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Plant-derived extracellular vesicles (PDEV) constitute nanoscale entities comprising lipids, proteins, nucleic acids and various components enveloped by the lipid bilayers of plant cells. These vesicles play a crucial role in facilitating substance and information transfer not only between plant cells but also across different species. Owing to its safety, stability, and the abundance of raw materials, this substance has found extensive utilization in recent years within research endeavors aimed at treating various diseases. This article provides an overview of the pathways and biological characteristics of PDEV, along with the prevalent methods employed for its isolation, purification, and storage. Furthermore, we comprehensively outline the therapeutic implications of diverse sources of PDEV in musculoskeletal system disorders. Additionally, we explore the utilization of PDEV as platforms for engineering drug carriers, aiming to delve deeper into the significance and potential contributions of PDEV in the realm of the musculoskeletal system.
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Vesículas Extracelulares , Músculo Esquelético , Plantas , Animales , Humanos , Portadores de Fármacos/química , Vesículas Extracelulares/metabolismo , Músculo Esquelético/metabolismo , Plantas/metabolismoRESUMEN
Breviscapine (BRE) is usually used for long-term use in patients with cardiovascular diseases such as coronary heart disease, angina pectoris, and cerebral thrombosis. It is possible to combine it with P-glycoprotein (P-gp) substrates in clinic. At present, little is known about whether the simultaneous use of BRE affects the disposal of P-gp substrates. The aim of this study was to evaluate the effect of BRE on the pharmacokinetics of fexofenadine (FEX), a P-gp probe substrate and its associations with the MDR1 C3435T genetic polymorphism in healthy volunteers. In this randomised, open-label, placebo-controlled, two-phase crossover clinical study, drug interactions were evaluated in healthy volunteers. FEX was used as a phenotypic probe for P-gp. In each phase, 18 volunteers were given daily doses of 120 mg (40 mg, three times a day) of BRE tablet or a placebo for 14 days. On day 15, a single oral dose of 120 mg FEX hydrochloride was given orally. Blood samples were collected at predefined time intervals, and plasma levels of FEX were determined by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The pharmacokinetic parameters were calculated by non-compartmental method, and bioequivalence was evaluated. Results showed that BRE pretreatment did not significantly affect the pharmacokinetics of FEX. The peak maximum plasma concentration (C max) and the area under the plasma concentration-time curve from zero to infinity (AUCinf) mean value of FEX with BRE and placebo-treated groups were 699 ng/mL vs. 710 ng/mL and 2972.5 ngâ h/mL vs. 3460.5 ngâ h/mL, respectively. The geometric mean ratios (90% confidence intervals) for FEX C max and AUCinf were within the pre-specified range of 0.8-1.25, indicating that FEX in the two pretreatment phases were bioequivalent. Pharmacokinetic parameters of FEX showed no statistically significant difference between MDR1 C3435T CC, CT and TT genotype, revealing that BRE and MDR1 C3435T gene polymorphisms did not affect the pharmacokinetics of FEX in healthy volunteers.
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Flavonoides/farmacología , Polimorfismo Genético , Terfenadina/análogos & derivados , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Área Bajo la Curva , Estudios Cruzados , Voluntarios Sanos , Humanos , Espectrometría de Masas en Tándem , Terfenadina/farmacocinéticaRESUMEN
Random skin flap is widely used in plastic surgery. However, flap necrosis caused by ischemia-reperfusion injury limits its clinical applications. Apigenin, a naturally occurring flavonoid mainly derived from plants, facilitates flap survival. In this study, we explored the effects of apigenin on flap survival and the underlying mechanisms. A total of 54 mice having a dorsal random flap model were randomly divided into control, apigenin, and apigenin +3-methyladenine groups. These groups were treated with dimethyl sulfoxide solution, apigenin, and apigenin +3-methyladenine, respectively. The animals were then euthanized to assess angiogenesis, apoptosis, oxidative stress, and autophagy levels through histological and protein analyses. Apigenin promotes survival of the skin flap area and reduces tissue edema. In addition, apigenin enhanced angiogenesis, attenuated apoptosis, alleviated oxidative stress, and activated autophagy. Interestingly, 3-methyladenine reversed the effects of apigenin on flap survival, angiogenesis, apoptosis, and oxidative stress through inhibition of autophagy. The findings of this study show that apigenin promotes angiogenesis, inhibits cell apoptosis, and lowers oxidative stress by mediating autophagy, thus the improving survival rate of random skin flaps.
