RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Viral pneumonia is the leading cause of death after SARS-CoV-2 infection. Despite effective at early stage, long-term treatment with glucocorticoids can lead to a variety of adverse effects and limited benefits. The Chinese traditional herb Pogostemonis Herba is the aerial part of Pogostemon Cablin (Blanco) Benth., which has potent antiviral, antibacterial, anti-inflammatory, and anticancer effects. It was used widely for treating various throat and respiratory diseases, including COVID-19, viral infection, cough, allergic asthma, acute lung injury and lung cancer. AIM OF THE STUDY: To investigate the antiviral and anti-inflammatory effects of chemical compounds from Pogostemonis Herba in SARS-CoV-2-infected hACE2-overexpressing mouse macrophage RAW264.7 cells and hACE2 transgenic mice. MATERIALS AND METHODS: The hACE2-overexpressing RAW264.7 cells were exposed with SARS-CoV-2. The cell viability was detected by CCK8 assay and cell apoptotic rate was by flow cytometric assay. The expressions of macrophage M1 phenotype markers (TNF-α and IL-6) and M2 markers (IL-10 and Arg-1) as well as the viral loads were detected by qPCR. The mice were inoculated intranasally with SARS-CoV-2 omicron variant to induce viral pneumonia. The levels of macrophages, neutrophils, and T cells in the lung tissues of infected mice were analyzed by full spectrum flow cytometry. The expressions of key proteins were detected by Western blot assay. RESULTS: Diosmetin-7-O-ß-D-glucopyranoside (DG) presented the strongest anti-SARS-CoV-2 activity. Intervention with DG at the concentrations of 0.625-2.5 µM not only reduced the viral replication, cell apoptosis, and the productions of inflammatory cytokines (IL-6 and TNF-α) in SARS-CoV-2-infected RAW264.7 cells, but also reversed macrophage polarity from M1 to M2 phenotype. Furthermore, treatment with DG (25-100 mg/kg) alleviated acute lung injury, and reduced macrophage infiltration in SARS-COV-2-infected mice. Mechanistically, DG inhibited SARS-COV-2 gene expression and HK3 translation via targeting YTHDF1, resulting in the inactivation of glycolysis-mediated NF-κB pathway. CONCLUSIONS: DG exerted the potent antiviral and anti-inflammatory activities. It reduced pneumonia in SARS-COV-2-infected mice via inhibiting the viral replication and accelerating M2 macrophage polarization via targeting YTHDF1, indicating its potential for COVID-19 treatment.

Asunto(s)

Antivirales , Tratamiento Farmacológico de COVID-19 , COVID-19 , Macrófagos , SARS-CoV-2 , Replicación Viral , Animales , Ratones , Células RAW 264.7 , Replicación Viral/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/virología , SARS-CoV-2/efectos de los fármacos , Antivirales/farmacología , Ratones Transgénicos , Pogostemon/química , Citocinas/metabolismo , Apoptosis/efectos de los fármacos , Pulmón/efectos de los fármacos , Pulmón/virología , Pulmón/patología , Glucósidos/farmacología , Glucósidos/aislamiento & purificación , Flavonoides/farmacología , Flavonoides/aislamiento & purificación , Flavonoides/uso terapéutico , Enzima Convertidora de Angiotensina 2/metabolismo , Antiinflamatorios/farmacología , Masculino , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/virología , Humanos

RESUMEN

Flowers of Crocus sativus L. are immensely important not only for arrangement of floral whorls but more because each floral organ is dominated by a different class of specialized compounds. Dried stigmas of C. sativus flowers form commercial saffron, and are known to accumulate unique apocarotenoids like crocin, picrocrocin and safranal. Inspite of being a high value crop, the molecular mechanism regulating flower development in Crocus remains largely unknown. Moreover, it would be very interesting to explore any co-regulatory mechanism which controls floral architecture and secondary metabolic pathways which exist in specific floral organs. Here we report transcriptome wide identification of MADS box genes in Crocus. A total of 39 full length MADS box genes were identified among which three belonged to type I and 36 to type II class. Phylogeny classified them into 11 sub-clusters. Expression pattern revealed some stigma up-regulated genes among which CstMADS19 encoding an AGAMOUS gene showed high expression. Transient over-expression of CstMADS19 in stigmas of Crocus resulted in increased crocin by enhancing expression of pathway genes. Yeast one hybrid assay demonstrated that CstMADS19 binds to promoters of phytoene synthase and carotenoid cleavage dioxygenase 2 genes. Yeast two hybrid and BiFC assays confirmed interaction of CstMADS19 with CstMADS26 which codes for a SEPALATA gene. Co-overexpression of CstMADS19 and CstMADS26 in Crocus stigmas enhanced crocin content more than was observed when genes were expressed individually. Collectively, these findings indicate that CstMADS19 functions as a positive regulator of stigma based apocarotenoid biosynthesis in Crocus.

