Future perspectives could include evaluating moderate exercise regimens in combination with dietary supplementation with genistein in humans to determine whether the same benefits translate clinically.

Asunto(s)

Enfermedad de Alzheimer , Encéfalo , Dieta Alta en Grasa , Genisteína , Condicionamiento Físico Animal , Animales , Masculino , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/etiología , Genisteína/farmacología , Genisteína/uso terapéutico , Dieta Alta en Grasa/efectos adversos , Ratones , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/patología , Biomarcadores , Resistencia a la Insulina , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Peso Corporal/efectos de los fármacos , Azúcares de la Dieta/efectos adversos , Caspasa 3/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética

RESUMEN

The phytoestrogens daidzein and genistein are ubiquitous in human food. This study aimed to elucidate their anxiety-liked effects, their effects on the reproductive organs, and the molecular mechanism behind any anxiety-liked effects in intact adult male Wistar rats. These phytoestrogens are of interest due to their posited health benefits, particularly for female, but with some effect on males as well. This study comprised two experiments: (1) Male Wistar rats received either a vehicle, daidzein, or genistein (0.25, 0.50, or 1.00 mg/kg) by subcutaneously injection for four weeks. They were then tested for anxiety-liked behaviors. Then, the brain monoamines in anxiolytic rats were determined; (2) The modulation of gamma aminobutyric acid receptors by phytoestrogens was further analyzed by administration of diazepam to phytoestrogen-treated rats before behavioral tests. In the first experiment, the biological parameters measured, including body weight, daily food intake and reproductive organ weights were unaffected by either genistein or daidzein. However, anxiolytic-like effect was observed in the low-dose daidzein (0.25 mg/kg) group. Higher doses of daidzein or genistein of all doses had no effect. Further, the low-dose daidzein did not alter brain monoamine levels. In the second experiment, the anxiolytic-like behavior of daidzein-treated rats receiving diazepam did not differ from that of the rats treated with just diazepam or just daidzein. In conclusion, 4-week exposure to daidzein or genistein had no negative effects on the reproductive organs, body weight, food intake, anxiogenic-like behavior, or monoaminergic and diazepam-modulated GABAergic neurotransmissions of intact male rats. However, beneficial anxiolytic-like effects were apparent after low-dose treatment with daidzein.

Asunto(s)

Ansiolíticos , Ansiedad , Genisteína , Isoflavonas , Ratas Wistar , Animales , Masculino , Genisteína/farmacología , Genisteína/administración & dosificación , Ansiolíticos/farmacología , Ansiolíticos/administración & dosificación , Isoflavonas/farmacología , Isoflavonas/administración & dosificación , Ansiedad/tratamiento farmacológico , Ratas , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Relación Dosis-Respuesta a Droga , Fitoestrógenos/farmacología , Fitoestrógenos/administración & dosificación , Diazepam/farmacología , Ingestión de Alimentos/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Tamaño de los Órganos/efectos de los fármacos

RESUMEN

Cell surface receptors play a key role in intracellular signaling, and their overexpression and activation are among the drivers of multiple diseases. Selective inhibition of cell surface receptors is important for regulating intracellular signaling pathways and cell behavior. Here, we design engineered aptamers to selectively inhibit receptor function. In this strategy, the aptamer specifically recognizing the extracellular structural domain of the EGFR, was conjugated to an adamantane moiety through linking arms of various lengths in order to obtain better performances toward EGFR. These interactions inhibit EGFR dimerization, thereby impeding the activation of downstream signaling pathways. It is shown that the adamantane-modified aptamers exhibit superior inhibition of downstream effector proteins relative to the unmodified aptamers. The optimal inhibitory effect was observed with a linker arm of 40 T-base in length. Notably, the best-performing adamantane-modified aptamer specifically binds to A549 cells with a dissociation constant (22.6 ± 4.5 nM) that is approximately 4-fold lower than that of the parent EGFR aptamer (94.4 ± 21.9 nM). We further combine the use of the adamantane-modified aptamer with that of genistein, a natural isoflavone compound with EGFR tyrosine kinase inhibition activity, to enhance the inhibitory effect on EGFR and its downstream signaling employing a synergistic action. This study is expected to provide a versatile approach for the improvement of existing aptamers obtaining increased selective inhibition of cell surface receptors.