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Apigenina , Autofagia , Supervivencia de Injerto/efectos de los fármacos , Piel , Colgajos Quirúrgicos , Inductores de la Angiogénesis , Animales , Apigenina/farmacología , Apoptosis/efectos de los fármacos , Ratones , Estrés Oxidativo , Piel/metabolismoRESUMEN
OBJECTIVE: Sarcopenia, as a condition of muscle mass loss and functional decline typically diagnosed in elderly individuals, severely affects human physical activity, metabolic homeostasis, and quality of life. Gui Qi Zhuang Jin Decoction (GQZJD), an approved hospital-based prescription with years of clinical application, has been demonstrated to have a notable therapeutic effect on sarcopenia. However, its potential mechanism of action in the treatment of sarcopenia remains uncertain. METHODS: Ultra-performance liquid chromatography paired with Q Exactive™ HF-X mass spectrometry (UPLC-QE-MS) was used to identify the ingredients of GQZJD. Subsequently, GQZJD observed the basic growth and muscles of the sarcopenia mouse, while the behavioral indicators were also tested. Muscle histopathology and serum oxidative stress biochemicals were also detected, and mitochondrial function and energy metabolism-related indicators in the gastrocnemius muscle were examined. Then, a metabolomics strategy was applied to predict possible pathways involving mitochondria by which GQZJD could improve sarcopenia. Finally, quantitative real-time polymerase chain reaction and western blot analyses were carried out to validate the effects of GQZJD on sarcopenia-induced mitochondrial dysfunction, together with uncovering the associated mechanisms. RESULTS: Twenty-seven ingredients absorbed into the blood (IAIBs) of GQZJD were identified using UPLC-QE-MS, which were regarded as the main active ingredients behind its sarcopenia treatment effects. GQZJD administration increased the body weight, gastrocnemius muscle mass, and autonomic activity, mitigated muscle tissue morphology and pathology; and alleviated the oxidative stress levels in sarcopenia mice. Treatment with GQZJD also decreased the mitochondrial reactive oxygen species level and serum lipid peroxide Malonaldehyde concentration. and increased the mitochondrial membrane potential, adenosine triphosphate level, 8hydroxy-2-deoxyguanosine content, mitochondrial DNA copy number, and the mitochondrial fission factor dynamin-related protein 1. Non-targeted metabolomics suggested that the sarcopenia therapeutic effect of GQZJD on sarcopenia may occur through the glycerophospholipid metabolism, choline metabolism in cancer, phenylalanine metabolism and tyrosine metabolism pathways, implying an association with AMP-activated protein kinase (AMPK) and related signals. Further, the molecular docking results hinted that AMPK performed well in terms of binding energy with the 27 IAIBs of GQZJD (average binding energy, -7.5 kcal/mol). Finally, we determined that GQZJD significantly activated the key targets of the AMPK/peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α)/nuclear factor erythroid 2-related factor 2 (Nrf2) axis.. CONCLUSIONS: Our results demonstrated that GQZJD ameliorated d-galactose-induced sarcopenia by promoting the animal behaviours, facilitating mitochondrial function and restoring mitochondrial energy metabolism. with its effects mediated by the AMPK/PGC-1α/Nrf2 axis. Over all, GQZJD represents a promising therapeutic candidate that ameliorated sarcopenia in aging mice.