Asunto(s)

Carotenoides , Crocus , Flores , Regulación de la Expresión Génica de las Plantas , Proteínas de Dominio MADS , Proteínas de Plantas , Crocus/genética , Crocus/metabolismo , Carotenoides/metabolismo , Flores/genética , Flores/metabolismo , Flores/crecimiento & desarrollo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Proteínas de Dominio MADS/genética , Proteínas de Dominio MADS/metabolismo , Filogenia , Perfilación de la Expresión Génica/métodos , Ciclohexenos/metabolismo , Transcriptoma , Terpenos/metabolismo , Glucósidos/metabolismo , Glucósidos/biosíntesis

RESUMEN

Objective: Evaluate the effects of sodium-glucose cotransporter 2 inhibitor (SGLT2i) on cardiovascular and cerebrovascular diseases. Methods: Articles of SGLT2i on cardiovascular and cerebrovascular diseases were searched. Two authors independently screened the literature, extracted the data, assessed the quality of the study and performed statistical analyses using Review Manager 5.4. Results: Random-effect model was used to merge the OR values, and the pooled effect showed that SGLT2i had significant preventive effects on cardiovascular death (OR=0.76, 95%CI 0.64 to 0.89), myocardial infarction (OR=0.90, 95%CI 0.84 to 0.96), heart failure (OR=0.69, 95%CI 0.64 to 0.74) and all-cause mortality (OR=0.65, 95%CI 0.58 to 0.73). Empagliflozin, dapagliflozin and canagliflozin all reduced the incidence of heart failure (OR=0.72, 95%CI 0.64 to 0.82; OR=0.56, 95%CI 0.39 to 0.80; OR=0.62, 95%CI 0.53 to 0.73), but only dapagliflozin displayed a favorable effect on inhibiting stroke (OR=0.78, 95%CI 0.63 to 0.98). SGLT2i could prevent stroke (OR=0.86, 95%CI 0.75 to 0.99), heart failure (OR=0.63, 95%CI 0.56 to 0.70) and all-cause mortality (OR=0.64, 95%CI 0.57 to 0.72) compared to DPP-4i. Furthermore, SGLT2i could reduce the incidence of heart failure (OR=0.72, 95%CI 0.67 to 0.77) and cardiovascular death (OR=0.72, 95%CI 0.54 to 0.95) in patients with high-risk factors. Conclusions: SGLT2i affects cardiovascular death, myocardial infarction, heart failure and all-cause mortality. Only dapagliflozin displayed a favorable effect on inhibiting stroke. SGLT2i could prevent stroke, heart failure and all-cause mortality compared to DPP-4i. In addition, SGLT2i significantly reduced the development of heart failure and cardiovascular death in patients with high-risk factors. Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier CRD42024532783.

Asunto(s)

Enfermedades Cardiovasculares , Trastornos Cerebrovasculares , Diabetes Mellitus Tipo 2 , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/prevención & control , Enfermedades Cardiovasculares/tratamiento farmacológico , Trastornos Cerebrovasculares/prevención & control , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Compuestos de Bencidrilo/uso terapéutico , Glucósidos/uso terapéutico , Ensayos Clínicos Controlados como Asunto , Hipoglucemiantes/uso terapéutico

RESUMEN

This meta-analysis investigated efficacy of dapagliflozin as adjunctive therapy for patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) stages 2-5. A systematic search was conducted of selected databases for randomised controlled trials that reported the mean change in estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR) from baseline. Out of 1,682 identified studies, 9 trials comprising 13,057 patients were included. A pooled estimate of 5 studies indicated that dapagliflozin did not affect eGFR; however, in 2 studies, it significantly reduced chronic eGFR decline compared to placebo (mean difference [MD] ± 2.74; 95% confidence interval [CI]: 1.55, 3.92; P <0.00001). Additionally, a pooled estimate of 4 studies showed that dapagliflozin significantly reduced UACR (MD -23.99%; 95% CI: -34.82--13.15; P <0.0001; I2 = 0%). Therefore, long-term use of dapagliflozin significantly attenuates eGFR decline and reduces albuminuria in patients with T2DM and CKD.