Asunto(s)

Aptámeros de Nucleótidos , Receptores ErbB , Humanos , Aptámeros de Nucleótidos/farmacología , Aptámeros de Nucleótidos/química , Receptores ErbB/metabolismo , Receptores ErbB/antagonistas & inhibidores , Adamantano/farmacología , Adamantano/análogos & derivados , Adamantano/química , Células A549 , Genisteína/farmacología , Genisteína/química , Unión Proteica , Transducción de Señal/efectos de los fármacos , Receptores de Superficie Celular/metabolismo , Receptores de Superficie Celular/antagonistas & inhibidores , Ingeniería de Proteínas/métodos

RESUMEN

Legume plants form symbiotic relationships with rhizobia, which allow plants to utilize atmospheric nitrogen as a nutrient. This symbiosis is initiated by secretion of specific signaling metabolites from the roots, which induce the expression of nod genes in rhizobia. These metabolites are called nod gene inducers (NGIs), and various flavonoids have been found to act as NGIs. However, NGIs of chickpea, the second major pulse crop, remain elusive. We conducted untargeted metabolome analysis of chickpea root exudates to explore metabolites with increased secretion under nitrogen deficiency. Principal component (PC) analysis showed a clear difference between nitrogen deficiency and control, with PC1 alone accounting for 37.5% of the variance. The intensity of two features with the highest PC1 loading values significantly increased under nitrogen deficiency; two prominent peaks were identified as O-methylated isoflavones, pratensein and biochanin A. RNA-seq analysis showed that they induce nodABC gene expression in the Mesorhizobium ciceri symbiont, suggesting that pratensein and biochanin A are chickpea NGIs. Pratensein applied concurrently with M. ciceri at sowing promoted chickpea nodulation. These results demonstrate that pratensein and biochanin A are chickpea NGIs, and pratensein can be useful for increasing nodulation efficiency in chickpea production.

Asunto(s)

Cicer , Isoflavonas , Mesorhizobium , Nodulación de la Raíz de la Planta , Simbiosis , Cicer/microbiología , Cicer/genética , Cicer/metabolismo , Isoflavonas/metabolismo , Isoflavonas/farmacología , Mesorhizobium/genética , Mesorhizobium/metabolismo , Mesorhizobium/fisiología , Nodulación de la Raíz de la Planta/genética , Nodulación de la Raíz de la Planta/efectos de los fármacos , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Raíces de Plantas/microbiología , Raíces de Plantas/metabolismo , Raíces de Plantas/química , Raíces de Plantas/genética , Metilación , Genisteína/metabolismo , Genisteína/farmacología

RESUMEN

INTRODUCTION: Exposure to high doses of ionizing radiation can result in hematopoietic acute radiation syndrome. Currently, there is no radiation medical countermeasure approved by the U.S. FDA which can be used before radiation exposure to protect exposed individuals. Here we aimed to evaluate the therapeutic potential of an aqueous suspension of synthetic genistein nanoparticles (BIO 300) as a radioprotectant in a pilot efficacy study using a nonhuman primate model of total body irradiation. MATERIALS AND METHODS: Eight rhesus macaques were divided into two groups; four received vehicle and four received BIO 300 Injectable Suspension 24 h before 5.8 Gy total-body irradiation. Survival, blood cell counts, blood chemistry, and clinical parameters were monitored over the 60 days of the study. Tissues were collected at necropsy 60 days post-irradiation or from animals that met unscheduled euthanasia criteria and subjected to histopathological analysis. Tissues analyzed included the duodenum, jejunum, ileum, sternum, lung, heart, liver, kidney, spleen, gut-associated lymphoid tissue, and urinary bladder. RESULTS: In this pilot study, all BIO 300 Injectable Suspension treated animals survived to day 60, while only 50% of the vehicle-treated animals survived. We found that BIO 300 Injectable Suspension did not mediate an improvement in blood cell counts (e.g., neutrophils, platelets, white blood cells). However, BIO 300 Injectable Suspension treated animals had a lower incidence of fever and febrile neutropenia, were able to better maintain their body weight post radiation exposure, and exhibited less anemia and faster recovery from anemia. Histopathological analysis revealed that BIO 300-treated animals had less irradiation-induced damage to the sternum and other tissues compared to vehicle controls. CONCLUSIONS: BIO 300's mechanism of action is complex and protection against irradiation is attainable without much improvement in the complete blood count (CBC) profile. BIO 300's mechanism for radioprotection involves multiple biological pathways and systems.