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Background: Osteoarthritis (OA) is a degenerative joint disease characterized by the breakdown of joint cartilage and underlying bone. Macrophages are a type of white blood cell that plays a critical role in the immune system and can be found in various tissues, including joints. Research on the relationship between OA and macrophages is essential to understand the mechanisms underlying the development and progression of OA. Objective: This study was performed to analyze the functions of the IRF1-GCN5-SETD2-SMARCC1 axis in osteoarthritis (OA) development. Methods: A single-cell RNA sequencing (scRNA-seq) dataset, was subjected to a comprehensive analysis aiming to identify potential regulators implicated in the progression of osteoarthritis (OA). In order to investigate the role of IRF1 and SMARCC1, knockdown experiments were conducted in both OA-induced rats and interleukin (IL)-1ß-stimulated chondrocytes, followed by the assessment of OA-like symptoms, secretion of inflammatory cytokines, and polarization of macrophages. Furthermore, the study delved into the identification of aberrant epigenetic modifications and functional enzymes responsible for the regulation of SMARCC1 by IRF1. To evaluate the clinical significance of the factors under scrutiny, a cohort comprising 13 patients diagnosed with OA and 7 fracture patients without OA was included in the analysis. Results: IRF1 was found to exert regulatory control over the expression of SMARCC1, thus playing a significant role in the development of osteoarthritis (OA). The knockdown of either IRF1 or SMARCC1 disrupted the pro-inflammatory effects induced by IL-1ß in chondrocytes, leading to a mitigation of OA-like symptoms, including inflammatory infiltration, cartilage degradation, and tissue injury, in rat models. Additionally, this intervention resulted in a reduction in the predominance of M1 macrophages both in vitro and in vivo. Significant epigenetic modifications, such as abundant H3K27ac and H3K4me3 marks, were observed near the SMARCC1 promoter and 10 kb upstream region. These modifications were attributed to the recruitment of GCN5 and SETD2, which are functional enzymes responsible for these modifications. Remarkably, the overexpression of either GCN5 or SETD2 restored SMARCC1 expression in rat cartilages or chondrocytes, consequently exacerbating the OA-like symptoms. Conclusion: This research postulates that the transcriptional activity of SMARCC1 can be influenced by IRF1 through the recruitment of GCN5 and SETD2, consequently regulating the H3K27ac and H3K4me3 modifications in close proximity to the SMARCC1 promoter and 10 kb upstream region. These modifications, in turn, facilitate the M1 skewing of macrophages and contribute to the progression of osteoarthritis (OA). The Translational Potential of this Article: The study demonstrated that the regulation of SMARCC1 by IRF1 plays a crucial role in the development of OA. Knocking down either IRF1 or SMARCC1 disrupted the pro-inflammatory effects induced by IL-1ß in chondrocytes, leading to a mitigation of OA-like symptoms in rat models. These symptoms included inflammatory infiltration, cartilage degradation, and tissue injury. These findings suggest that targeting the IRF1-SMARCC1 regulatory axis, as well as the associated epigenetic modifications, could potentially be a novel approach in the development of OA therapies, offering new opportunities for disease management and improved patient outcomes.
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The degeneration of intervertebral discs is strongly associated with the occurrence of pyroptosis in nucleus pulposus (NP) cells. This pyroptosis is characterized by abnormal metabolism of fatty acids in the degenerative pathological state, which is further exacerbated by the inflammatory microenvironment and degradation of the extracellular matrix. In order to address this issue, we have developed a fibrin hydrogel complex (FG@PEV). This intricate formulation amalgamates the beneficial attributes of platelet extravasation vesicles, contributing to tissue repair and regeneration. Furthermore, this complex showcases exceptional stability, gradual-release capabilities, and a high degree of biocompatibility. In order to substantiate the biological significance of FG@PEV in intervertebral disc degeneration (IVDD), we conducted a comprehensive investigation into its potential mechanism of action through the integration of RNA-seq sequencing and metabolomics analysis. Furthermore, these findings were subsequently validated through experimentation in both in vivo and in vitro models. The experimental results revealed that the FG@PEV intervention possesses the capability to reshape the inflammatory microenvironment within the disc. It also addresses the irregularities in fatty acid metabolism of nucleus pulposus cells, consequently hindering cellular pyroptosis and slowing down disc degeneration through the regulation of extracellular matrix synthesis and degradation. As a result, this injectable gel system represents a promising and innovative therapeutic approach for mitigating disc degeneration.