Asunto(s)

Compuestos de Bencidrilo , Diabetes Mellitus Tipo 2 , Glucósidos , Insuficiencia Renal Crónica , Humanos , Glucósidos/uso terapéutico , Glucósidos/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Compuestos de Bencidrilo/uso terapéutico , Compuestos de Bencidrilo/farmacología , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/fisiopatología , Progresión de la Enfermedad , Tasa de Filtración Glomerular/efectos de los fármacos , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Femenino , Masculino

RESUMEN

BACKGROUND/AIMS: One of the treatments for breast cancer is surgical resection of the tumour and prevention of recurrence with postoperative radiotherapy. Unfortunately, radiotherapy is not always effective enough due to the low sensitivity of cancer cells to ionising radiation. This study aimed to evaluate the radiosensitising properties of resveratrol, piceatannol and polydatin on breast cancer cells, which differ in the presence of hormonal receptors on their surface. METHODS: The experimental part was carried out on triple-negative breast cancer cells (HCC38) and hormone-dependent cells (MCF7). The study assessed the level of cell death, changes in the expression of genes (BAX, BCL-2) and proteins related to the apoptosis process (CASPASE 3, 8 and P53), changes in the expression of antioxidant enzymes (CATALASE, SOD, GPx1/2) and NRF-2. Additionally, the expression level of RAD51 protein and histone H2AX, which are involved in DNA repair processes, was assessed. Statistical significance was evaluated by a two-way analysis of variance (ANOVA) followed by Tukey's post hoc test (p < 0.05). RESULTS: Ionising radiation in combination with resveratrol or piceatannol activates the apoptosis process by internal and external pathways. Greater sensitivity of MCF7 cells compared to HCC38 cells to ionising radiation in combination with resveratrol is associated with a weaker antioxidant response of cells and reduced intensity of DNA damage repair. DNA repair induced by ionising radiation occurs more effectively in HCC38 cells than in MCF7 cells. CONCLUSION: Resveratrol has the highest radiosensitising potential among the tested stilbene for cells of both lines. The effectiveness of ionizing radiation in combination with resveratrol (to a lesser extent with piceatannol) is more significant in MCF7 than in HCC38 cells.

Asunto(s)

Apoptosis , Radiación Ionizante , Fármacos Sensibilizantes a Radiaciones , Resveratrol , Estilbenos , Humanos , Estilbenos/farmacología , Resveratrol/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Femenino , Fármacos Sensibilizantes a Radiaciones/farmacología , Línea Celular Tumoral , Células MCF-7 , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/radioterapia , Neoplasias de la Mama/tratamiento farmacológico , Histonas/metabolismo , Reparación del ADN/efectos de los fármacos , Reparación del ADN/efectos de la radiación , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Recombinasa Rad51/metabolismo , Caspasa 3/metabolismo , Glucósidos

RESUMEN

Due to its high polyphenol content, black rice plays a significant role in good nutrition; however, these antioxidant compounds are affected by heat treatments required for the rice consumption. The aim of this work was to investigate how cooking affects the composition of Artemide black rice, comparing innovative methods, such as sous vide, with traditional domestic techniques (risotto and pilaf). Proteins and ashes were not affected by cooking, except for pilaf rice, where a 42 % ashes decrease was observed; fiber content increased after all cooking methods, reaching a 29 % increase in the risotto. Antioxidant activity, total polyphenols, anthocyanins and proanthocyanidins were reduced on average of 40 %, 34 %, 43 % and 39 %, respectively. Individual anthocyanins decreased, while phenolic acids and other flavonoids presented different behaviours, also depending if considered in their free or bound form. Cyanidin-3-O-glucoside was reduced up to 56 % in the sous vide cooked rice at 99 °C, and only by 45 % and 37 % in the risotto and sous vide cooked rice at 89 °C, respectively. Traditional risotto preparation and the innovative sous vide cooking at 89 °C also maintained the highest antioxidant polyphenols content, saving 63 % of the antioxidant activity in respect to the raw black rice. Concluding, these last techniques can be suggested for a better preservation of bioactive compounds.