Asunto(s)

Síndrome de Radiación Aguda , Macaca mulatta , Protectores contra Radiación , Animales , Síndrome de Radiación Aguda/prevención & control , Síndrome de Radiación Aguda/tratamiento farmacológico , Proyectos Piloto , Protectores contra Radiación/uso terapéutico , Protectores contra Radiación/farmacología , Genisteína/farmacología , Genisteína/uso terapéutico , Masculino , Nanopartículas/uso terapéutico , Irradiación Corporal Total/métodos , Irradiación Corporal Total/efectos adversos , Femenino , Modelos Animales de Enfermedad

RESUMEN

Heavy metal contamination is an alarming concern on a global scale, as drinking tainted water significantly increases human susceptibility to heavy metals. In a realistic scenario, humans are often exposed to a combination of harmful chemicals rather than a single toxicant. Phloretin (PHL), biochanin-A (BCA), and coenzyme Q10 (CoQ10) are bioactive compounds owning plentiful pharmacological properties. Henceforth, the current research explored the putative energizing effects of selected nutraceuticals in combined chromium (Cr) and arsenic (As) intoxicated Swiss albino mice. Potassium dichromate (75 ppm) and sodium meta-arsenite (100 ppm) were given in the drinking water to induce hepatotoxicity, conjugated with PHL and BCA (50 mg/kg each), and CoQ10 (10 mg/kg) intraperitoneally for 2 weeks. After the statistical evaluation, it was observed that the hepato-somatic index, metal load, and antioxidant activity (lipid peroxidation and protein carbonyl content) increased along with the concomitant decrease in the antioxidants (catalase, glutathione-S-transferase, superoxide dismutase, reduced glutathione, and total thiol) in the Cr and As intoxicated mice. Additionally, light microscopy observations, DNA breakages, decreased silent information regulator 1 (SIRT1), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), heme oxygenase (HO-1), and NAD(P)H quinone dehydrogenase 1 (NQO1) gene expressions, together with stimulated apoptotic cell death manifested by the increased expressions of caspase 8 and caspase 3, thus, proved consistency with the aforementioned outcomes. Importantly, the treatment with nutraceuticals not only restored the antioxidant activity but also favorably altered the expressions of SIRT1, Nrf2, HO-1, and NQO1 signaling and apoptosis markers. These findings highlight the crucial role of the PHL, BCA, and CoQ10 combination in reducing Cr and As-induced hepatotoxicity in mice. By averting the triggered apoptosis in conjunction with oxidative stress, this combination increases the SIRT1, Nrf2, HO-1, and NQO1 signaling, thereby reassuringly maintaining the cellular equilibrium.

Asunto(s)

Apoptosis , Cromo , Genisteína , Hígado , NAD(P)H Deshidrogenasa (Quinona) , Factor 2 Relacionado con NF-E2 , Estrés Oxidativo , Floretina , Transducción de Señal , Sirtuina 1 , Ubiquinona , Animales , Sirtuina 1/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ubiquinona/análogos & derivados , Ubiquinona/farmacología , Ratones , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Genisteína/farmacología , Apoptosis/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Cromo/toxicidad , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Floretina/farmacología , Transducción de Señal/efectos de los fármacos , Masculino , Arsénico/toxicidad , Hemo Oxigenasa (Desciclizante)/metabolismo , Hemo-Oxigenasa 1/metabolismo , Proteínas de la Membrana