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The aim of the study was to investigate the factors that promote the development of gout in Chinese patients with hyperuricemia. Chinese cohort with 659 patients with hyperuricemia who had no history of gout at base line had been followed up for 5 years. The baseline data of the general states (gender, age, occupation and education level), lifestyle and behavior (smoking, drinking, and diet), the major chronic diseases (diabetes and hypertension), family history and gout attacks, physical examination (height, weight and blood pressure), and blood parameters (creatinine, urea nitrogen, triglycerides, total cholesterol and high-density lipoprotein cholesterol) were recorded before the follow-up. Over the five-year period, 75 hyperuricemia patients developed gout. In the logistic regression model, shrimp intake and shell intake were the risk factors (P = 0.038 and P < 0.001, respectively) and, combined with diabetes, also served as risk factor for gout developed from hyperuricemia, with relative risk (RR) of 2.571 (95 % confidence interval (95 % CI), 1.110-5.953), and females served as protective factors of gout, with RR of 0.113 (95 % CI, 0.041-0.312, referred to male). We identified that shrimp intake and shell intake, combined with diabetes, were the independent risk factors, and females served as protective factors of gout in those suffering from hyperuricemia in coast regions of Shandong province, China.
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Gota/etiología , Hiperuricemia/complicaciones , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , China , Estudios de Cohortes , Creatinina/sangre , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , Triglicéridos/sangreRESUMEN
To investigate whether the hypothermia induced by Adenosine 5'-Monophosphate (5'-AMP) could attenuate early stage injury in a rat acute gouty arthritis model. Ankle joint injection with monosodium urate monohydrate crystals (MSU crystals) in hypothermia rat model which was induced by 5'-AMP and then observe whether hypothermia induced by 5'-AMP could be effectively inhibit the inflammation on acute gouty arthritis in rats. AMP-induced hypothermia has protective effects on our acute gouty arthritis, which was demonstrated by the following criteria: (1) a significant reduction in the ankle swelling (p < 0.001); (2) a significant decrease in the occurrence of leukocyte infiltration and mild hemorrhage; (3) a significant reduction in the presence of serum Interleukin-1ß (IL-1ß, p < 0.001) and metalloproteinase-9 (MMP-9, p < 0.001); and (4) a significant inhibition in the Nuclear Factor -κappaB (NF-κB) activity (p < 0.001). AMP-induced hypothermia could inhibit acute inflammation reaction and protect the synovial tissue against acute injury in a rat acute gouty arthritis model.
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Artritis Gotosa/terapia , Hiperuricemia/terapia , Hipotermia Inducida/métodos , Animales , Articulación del Tobillo/metabolismo , Articulación del Tobillo/patología , Artritis Gotosa/inducido químicamente , Artritis Gotosa/metabolismo , Artritis Gotosa/patología , Modelos Animales de Enfermedad , Hiperuricemia/inducido químicamente , Hiperuricemia/metabolismo , Hiperuricemia/patología , Interleucina-1beta/sangre , Masculino , Metaloproteinasa 9 de la Matriz/sangre , FN-kappa B/metabolismo , Ratas , Ratas Wistar , Membrana Sinovial/metabolismo , Membrana Sinovial/patología , Ácido ÚricoRESUMEN
BACKGROUND: Breviscapine is a flavonoid extracted from Erigeron breviscapus (Vant.) Hand.-Mazz., and mainly contains scutellarin. Nuclear receptors play important roles in regulating transporter and drug metabolic enzymes. OBJECTIVE: To investigate the regulatory effects of scutellarin on CYP3A4 and 2C19 in HepG2 and Caco-2 cells based on nuclear receptors PXR and CAR. METHODS: The proteins and mRNA levels of CYP3A4 and CYP2C19 treated with scutellarin were detected by Western Blot and RT-qPCR. Using assays of the dual-luciferase reporter, promoter sequences containing hPXR and hCAR protein recognition and binding regulatory elements CYP3A4 and CYP2C19 were inserted upstream of the reporter gene, and the expression vector and the reporter vector were cotransfected into HepG2 and Caco-2 cells. RESULTS: Scutellarin inhibited mRNA of CYP3A4 and PXR, and promoted mRNA expression of CYP2C19 and CAR in RT-qPCR results. Western-blot results showed scutellarin inhibited the expression of CYP3A4 and promoted the expression of CYP2C19. The dual-luciferase reporter genes showed that scutellarin enhanced the expression level of CYP2C19, and when its concentration was 40 and 80µmol/L, CYP3A4 was significantly increased. CONCLUSION: Scutellarin down-regulates CYP3A4 through PXR, and its mechanism may work by up-regulating CAR, binding to PXR to inhibit PXR-mediated expression of CYP3A4. Scutellarin up-regulates CYP2C19 through CAR.