Asunto(s)

Antocianinas , Antioxidantes , Culinaria , Oryza , Polifenoles , Oryza/química , Culinaria/métodos , Antioxidantes/análisis , Antocianinas/análisis , Polifenoles/análisis , Fibras de la Dieta/análisis , Calor , Proantocianidinas/análisis , Glucósidos/análisis , Hidroxibenzoatos/análisis , Valor Nutritivo

RESUMEN

In this research, accelerated aroma release experiments and malvidin-3-O-glucoside copigmentation experiments in model red wine solutions were designed to investigate the abilities and molecular mechanisms of mannoproteins in modulating olfactory/chromatic properties of red wines. Results indicate that under orthonasal condition, mannoprotein MP2 was promising aroma modulator due to its predictable behaviors in expelling and retaining the aroma compounds during different periods. Low field nuclear magnetic resonance and molecular dynamic simulation proved that the modulation ability of MP2 should be explained by its transitionary interacting preferences with water/aroma compound molecules. Retronasal results show that the release of aroma compounds and olfactory perceptions were irregular and difficult to predict, probably due to the complexity of the retronasal condition. All mannoproteins protected malvidin-3-O-glucoside and quercetin via the formation of binary/ternary complexes, and quercetin was found prior to be protected than malvidin-3-O-glucoside. Principal mannoprotein A0A6C1DV26 might be the critical malvidin-3-O-glucoside protector. With the presence of quercetin, principal mannoproteins B3LQU1/B5VL26 in mannoprotein MP1 might exhibit intramolecular and/or intermolecular mechanisms that strengthened the hyperchromic effect, thus enhanced the copigmentation.

Asunto(s)

Antocianinas , Glucósidos , Glicoproteínas de Membrana , Vino , Vino/análisis , Glucósidos/química , Glicoproteínas de Membrana/metabolismo , Antocianinas/química , Odorantes/análisis , Quercetina/química , Percepción Olfatoria , Simulación de Dinámica Molecular , Humanos

RESUMEN

BACKGROUND: Drug-induced liver injury (DILI) is gradually becoming a common global problem that causes acute liver failure, especially in acute hepatic damage caused by acetaminophen (APAP). Paeoniflorin (PF) has a wide range of therapeutic effects to alleviate a variety of hepatic diseases. However, the relationship between them is still poorly investigated in current studies. PURPOSE: This work aimed to explore the protective effects of PF on APAP-induced hepatic damage and researched the potential molecular mechanisms. METHODS: C57BL/6J male mice were injected with APAP to establish DILI model and were given PF for five consecutive days for treatment. Aiming to clarify the pharmacological effects, the molecular mechanisms of PF in APAP-induced DILI was elucidated by high-throughput and other techniques. RESULTS: The results demonstrated that serum levels of ALP, γ-GT, AST, TBIL, and ALT were decreased in APAP mice by the preventive effects of PF. Moreover, PF notably alleviated hepatic tissue inflammation and edema. Meanwhile, the results of TUNEL staining and related apoptotic factors coincided with the results of transcriptomics, suggesting that PF inhibited hepatocyte apoptosis by regulated MAPK signaling. Besides, PF also acted on reactive oxygen species (ROS) to regulate the oxidative stress for recovery the damaged mitochondria. More importantly, transmission electron microscopy showed the generation of autophagosomes after PF treatment, and PF was also downregulated mTOR and upregulated the expression of autophagy markers such as ATG5, ATG7, and BECN1 at the mRNA level and LC3, p62, ATG5, and ATG7 at the protein level, implying that the process by which PF exerted its effects was accompanied by the occurrence of autophagy. In addition, combinined with molecular dynamics simulations and western blotting of MAPK, the results suggested p38 as a direct target for PF on APAP. Specifically, PF-activated autophagy through the downregulation of MAPK/mTOR signaling, which in turn reduced APAP injury. CONCLUSIONS: Paeoniflorin mitigated liver injury by activating autophagy to suppress oxidative stress and apoptosis via the MAPK/mTOR signaling pathway. Taken together, our findings elucidate the role and mechanism of paeoniflorin in DILI, which is expected to provide a new therapeutic strategy for the development of paeoniflorin.