RESUMEN

Genistein (Gen); a naturally occurring isoflavone, acts as a tyrosine kinase inhibitor and efficiently downregulates inflammatory cytokines, which are pivotal in eye inflammation. Also, Gen suffers from sparse ocular bioavailability due to poor solubility. In this work, nanostructured lipid carriers (NLCs) were successfully fabricated by using solid (stearic acid and compritol) and liquid (oleic acid) lipids. The optimized Gen-loaded NLCs showed a nanosize range of 140-246 nm, ≥ 98 % entrapment efficiency, and controlled release over 48 h. The ζ-potential of NLCs was increased from -27.3 mV to 25-27.4 mV due to surface modification with chitosan (CS) or eudragit RS100 (ERS 100). All NLCs showed prominent biocompatibility with enhanced cellular uptake on corneal stromal fibroblasts. Moreover, the different NLCs were incorporated into a mucoadhesive in situ gel. The optimized in situ gel (G9), containing 20 % poloxamers and 0.5 % hydroxyethyl cellulose, exhibited excellent gelling ability within 10.5 s, gelling temperature at 33.1 ± 0.6 ℃, spreadability diameter of 4.73 ± 0.12 cm, shear-thinning behavior, and 20 min ex vivo mucoadhesion time with drug release for 120 h. The in vivo results showed distinguished permeation and distribution potential for ocular delivery. In vivo anti-inflammatory effects after 3 days of treatment with CS-Gen-NLCs/G9 and ERS-Gen-NLCs/G9 revealed a downregulation of interleukin-6 levels in the cornea and retina compared to the untreated group. Our research highlights the promising anti-inflammatory potential of ERS-Gen-NLCs/G9 as an efficient, non-irritant Gen nanodelivery system for managing anterior and posterior ocular inflammation.

Asunto(s)

Antiinflamatorios , Quitosano , Portadores de Fármacos , Liberación de Fármacos , Geles , Genisteína , Genisteína/administración & dosificación , Genisteína/farmacocinética , Genisteína/farmacología , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/farmacocinética , Antiinflamatorios/farmacología , Antiinflamatorios/química , Quitosano/química , Portadores de Fármacos/química , Conejos , Resinas Acrílicas/química , Lípidos/química , Nanoestructuras/administración & dosificación , Masculino , Córnea/metabolismo , Córnea/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Administración Oftálmica , Ácidos Esteáricos/química , Nanopartículas , Ácido Oléico/química , Preparaciones de Acción Retardada , Humanos

RESUMEN

The research study focused on the development and characterization of sustained release formulation of genistein (GEN)-loaded chitosan (CS) nanoparticles to deliver in the form of dry powder inhaler (DPI) via pulmonary route to offer higher stability and anti-diabetic activity. The GEN-loaded nanoparticles were prepared by cross-linking reaction of CS and sodium hexametaphosphate (SHMP). The optimized formulation displayed particle size (PS) of 684.2 ± 26.5 nm, zeta potential (ZP) of 19.6 ± 4.50 mV, % entrapment efficiency (% EE) of 87.33 ± 8.46 % and drug release profile of 85.48 ± 5.50 % for 48 h. The in-vivo studies exhibited a superior sustained release formulation of GEN in the regulation of blood glucose levels (BGLs). The powder showed the emitted fraction (EF) of 86.76 % and effective inhalation index (EI) of 85.41 %. The reduction of BGLs (85 %) was observed in the diabetic group. This might be due to the inhibition of proliferation of pancreatic ß-cells (growth factor inhibition targeting cAMP and ERK1/2 pathway), antioxidative activity, reducing insulin resistance, and the adipose tissue mass and alteration of the hepatic glucose metabolism. Hence, these results proved the delivery of GEN in the form of DPI system as a favorable route for treating type-1 diabetes mellitus with a longer duration of action.

Asunto(s)

Glucemia , Quitosano , Genisteína , Nanopartículas , Quitosano/química , Nanopartículas/química , Genisteína/farmacología , Genisteína/química , Animales , Glucemia/efectos de los fármacos , Ratas , Administración por Inhalación , Liberación de Fármacos , Tamaño de la Partícula , Masculino , Diabetes Mellitus Experimental/tratamiento farmacológico , Portadores de Fármacos/química , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Hipoglucemiantes/farmacología , Hipoglucemiantes/química