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Receptor de Androstano Constitutivo , Receptores de Esteroides , Humanos , Receptor X de Pregnano , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Citocromo P-450 CYP2C19 , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo , Células CACO-2 , Receptores Citoplasmáticos y Nucleares/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , LuciferasasRESUMEN
Osteoarthritis (OA), which is a major cause of serious arthralgia and disability among the elderly, has long plagued numerous populations. However, the specific molecular mechanisms involved in the etiology of OA are unclear. SIRT6 plays a critical function in the development of several inflammatory and aging-associated diseases. A study by D'Onofrio demonstrates that ergothioneine (EGT) is an effective activator of SIRT6. As revealed by previous reports, EGT exerts beneficial effects on the mouse body, including resistance to oxidation, tumor, and inflammation. Therefore, this work attempted to identify the inflammatory resistance of EGT and explore its effects on the incidence and development of OA. Mouse chondrocyte stimulation using varying levels of EGT and 10 ng/mL IL-1ß. According to in vitro experiments, EGT significantly reduced the decomposition of collagen II and aggrecan in OA chondrocytes, as well as inhibited the overexpression of PGE2, NO, IL-6, TNF-α, iNOs, COX-2, MMP-13, and ADAMTS5. In the present work, EGT hindered the NF-κB activity by activating the SIRT6 pathway in OA chondrocytes, which in turn, significantly attenuated the inflammatory response resulting from IL to 1ß. The inhibitory effect of EGT on the progression of OA was demonstrated by the mouse DMM model experiment. Thus, this study revealed that EGT was effective in anti-OA treatment.
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Ergotioneína , Osteoartritis , Sirtuinas , Animales , Ratones , Células Cultivadas , Condrocitos , Modelos Animales de Enfermedad , Ergotioneína/uso terapéutico , Inflamación/metabolismo , Interleucina-1beta/metabolismo , FN-kappa B/metabolismo , Osteoartritis/tratamiento farmacológico , Osteoartritis/metabolismo , Sirtuinas/metabolismoRESUMEN
Osteoarthritis (OA) is a common joint illness that negatively impacts people's lives. The main active ingredient of cassia seed or rhubarb is chrysophanol. It has various pharmacological effects including anticancer, anti-diabetes and blood lipid regulation. Previous evidence suggests that chrysophanol has anti-inflammatory properties in various diseases, but its effect on OA has not been investigated yet. In this study, chrysophanol inhibited IL-1ß -induced expression of ADAMTS-4, MMP13, COX-2 and iNOS. Meanwhile, it can inhibit aggrecan and collagen degradation in osteoarthritic chondrocytes induced by IL-1ß.Further studies depicted that SIRT6 silencing eliminated the chrysophanol effect on IL-1ß. The results demonstrated that chrysophanol could stimulate SIRT6 activation and, more importantly, increase SIRT6 levels. We also discovered that chrysophanol might impede the NF-κB pathway of OA mice's chondrocytes induced by IL-1ß, which could be because it depends on SIRT6 activation to some extent. It had also been previously covered that chrysophanol could produce a marked effect on Nrf2/NF-κB axis [1]. Therefore, we can infer that chrysophanol may benefit chondrocytes by regulating the SIRT6/NF-κB and Nrf2/NF-κB signaling axis.We examined the anti-inflammatory mechanism and the impact of chrysophanol on mice in vitro and in vivo. In summary, we declare that chrysophanol diminishes the inflammatory reaction of OA in mice in vitro by regulating SIRT6/NF-κB and Nrf2/NF-κB signaling pathway and protects articular cartilage from degradation in vivo. We can infer that chrysophanol could be an efficient therapy for OA.
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Osteoartritis , Sirtuinas , Ratones , Animales , FN-kappa B/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Osteoartritis/inducido químicamente , Osteoartritis/tratamiento farmacológico , Osteoartritis/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Antiinflamatorios/metabolismo , Interleucina-1beta/metabolismo , Sirtuinas/genética , Sirtuinas/metabolismo , Sirtuinas/farmacología , Condrocitos , Células CultivadasRESUMEN
Several genome-wide association studies (GWASs) have reported associations between single nucleotide polymorphisms (SNPs) and uric acid concentrations or gout in a number of different ethnic populations. To clarify the global relevance of the previously identified SNPs in the development of the qualitative trait gout, in the present study, the associations between two SNPs in the glucokinase (hexokinase 4) regulator (GCKR) gene and gout were assessed in a male Chinese Han population. The study population comprised 476 male gout patients and 465 male controls. Multiple PCR was performed using time-of-flight mass spectrometry (MALDI-TOF MS) to identify genotypes. Two SNPs, rs780093 and rs780094, located in intronic regions of the GCKR gene were found to be significantly associated with the development of gout. Thus, the association between the two GCKR SNPs and gout was replicated in the male Han Chinese population investigated in the present study. Furthermore, GCKR was identified as a novel candidate gene associated with gout.