Asunto(s)

Acetaminofén , Autofagia , Enfermedad Hepática Inducida por Sustancias y Drogas , Glucósidos , Hepatocitos , Ratones Endogámicos C57BL , Monoterpenos , Serina-Treonina Quinasas TOR , Animales , Autofagia/efectos de los fármacos , Glucósidos/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Monoterpenos/farmacología , Masculino , Hepatocitos/metabolismo , Hepatocitos/efectos de los fármacos , Ratones , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Acetaminofén/efectos adversos , Transducción de Señal/efectos de los fármacos , Apoptosis/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sustancias Protectoras/farmacología , Especies Reactivas de Oxígeno/metabolismo , Estrés Oxidativo/efectos de los fármacos

Asunto(s)

Insuficiencia Cardíaca , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Insuficiencia Cardíaca/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Enfermedad Aguda , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucósidos/uso terapéutico , Glucósidos/efectos adversos , Glucósidos/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Compuestos de Bencidrilo/uso terapéutico , Compuestos de Bencidrilo/efectos adversos

RESUMEN

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) inhibit urinary glucose and sodium reabsorption in the proximal tubule of the nephron and result in glucosuria, natriuresis and diuresis. In patients with T2DM who have atherosclerotic cardiovascular (CV) disease or CV risk factors, SGLT2is have been shown to reduce major CV events and heart failure (HF) hospitalization. The greatest and most consistent effect of SGLT2is in these trials was found to be reduction in HF hospitalization, which raised the possibility of clinical benefit of SGLT2i in HF patients. In DAPA-HF and EMPEROR-Reduced trials in HFrEF patients with or without T2DM, SGLT2is, dapagliflozin and empagliflozin treatment on top of standard HF therapy has been shown to have clear clinical benefit in reducing primary endpoint of CV mortality or HF hospitalization and improving quality of life. Recently published EMPEROR-Preserved and DELIVER trials showed that SGLT2is were also very effective in the treatment of HFpEF (EF >40%). Furthermore, SGLT2is have also been shown to have potential in improving clinical outcomes in hospitalized acute HF patients in EMPULSE and DICTATE-AHF trials. All of this evidence has changed guidelines recommended therapies, not only for HFrEF but also for HFpEF treatment. The aim of this article is to provide a comprehensive overview focused on the role of SGLT2i in the treatment of HF based on the recent evidence.

Asunto(s)

Insuficiencia Cardíaca , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Insuficiencia Cardíaca/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Compuestos de Bencidrilo/uso terapéutico , Hospitalización , Glucósidos/uso terapéutico

RESUMEN

PURPOSE: Gentamicin is a broad-spectrum antibiotic commonly used in clinical practice. However, the drug causes side effects of ototoxicity, leading to disruption in balance functionality. This study investigated the effect of gastrodin, a prominent compound present in Gastrodia, and the underlying mechanism on the development of gentamicin-induced vestibular dysfunction. METHODS: Wild-type C57BL/6 mice were randomly assigned to three groups: control, gentamicin, and gentamicin + gastrodin groups. The extent of gentamicin-induced vestibular impairment was assessed through a series of tests including the swimming test, contact righting reflex test, and air-righting reflex. Alterations in vestibular hair cells were monitored through immunofluorescence assay, and cellular apoptosis was observed using TUNEL staining. The mRNA and protein expression of Notch1, Jagged1, and Hes1 was quantified through qRT-PCR, immunofluorescence, and western blot analyses. RESULTS: Gentamicin treatment led to pronounced deficits in vestibular function and otolith organ hair cells in mice. Nevertheless, pretreatment with gastrodin significantly alleviated these impairments. Additionally, the Notch signaling pathway was activated by gentamicin in the utricle, contributing to a notable increase in the expression levels of apoptosis-associated proteins. By contrast, gastrodin treatment effectively suppressed the Notch signaling pathway, thereby mitigating the occurrence of apoptosis. CONCLUSION: Collectively, these findings underscore the crucial role of gastrodin in safeguarding against gentamicin-induced vestibular dysfunction through the modulation of the Notch signaling pathway. This study suggests the potential of gastrodin as a promising therapeutic agent for preventing vestibular injuries.

Asunto(s)

Alcoholes Bencílicos , Gentamicinas , Glucósidos , Ratones Endogámicos C57BL , Transducción de Señal , Animales , Gentamicinas/toxicidad , Alcoholes Bencílicos/farmacología , Transducción de Señal/efectos de los fármacos , Glucósidos/farmacología , Ratones , Apoptosis/efectos de los fármacos , Enfermedades Vestibulares/inducido químicamente , Enfermedades Vestibulares/patología , Antibacterianos/toxicidad , Antibacterianos/farmacología , Receptor Notch1/metabolismo , Receptor Notch1/genética , Células Ciliadas Vestibulares/efectos de los fármacos , Células Ciliadas Vestibulares/metabolismo , Masculino

Asunto(s)