RESUMEN

OBJECTIVE: Blood-brain barrier is a protective layer that regulates the influx and efflux of biological materials for cerebral tissue. The aim of this study was to investigate the effects of Biochanin A on cerebral histopathology and blood-brain barrier immunohistochemically. METHODS: A total of 24 rats were assigned to three groups: sham, ischemia-reperfusion, and ischemia-reperfusion+Biochanin A. Ischemia-reperfusion was performed by occluding the left carotid artery for 2/24 h. Notably, 20 mg/kg Biochanin A was administered to rats for 7 days after ischemia-reperfusion. Blood was collected for malondialdehyde and total oxidant/antioxidant status analysis. Cerebral tissues were processed for histopathology and further for immunohistochemical analysis. RESULTS: Malondialdehyde content with total oxidant status value was significantly increased and total antioxidant status values were significantly decreased in the ischemia-reperfusion group compared with the sham group. Biochanin A treatment significantly improved scores in the ischemia-reperfusion+Biochanin A group. The normal histological appearance was recorded in the cerebral sections of the sham group. Degenerated neurons and vascular structures with disrupted integrity of the cerebral cortex were observed after ischemia-reperfusion. Biochanin A alleviated the histopathology in the cerebrum in the ischemia-reperfusion+Biochanin A group. Ischemia-reperfusion injury decreased the expression of blood-brain barrier in the ischemia-reperfusion group compared to the sham group. Administration of Biochanin A upregulated the blood-brain barrier immunoreactivity in the cerebrum by restoring blood-brain barrier. CONCLUSION: Cerebral ischemia-reperfusion caused an increase in oxidative stress and pathological lesions in the cerebrum. Biochanin A treatment restored the adverse effects of ischemia-reperfusion injury by restoring blood-brain barrier.

Asunto(s)

Barrera Hematoencefálica , Genisteína , Malondialdehído , Daño por Reperfusión , Animales , Genisteína/farmacología , Genisteína/uso terapéutico , Daño por Reperfusión/tratamiento farmacológico , Barrera Hematoencefálica/efectos de los fármacos , Masculino , Malondialdehído/análisis , Ratas , Isquemia Encefálica/tratamiento farmacológico , Ratas Wistar , Antioxidantes/farmacología , Inmunohistoquímica , Estrés Oxidativo/efectos de los fármacos , Modelos Animales de Enfermedad

RESUMEN

Skin melanoma is considered the most dangerous form of skin cancer due to its association with high risk of metastasis, high mortality rate and high resistance to different treatment options. Genistein is a natural isoflavonoid with known chemotherapeutic activity. Unfortunately, it has low bioavailability due to its poor aqueous solubility and excessive metabolism. In the current study, genistein was incorporated into transferosomal hydrogel to improve its bioavailability. The prepared transferosomal formulations were characterized regarding: particle size; polydispersity index; zeta potential; encapsulation efficiency; TEM; FTIR; DSC; XRD; in vitro drug release; viscosity; pH; ex vivo anti-tumor activity on 3D skin melanoma spheroids and 1-year stability study at different storage temperatures. The optimized formulation has high encapsulation efficiency with an excellent particle size that will facilitate its penetration through the skin. The transfersomes have a spherical shape with sustained drug release profile. The anti-tumor activity evaluation of genistein transfersome revealed that genistein is a potent chemotherapeutic agent with enhanced penetration ability through the melanoma spheroids when incorporated into transfersomes. Stability study results demonstrate the high physical and chemical stability of our formulations. All these outcomes provide evidence that our genistein transferosomal hydrogel is a promising treatment option for skin melanoma.

Asunto(s)

Liberación de Fármacos , Genisteína , Hidrogeles , Melanoma , Tamaño de la Partícula , Neoplasias Cutáneas , Genisteína/administración & dosificación , Genisteína/farmacología , Genisteína/farmacocinética , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Humanos , Hidrogeles/química , Sistemas de Liberación de Medicamentos/métodos , Línea Celular Tumoral , Estabilidad de Medicamentos , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Antineoplásicos/farmacocinética , Solubilidad , Portadores de Fármacos/química , Química Farmacéutica , Viscosidad , Disponibilidad Biológica , Administración Cutánea , Esferoides Celulares/efectos de los fármacos