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Proteínas Adaptadoras Transductoras de Señales/genética , Pueblo Asiatico/genética , Gota/etnología , Gota/genética , Glucemia/análisis , Estudios de Casos y Controles , China/epidemiología , Colesterol/sangre , Creatinina/sangre , Predisposición Genética a la Enfermedad , Genotipo , Gota/complicaciones , Humanos , Hipertensión/complicaciones , Hiperuricemia/complicaciones , Masculino , Persona de Mediana Edad , Obesidad/complicaciones , Polimorfismo de Nucleótido Simple , Triglicéridos/sangre , Ácido Úrico/sangreRESUMEN
We have built a rat's model to investigate whether the hypothermia induced by adenosine 5'-monophosphate (5'-AMP) (AIH) could attenuate acute lung injury induced by LPS in rats. We detected the inflammatory cytokine levels in the plasma and bronchoalveolar lavage fluid samples, and we analyzed the pathological changes in the lungs. We have found that AIH can effectively inhibit acute inflammatory reactions and protect the lung from acute injury induced by LPS in rats.
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Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/tratamiento farmacológico , Adenosina Monofosfato/uso terapéutico , Hipotermia/inducido químicamente , Lipopolisacáridos/toxicidad , Lesión Pulmonar Aguda/sangre , Lesión Pulmonar Aguda/metabolismo , Animales , Hipotermia/sangre , Hipotermia/metabolismo , Interleucina-10/sangre , Interleucina-10/metabolismo , Interleucina-1beta/sangre , Interleucina-1beta/metabolismo , Interleucina-6/sangre , Interleucina-6/metabolismo , Ratas , Ratas Wistar , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
In the centrosymmetric title compound, C(12)H(10)O(2)S(2), the alkyl chains adopt a fully extended all-trans conformation with respect to the C(thio-phene)-C bond. The non-H atoms of the mol-ecule are nearly planar, with a maximum deviation of 0.063â (2)â Å from the mean plane of the constituent atoms. In the crystal, symmetry-related mol-ecules are linked via pairs of C-Hâ¯π contacts [H-centroid distances of the thio-phene units = 2.79â (9) and 2.82â (4)â Å], in turn inter-digitating with each other along the bc plane, thus leading to an inter-woven two-dimensional network.
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Osteoarthritis (OA) is a chronic injury of joints, which is characterized by the destruction and degeneration of articular cartilage. Currently, there is a lack of effective treatments for OA. Linalool is a natural compound with anti-inflammatory effects in various diseases. However, the anti-inflammatory effect of linalool in the development of osteoarthritis remains unclear. This study aimed to investigate the anti-inflammatory effect of linalool on IL-1ß-induced mouse chondrocytes, as well as its protective effect on joints in a mouse model of OA. Mouse chondrocytes were co-treated with 10 ng/mL IL-1ß and different concentration gradients of linalool. These in vitro experiments demonstrated that linalool could inhibit the expression of Interleukin-1ß (IL-1ß)-induced inflammatory factors, such as nitric oxide synthase, cyclooxygenase-2 (COX-2), nitric oxide (NO), prostaglandin E2 (PGE2), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). Furthermore, linalool reduced the catabolism of the extracellular matrix (ECM) by inhibiting the expression of matrix metalloproteinase-13 (MMP-13) and thrombospondin motif-5 (ADAMTS5) while upregulating the expression of type II collagen (COL II) and aggrecan. Regarding the mechanism of OA, it was observed that linalool inhibited the signal transduction of nuclear factor kappa B (NF-κB) by activating the nuclear factor-erythroid 2-related factor-2 (Nrf2) in chondrocytes. The inhibitory effect of linalool on the development of OA was demonstrated by the mouse DMM model experiment. The results suggested that linalool may be a potential drug for the treatment of OA.