Diabetes Mellitus Tipo 2 , Hipoglucemiantes , Metformina , Vildagliptina , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Metformina/uso terapéutico , Metformina/farmacología , Vildagliptina/farmacología , Vildagliptina/uso terapéutico , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacología , Glucósidos/uso terapéutico , Glucósidos/farmacología , Glucósidos/efectos adversos , Pirrolidinas/uso terapéutico , Pirrolidinas/farmacología , Pirrolidinas/efectos adversos , Quimioterapia Combinada/métodos , Nitrilos/uso terapéutico , Nitrilos/efectos adversos , Adamantano/análogos & derivados , Adamantano/uso terapéutico , Adamantano/efectos adversos , Compuestos de Bencidrilo/uso terapéutico , Compuestos de Bencidrilo/efectos adversos , Compuestos de Bencidrilo/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología

RESUMEN

BACKGROUND: Bone loss caused by microgravity exposure presents a serious threat to the health of astronauts, but existing treatment strategies have specific restrictions. This research aimed to investigate whether salidroside (SAL) can mitigate microgravity-induced bone loss and its underlying mechanism. METHODS: In this research, we used hindlimb unloading (HLU) and the Rotary Cell Culture System (RCCS) to imitate microgravity in vivo and in vitro. RESULTS: The results showed that salidroside primarily enhances bone density, microstructure, and biomechanical properties by stimulating bone formation and suppressing bone resorption, thereby preserving bone mass in HLU rats. In MC3T3-E1 cells cultured under simulated microgravity in rotary wall vessel bioreactors, the expression of osteogenic genes significantly increased after salidroside administration, indicating that salidroside can promote osteoblast differentiation under microgravity conditions. Furthermore, the Nrf2 inhibitor ML385 diminished the therapeutic impact of salidroside on microgravity-induced bone loss. Overall, this research provides the first evidence that salidroside can mitigate bone loss induced by microgravity exposure through stimulating the Nrf2/HO-1 pathway. CONCLUSION: These findings indicate that salidroside has great potential for treating space-related bone loss in astronauts and suggest that Nrf2/HO-1 is a viable target for counteracting microgravity-induced bone damage.

Asunto(s)

Glucósidos , Factor 2 Relacionado con NF-E2 , Fenoles , Simulación de Ingravidez , Glucósidos/farmacología , Glucósidos/uso terapéutico , Animales , Fenoles/farmacología , Fenoles/uso terapéutico , Factor 2 Relacionado con NF-E2/metabolismo , Ratones , Simulación de Ingravidez/efectos adversos , Ratas , Masculino , Hemo-Oxigenasa 1/metabolismo , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Ingravidez/efectos adversos , Osteogénesis/efectos de los fármacos , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Suspensión Trasera , Resorción Ósea/prevención & control , Resorción Ósea/etiología , Resorción Ósea/metabolismo , Densidad Ósea/efectos de los fármacos , Proteínas de la Membrana

RESUMEN

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is marked by the deterioration of both cortical and spinal cord motor neurons. Despite the underlying causes of the disease remain elusive, there has been a growing attention on the well-being of cortical motor neurons in recent times. Focused ultrasound combined with microbubbles (FUS/MB) for opening the blood-brain barrier (BBB) provides a means for drug delivery to specific brain regions, holding significant promise for the treatment of neurological disorders. OBJECTIVES: We aim to explore the outcomes of FUS/MB-mediated delivery of arctiin (Arc), a natural compound with anti-inflammatory activities, to the cerebral motor cortex area by using a transgenic ALS mouse model. METHODS: The ALS mouse model with the SOD1G93A mutation was used and subjected to daily Arc administration with FUS/MB treatment twice a week. After six-week treatments, the motor performance was assessed by grip strength, wire hanging, and climbing-pole tests. Mouse brains, spinal cords and gastrocnemius muscle were harvested for histological staining. RESULTS: Compared with the mice given Arc administration only, the combined treatments of FUS/MB with Arc induced further mitigation of the motor function decline, accompanied by improved health of the gastrocnemius muscle. Furthermore, notable neuroprotective effect was evidenced by the amelioration of motor neuron failure in the cortex and lumbar spinal cord. CONCLUSION: These preliminary results indicated that the combined treatment of FUS/MB and arctiin exerted a potentially beneficial effect on neuromuscular function in the ALS disease.