RESUMEN

Given the hierarchical nature of bone and bone interfaces, osseointegration, namely the formation of a direct bone-implant contact, is best evaluated using a multiscale approach. However, a trade-off exists between field of view and spatial resolution, making it challenging to image large volumes with high resolution. In this study, we combine established electron microscopy techniques to probe bone-implant interfaces at the microscale and nanoscale with plasma focused ion beam-scanning electron microscopy (PFIB-SEM) tomography to evaluate osseointegration at the mesoscale. This characterization workflow is demonstrated for bone response to an additively manufactured Ti-6Al-4V implant which combines engineered porosity to facilitate bone ingrowth and surface functionalization via genistein, a phytoestrogen, to counteract bone loss in osteoporosis. SEM demonstrated new bone formation at the implant site, including in the internal implant pores. At the nanoscale, scanning transmission electron microscopy and energy-dispersive X-ray spectroscopy confirmed the gradual nature of the bone-implant interface. By leveraging mesoscale analysis with PFIB-SEM tomography that captures large volumes of bone-implant interface with nearly nanoscale resolution, the presence of mineral ellipsoids varying in size and orientation was revealed. In addition, a well-developed lacuno-canalicular network and mineralization fronts directed both towards the implant and away from it were highlighted.

Asunto(s)

Genisteína , Oseointegración , Titanio , Oseointegración/efectos de los fármacos , Genisteína/farmacología , Genisteína/química , Titanio/química , Animales , Materiales Biocompatibles Revestidos/química , Interfase Hueso-Implante , Microscopía Electrónica de Rastreo , Prótesis e Implantes , Porosidad , Aleaciones/química

RESUMEN

The activation and polarization of astrocytes are involved in neuroinflammation and brain functional rehabilitation after ischemic stroke. Our previous studies display the neuroprotective effect of genistein-3'-sodium sulfonate (GSS) in the acute phase of cerebral ischemia-reperfusion injury (CI/RI). This study aimed to investigate the brain function improvement of GSS during the recovery period after CI/RI in rats and to explore the potential mechanism from the perspective of astrocyte activation and polarization. The transient middle cerebral artery occlusion (tMCAO) rats were treated with GSS (1 mg/kg) continuously for 28 days. The behavior tests were measured to assess neurological function. The mRNA and protein expression in affected cerebral cortex were detected on day 29 after tMCAO. Our results demonstrated that GSS treatment significantly improved the spatial and temporal gait parameters in the Catwalk gait test, prolonged the time on the stick and increased the rotation speed in the rotarod test, and decreased the time to find the hidden platform and increased the time in the target quadrant in the Morris water maze test. In addition, GFAP, GBP2, C3, IL-1ß protein expressions and Nos2A mRNA level were decreased, while Nrf2, BDNF, IL-10 protein expressions and Sphk1 and Nef2l2 mRNA levels increased after GSS treatment. Interestingly, GSS presented a strong binding affinity to TLR4 and suppressed the activation of NF-κB signaling. In conclusion, GSS can promote brain function recovery by inhibiting astrocyte activation and polarization to A1 phenotype, and enhancing astrocyte polarization to A2 phenotype via inactivating TLR4/NF-κB signaling, which provide a candidate compound for clinical rehabilitation therapy in the recovery period after ischemic stroke.

Asunto(s)

Astrocitos , Genisteína , FN-kappa B , Ratas Sprague-Dawley , Transducción de Señal , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Transducción de Señal/efectos de los fármacos , FN-kappa B/metabolismo , Ratas , Masculino , Genisteína/farmacología , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/metabolismo , Fármacos Neuroprotectores/farmacología , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Receptor Toll-Like 4/metabolismo , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo

RESUMEN

The enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH), which acts as a negative regulator of prostaglandin E2 (PGE2) levels and activity, represents a promising pharmacological target for promoting liver regeneration. In this study, we collected data on 15-PGDH homologous family proteins, their inhibitors, and traditional Chinese medicine (TCM) compounds. Leveraging machine learning and molecular docking techniques, we constructed a prediction model for virtual screening of 15-PGDH inhibitors from TCM compound library and successfully screened genistein as a potential 15-PGDH inhibitor. Through further validation, it was discovered that genistein considerably enhances liver regeneration by inhibiting 15-PGDH, resulting in a significant increase in the PGE2 level. Genistein's effectiveness suggests its potential as a novel therapeutic agent for liver diseases, highlighting this study's contribution to expanding the clinical applications of TCM.