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Factor 2 Relacionado con NF-E2 , Osteoartritis , Animales , Ratones , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Antiinflamatorios/metabolismo , Condrocitos , Ciclooxigenasa 2/metabolismo , Modelos Animales de Enfermedad , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Osteoartritis/metabolismo , Transducción de Señal , Hemo-Oxigenasa 1/metabolismoRESUMEN
OBJECTIVE: This study aimed to investigate whether surgical resection of multifidus in rats could generate a reliable model of intervertebral disc degeneration (IVDD). METHODS: Instability of the lumbar spine in Sprague-Dawley rats was induced by multifidus resection. Longissimus changes were examined by hematoxylin and eosin staining and immunohistochemistry. Specific protein and mRNA changes in the nucleus pulposus (NP) were quantified by Western blot and reverse transcription-polymerase chain reaction. Bone alterations were assessed using X-ray imaging, and disc changes were evaluated by hematoxylin and eosin staining, immunofluorescence, and immunohistochemistry. RESULTS: Fat infiltration and increased tumor necrosis factor-α expression in the longissimus were detected following surgery. Reverse transcription-polymerase chain reaction and Western blot results demonstrated that the inflammation and catabolism in the NP were increased after the surgical intervention. Moreover, X-ray imaging showed that the disc height had decreased and bone spurs had formed at the vertebral rims. Histological analyses further revealed degeneration of the annulus fibrosus, endplate, and NP. Furthermore, in contrast to the sham group, the collagen II expression was reduced, while matrix metalloproteinase-13 was increased in the surgery group. CONCLUSIONS: Surgical resection of the multifidus in rats resulted in a reproducible IVDD model. Because the present procedure does not impart direct injury to the intervertebral disc, it can better imitate the pathological states in humans. Therefore, our rat multifidus resection model might help us further understand the intrinsic pathophysiology of IVDD.
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Degeneración del Disco Intervertebral , Disco Intervertebral , Núcleo Pulposo , Animales , Colágeno/metabolismo , Eosina Amarillenta-(YS)/metabolismo , Hematoxilina/metabolismo , Humanos , Disco Intervertebral/diagnóstico por imagen , Disco Intervertebral/cirugía , Degeneración del Disco Intervertebral/diagnóstico por imagen , Degeneración del Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/cirugía , Metaloproteinasa 13 de la Matriz/genética , Metaloproteinasa 13 de la Matriz/metabolismo , Núcleo Pulposo/metabolismo , Músculos Paraespinales/patología , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
OBJECTIVE: We suspect that genes or loci that contribute to coronary artery disease (CAD) may also play a role in the pathogenesis of gout, since hyperuricaemia leads to gout, and serum uric acid (SUA) levels are potential risk factors for CAD. The single nucleotide polymorphism (SNP) rs1333049 (C/G) on chromosome 9p21 has been implicated in previous studies to be associated with CAD. The aim of this study was to evaluate the relationship between this SNP and gout pathogenesis. METHODS: Nine hundred Chinese Han were recruited for this study (461 gout patients and 439 gout-free individuals). The rs1333049 SNP and surrounding sequences were PCR sequenced. RESULTS: There was a clear link between the rs1333049 genotypic and allelic frequencies between gout cases and controls (χ(2) = 6.81, df = 2, P = 0.033 by genotype; χ(2) = 6.63, df = 1, P = 0.01 by allele). There was a significantly increased risk of gout in carriers of the CC genotype (odds ratio = 1.43, 95% CI 1.07, 1.91). CONCLUSION: To the best of our knowledge, our findings are the first to establish an association of rs1333049 with gout in a Chinese Han population. Meanwhile, this SNP is homologous to miR-519 and miR-520.