Asunto(s)

Esclerosis Amiotrófica Lateral , Modelos Animales de Enfermedad , Ratones Transgénicos , Corteza Motora , Animales , Ratones , Corteza Motora/efectos de los fármacos , Corteza Motora/fisiopatología , Glucósidos/farmacología , Glucósidos/administración & dosificación , Microburbujas , Sistemas de Liberación de Medicamentos , Terapia por Ultrasonido/métodos , Superóxido Dismutasa-1/genética , Furanos/farmacología , Furanos/administración & dosificación , Masculino , Mutación

RESUMEN

Gastrodia elata Blume is a traditional medicinal and food homology substance that has been used for thousands of years, is mainly distributed in China and other Asian countries, and has always been distinguished as a superior class of herbs. Gastrodin is the main active ingredient of G. elata Blume and has attracted increasing attention because of its extensive pharmacological activities. In addition to extraction and isolation from the original plant, gastrodin can also be obtained via chemical synthesis and biosynthesis. Gastrodin has significant pharmacological effects on the central nervous system, such as sedation and improvement of sleep. It can also improve epilepsy, neurodegenerative diseases, emotional disorders and cognitive impairment to a certain extent. Gastrodin is rapidly absorbed and widely distributed in the body and can also penetrate the blood-brain barrier. In brief, gastrodin is a promising natural small molecule with significant potential in the treatment of brain diseases. In this review, we summarised studies on the synthesis, pharmacological effects and pharmacokinetic characteristics of gastrodin, with emphasis on its effects on central nervous system disorders and the possible mechanisms, in order to find potential therapeutic applications and provide favourable information for the research and development of gastodin.

Asunto(s)

Alcoholes Bencílicos , Enfermedades del Sistema Nervioso Central , Glucósidos , Alcoholes Bencílicos/farmacocinética , Alcoholes Bencílicos/uso terapéutico , Alcoholes Bencílicos/farmacología , Alcoholes Bencílicos/química , Glucósidos/farmacocinética , Glucósidos/uso terapéutico , Glucósidos/química , Glucósidos/farmacología , Humanos , Animales , Enfermedades del Sistema Nervioso Central/tratamiento farmacológico , Enfermedades del Sistema Nervioso Central/metabolismo , Gastrodia/química

RESUMEN

A predictive model utilizing near-infrared spectroscopy was developed to estimate the loss on drying, total contents of crocin I and crocin II, and picrocrocin content of saffron. Initially, the LD values were determined using a moisture-ash analyzer, while HPLC was employed for measuring the total contents of crocin I, crocin II, and picrocrocin. The near-infrared spectra of 928 saffron samples were collected and preprocessed using first derivative, standard normal variable transformation, detrended correction, multivariate scattering correction, Savitzky-Golay smoothing, and mean centering methods. Leveraging the partial least squares method, regression models were constructed, with parameters optimized through a selective combination of the above six preprocessing methods. Subsequently, prediction models for loss on drying, total contents of crocin I and crocin II, and picrocrocin content were established, and the prediction accuracy of the models was verified. The correlation coefficients and root mean square error of loss on drying, total contents of crocin I and crocin II, and picrocrocin content demonstrated high accuracy, with R2 values of 0.8627, 0.8851, and 0.8592 and root mean square error values of 0.0260, 0.0682, and 0.0465. This near-infrared prediction model established in the present study offers a precise and efficient means of assessing loss on drying, total contents of crocin I and crocin II, and picrocrocin content in saffron and is useful for the development of a rapid quality evaluation system.

Asunto(s)

Carotenoides , Crocus , Espectroscopía Infrarroja Corta , Crocus/química , Espectroscopía Infrarroja Corta/métodos , Carotenoides/análisis , Análisis de los Mínimos Cuadrados , Cromatografía Líquida de Alta Presión/métodos , Glucósidos , Terpenos , Ciclohexenos

RESUMEN

Sodium-glucose cotransporter-2 (SGLT-2) is expressed in the kidney and may contribute to anaemia and cardiovascular diseases. The effect of SGLT-2 inhibition on anaemia and vascular endpoints in sickle cell disease (SCD) is unknown. A murine model of SCD was studied to determine the effects of the SGLT-2 inhibitor, empagliflozin, on anaemia and stroke size. The University of Michigan's Precision Health Database was used to evaluate the effect of SGLT-2 inhibitors on anaemia in humans with SCD. SCD mice treated with daily empagliflozin for 8 weeks demonstrated increases in haemoglobin, haematocrit, erythrocyte counts, reticulocyte percentage and erythropoietin compared to vehicle-treated mice. Following photochemical-induced thrombosis of the middle cerebral artery, mice treated with empagliflozin demonstrated reduced stroke size compared to vehicle treated mice. In the electronic health records analysis, haemoglobin, haematocrit and erythrocyte counts increased in human SCD subjects treated with an SGLT-2 inhibitor. SGLT-2 inhibitor treatment of humans and mice with SCD is associated with improvement in anaemic parameters. Empagliflozin treatment is also associated with reduced stroke size in SCD mice suggesting SGLT-2 inhibitor treatment may be beneficial with regard to both anaemia and vascular complications in SCD patients.