Asunto(s)

Inhibidores Enzimáticos , Hidroxiprostaglandina Deshidrogenasas , Regeneración Hepática , Medicina Tradicional China , Simulación del Acoplamiento Molecular , Hidroxiprostaglandina Deshidrogenasas/antagonistas & inhibidores , Hidroxiprostaglandina Deshidrogenasas/metabolismo , Animales , Regeneración Hepática/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Humanos , Dinoprostona/metabolismo , Simulación por Computador , Genisteína/farmacología , Genisteína/química , Masculino , Evaluación Preclínica de Medicamentos , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Ratones , Aprendizaje Automático

RESUMEN

Biochanin A, an isoflavone flavonoid with estrogenic activity, is naturally found in red clover and other legumes. It possesses a wide range of pharmacological properties, including antioxidant, anti-inflammatory, anti-apoptotic, neuroprotective, and anticancer effects. In recent years, a growing body of pre-clinical research has focused on exploring the therapeutic potential of biochanin A in various neurological disorders, such as Alzheimer's and Parkinson's disease, multiple sclerosis, epilepsy, ischemic brain injury, gliomas, and neurotoxicity. This comprehensive review aims to shed light on the underlying molecular mechanisms that contribute to the neuroprotective role of biochanin A based on previous pre-clinical studies. Furthermore, it provides a detailed overview of the protective effects of biochanin A in diverse neurological disorders. The review also addresses the limitations associated with biochanin A administration and discusses different approaches employed to overcome these challenges. Finally, it highlights the future opportunities for translating biochanin A from pre-clinical research to clinical studies while also considering its commercial viability as a dietary supplement or a potential treatment for various diseases.

Asunto(s)

Genisteína , Enfermedades del Sistema Nervioso , Fármacos Neuroprotectores , Genisteína/farmacología , Genisteína/química , Genisteína/uso terapéutico , Humanos , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Enfermedades del Sistema Nervioso/metabolismo , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Animales

RESUMEN

Genistein, a potent phytoconstituent, has garnered significant attention for its diverse bioactivities, making it a subject of extensive research and exploration. This review delves into the multifaceted properties of genistein, encompassing its antioxidant and anticancer potential. Its ability to modulate various cellular pathways and interact with diverse molecular targets has positioned it as a promising candidate in the prevention and treatment of various diseases. This review provides a comprehensive examination of Genistein, covering its chemical properties, methods of isolation, synthesis, therapeutic attributes with regard to cancer management, and the proposed mechanisms of action as put forth by researchers.

Asunto(s)

Antioxidantes , Genisteína , Genisteína/farmacología , Genisteína/química , Humanos , Antioxidantes/farmacología , Antioxidantes/química , Animales , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Neoplasias/tratamiento farmacológico , Fitoquímicos/farmacología , Fitoquímicos/química

RESUMEN

Throughout the past several centuries, herbal constituents have been the subject of scientific interest and the latest research into their therapeutic potential is underway. Genistein is a soy-derived isoflavone found in huge amounts in soy, along with the plants of the Fabaceae family. Scientific studies have demonstrated the beneficial effects of genistein on various health conditions. Genistein presents a broad range of pharmacological activities, including anticancer, neuroprotective, cardioprotective, antiulcer, anti-diabetic, wound healing, anti-bacterial, antiviral, skin, and radioprotective effects. However, the hydrophobic nature of genistein results in constrained absorption and restricts its therapeutic potential. In this review, the number of nanocarriers for genistein delivery has been explored, such as polymeric nanoparticles, nanostructured lipid carriers, solid lipid nanoparticles, liposomes, micelles, transferosomes, and nanoemulsions and nanofibers. These nano-formulations of genistein have been utilized as a potential strategy for various disorders, employing a variety of ex vivo, in vitro, and in vivo models and various administration routes. This review concluded that genistein is a potential therapeutic agent for treating various diseases, including cancer, neurodegenerative disorders, cardiovascular disorders, obesity, diabetes, ulcers, etc., when formulated in suitable nanocarriers.