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Gota/genética , Polimorfismo de Nucleótido Simple/genética , Alelos , Pueblo Asiatico/genética , Estudios de Casos y Controles , China , Femenino , Predisposición Genética a la Enfermedad , Genética de Población , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa/métodos , ARN Mensajero/metabolismoRESUMEN
OBJECTIVE: The present study investigated whether single nucleotide polymorphisms (SNPs) in the human urate transporter 1 (hURAT1) gene are associated with primary hyperuricaemia (HUA) in Han Chinese people. METHODS: A total of 538 subjects (215 cases and 323 control subjects) were recruited from Qingdao, China. SNPs in potentially functional regions of the gene were identified and genotypes determined by direct sequencing. Association analyses were conducted using Fisher's exact test and logistic regression assuming a genotype model. RESULTS: By sequencing the promoter, 10 exons, and the exon-intron junctions of the hURAT1 gene, 14 SNPs were identified. Two of the SNPs identified were associated with susceptibility to HUA. The first was a rare intron 3 (11 G-->A) SNP (p=0.0005), where carriers of the 'A' allele had a 3.4-fold (95% CI 1.67 to 6.93) increased risk of HUA. The second was a common exon 8 (T1309C) SNP (rs7932775), where carriers of one and two 'C' alleles had respective fold increased risks of 1.64 (95% CI 1.07 to 2.52) and 2.32 (95% CI 1.37 to 3.95). These SNPs had a joint additive effect of risk of HUA, with those individuals carrying at least one 'A' allele at the intron 3 SNP and two 'C' alleles at rs7932775 having a 5.88-fold (95% CI 1.25 to 15.57) increased risk of HUA in comparison to those with no risk alleles. CONCLUSION: In conjunction with other studies, our results suggest that there are multiple genetic variants within or near hURAT1 that are associated with susceptibility to HUA in Han Chinese, including a novel SNP located in intron 3.
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Pueblo Asiatico/genética , Hiperuricemia/genética , Transportadores de Anión Orgánico/genética , Proteínas de Transporte de Catión Orgánico/genética , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Estudios de Casos y Controles , Análisis Mutacional de ADN , Femenino , Predisposición Genética a la Enfermedad , Humanos , Intrones/genética , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/fisiología , Regiones Promotoras Genéticas/genéticaRESUMEN
This study was designed to investigate the association of the xanthine oxidase (XO) polymorphisms and susceptibility to anti-tuberculosis drug-induced liver injury (ATDILI) in Chinese population. A total of 183 tuberculosis patients were enrolled. Patients with ATDILI were classified as cases and those without ATDILI were classified as controls. Genotyping for XO polymorphisms was determined by polymerase chain reaction and direct sequencing. The allele frequencies and genotype distribution was analyzed using the Chi square test to analyze the association between the gene polymorphisms and ATDILI. Binary logistic regression analysis was performed to assess the risk factors of ATDILI. A total of 21 patients were developed liver injury during anti-tuberculosis treatment in this study, with an incidence of 11.48%. In genotype analysis, no significant difference was observed in the alleles and genotypes frequencies of the six SNPs between two groups (P > 0.05). In haplotype analysis, carriers with GGGATA (rs1884725- rs2295475 -rs45523133- rs206812- rs206813- rs7575607) haplotype had a significantly higher risk of ATDILI compared with other haplotypes (OR = 2.445, 95%CI: 1.058-5.652, P < 0.05). This study suggested that the haplotype GGGATA constructed with rs206812 and rs7575607 mutant alleles might contribute to ATDILI susceptibility in a Chinese population.
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Antituberculosos/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Polimorfismo Genético , Tuberculosis/prevención & control , Xantina Oxidasa/genética , Adulto , Anciano , Enfermedad Hepática Inducida por Sustancias y Drogas/epidemiología , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , China/epidemiología , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido SimpleRESUMEN
Liver injury is a clinical disorder caused by toxins, drugs, and alcohol stimulation without effective therapeutic approaches thus far. Scutellarin (SCU), isolated from the edible herb Erigeron breviscapus (Vant.) Hand. -Mazz. showed potential hepatoprotective effects, but the mechanisms remain unknown. In this study, transcriptomics combined with nontargeted metabolomics and 16S rRNA amplicon sequencing were performed to elucidate the functional mechanisms of SCU in carbon tetrachloride (CCl4)-induced liver injury in mice. The results showed that SCU exerted potential hepatoprotective effects against CCl4-induced liver injury by repressing CYP2E1 and IκBα/NF-κB signaling pathways, modulating the gut microbiota (especially enriching Lactobacillus), and regulating the endogenous metabolites involved in lipid metabolism and bile acid homeostasis. SCU originates from a functional food that appears to be a promising agent to guard against liver injury.