Asunto(s)

Genisteína , Nanopartículas , Genisteína/farmacología , Genisteína/uso terapéutico , Genisteína/química , Humanos , Animales , Nanopartículas/química , Nanotecnología/métodos , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos/métodos , Neoplasias/tratamiento farmacológico

RESUMEN

Deep-sea environments, as relatively unexplored extremes within the Earth's biosphere, exhibit notable distinctions from terrestrial habitats. To thrive in these extreme conditions, deep-sea actinomycetes have evolved unique biochemical metabolisms and physiological capabilities to ensure their survival in this niche. In this study, five actinomycetes strains were isolated and identified from the Mariana Trench via the culture-dependent method and 16S rRNA sequencing approach. The antimicrobial activity of Microbacterium sp. B1075 was found to be the most potent, and therefore, it was selected as the target strain. Molecular networking analysis via the Global Natural Products Social Molecular Networking (GNPS) platform identified 25 flavonoid compounds as flavonoid secondary metabolites. Among these, genistein was purified and identified as a bioactive compound with significant antibacterial activity. The complete synthesis pathway for genistein was proposed within strain B1075 based on whole-genome sequencing data, with the key gene being CHS (encoding chalcone synthase). The expression of the gene CHS was significantly regulated by high hydrostatic pressure, with a consequent impact on the production of flavonoid compounds in strain B1075, revealing the relationship between actinomycetes' synthesis of flavonoid-like secondary metabolites and their adaptation to high-pressure environments at the molecular level. These results not only expand our understanding of deep-sea microorganisms but also hold promise for providing valuable insights into the development of novel pharmaceuticals in the field of biopharmaceuticals.

Asunto(s)

Antibacterianos , Genisteína , Genisteína/farmacología , Genisteína/metabolismo , Antibacterianos/farmacología , Antibacterianos/biosíntesis , Microbacterium , ARN Ribosómico 16S/genética , Actinobacteria/metabolismo , Actinobacteria/genética , Metabolismo Secundario , Filogenia , Aciltransferasas

Asunto(s)

Endotoxinas , Genisteína , Proteínas Tirosina Quinasas , Animales , Genisteína/farmacología , Ratas , Endotoxinas/toxicidad , Proteínas Tirosina Quinasas/metabolismo

RESUMEN

The aryl hydrocarbon receptor (AhR) is a transcription factor that regulates the immune system through complicated transcriptional programs. Genistein, an AhR ligand, exhibits anti-inflammatory properties. However, its role in modulating immune responses via the AhR signaling pathway remains unclear. In this study, 360 male Arbor Acre broilers (1-day-old) were fed a basal diet supplemented with 40 or 80 mg/kg genistein and infected with or without Clostridium perfringens (Cp). Our results demonstrated that genistein ameliorated Cp-induced intestinal damage, as reflected by the reduced intestinal lesion scores and improved intestinal morphology and feed-to-gain ratio. Moreover, genistein increased intestinal sIgA, TGF-ß, and IL-10, along with elevated serum IgG, IgA, and lysozyme levels. Genistein improved intestinal AhR and cytochrome P450 family 1 subfamily A member 1 (CYP1A1) protein levels and AhR+ cell numbers in Cp-challenged broilers. The increased number of AhR+CD163+ cells in the jejunum suggested a potential association between genistein-induced AhR activation and anti-inflammatory effects mediated through M2 macrophage polarization. In IL-4-treated RAW264.7 cells, genistein increased the levels of AhR, CYP1A1, CD163, and arginase (Arg)-1 proteins, as well as IL-10 mRNA levels. This increase was attenuated by the AhR antagonist CH223191. In summary, genistein activated the AhR signaling pathway in M2 macrophages, which enhanced the secretion of anti-inflammatory cytokines and attenuated intestinal damage in Cp-infected broilers Cp.

Asunto(s)

Pollos , Enteritis , Genisteína , Macrófagos , Receptores de Hidrocarburo de Aril , Animales , Receptores de Hidrocarburo de Aril/metabolismo , Genisteína/farmacología , Genisteína/uso terapéutico , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Enteritis/tratamiento farmacológico , Enteritis/metabolismo , Masculino , Células RAW 264.7 , Enfermedades de las Aves de Corral/tratamiento farmacológico , Enfermedades de las Aves de Corral/metabolismo , Intestinos/efectos de los fármacos , Intestinos/patología , Clostridium perfringens , Infecciones por Clostridium/tratamiento farmacológico , Necrosis , Activación de Macrófagos/efectos de los fármacos , Inflamación/tratamiento farmacológico , Inflamación/patología , Inflamación/metabolismo , Transducción de Señal/efectos de los fármacos