Asunto(s)

Anemia de Células Falciformes , Anemia , Compuestos de Bencidrilo , Modelos Animales de Enfermedad , Glucósidos , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Accidente Cerebrovascular , Animales , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/tratamiento farmacológico , Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/patología , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Humanos , Ratones , Compuestos de Bencidrilo/farmacología , Glucósidos/farmacología , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/patología , Masculino , Anemia/tratamiento farmacológico , Anemia/etiología , Femenino , Transportador 2 de Sodio-Glucosa/metabolismo , Ratones Endogámicos C57BL

RESUMEN

Chinese Olea europaea leaves, rich in verbascosides, were extracted using ultrasound-assisted extraction (UAE) and wall-breaking extraction (WBE) with deep eutectic solvents (Optimal UAE: 55 min, 200 mL/g liquid-solid ratio, 20% moisture, yielding 206.23 ± 0.58 mg GAE/g total phenolic content (TPC) and 1.59 ± 0.04% verbascoside yield (VAY); Optimal WBE: 140 s, 210 mL/g, 30% moisture, giving 210.69 ± 0.97 mg GAE/g TPC and 1.33 ± 0.2% VAY). HPLC analysis showed that young leaves accumulated higher TPC and phenolic compounds. Among the five olive varieties, Koroneiki and Chemlal showed the highest TPC in UAE, while Arbosana and Chemlal excelled in WBE. WBE yielded a higher TPC and rutin, whereas UAE marginally increased other phenolics. Additionally, the DPPH• assay showed that WBE-extracted verbascoside-rich extracts (VREs) of Chemlal exhibited high antioxidant activity (EC50 of 57 mg/mL), but Koroneiki-VREs exhibited lower activity against the ABTS•+ radical (EC50 of 134 mg/mL). Remarkably, the UAE/WBE-extracted Chemlal-VREs promoted the normal esophageal Het-1A cell line at 25 µg/mL for 24 h; yet, the esophageal cancer Eca-109 cells were sensibly inhibited, especially at 50 µg/mL; and the cell viability decreased dramatically. The results confirmed WBE as a relatively efficient method, and the Chemlal variety may be an excellent source of verbascoside.

Asunto(s)

Antioxidantes , Glucósidos , Olea , Fenoles , Extractos Vegetales , Hojas de la Planta , Solventes , Olea/química , Hojas de la Planta/química , Fenoles/química , Fenoles/aislamiento & purificación , Fenoles/farmacología , Antioxidantes/farmacología , Antioxidantes/química , Antioxidantes/aislamiento & purificación , Glucósidos/aislamiento & purificación , Glucósidos/química , Glucósidos/farmacología , Solventes/química , Humanos , Línea Celular Tumoral , Extractos Vegetales/química , Extractos Vegetales/farmacología , Cromatografía Líquida de Alta Presión , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Supervivencia Celular/efectos de los fármacos , Pueblos del Este de Asia , Polifenoles

RESUMEN

OBJECTIVE: Sodium-glucose co-transporter-2 inhibitors (SGLT-2i) are a new class of drugs that lower blood glucose and reduce mortality in heart failure patients with reduced ejection fraction (HFrEF). They also have antioxidant effects. The exact mechanism of SGLT-2i is unknown. This study investigated the effects of SGLT-2i on asprosin, matrix metalloproteinase (MMP), and tissue inhibitor of MMP (TIMP-1) concentrations and echocardiographic measurements of strain in the left heart chamber. PATIENTS AND METHODS: This prospective follow-up study included 56 patients with HFrEF and diabetes mellitus (DM) who did not initially receive SGLT-2 inhibitors. The control group consisted of 30 healthy individuals. Patients with HFrEF were administered either empagliflozin (n=28) or dapagliflozin (n=28) in addition to their treatment. The patient group was evaluated for left ventricular global longitudinal strain (LVGLS), left atrial (LA) strain, and LA volumes at the beginning and third month of the study. The control group had blood collected once, while the patient group had it twice: at the start of the trial, on the same day as the echocardiographic evaluation, and at the end of the third month after starting an SGLT-2i. Serum levels of asprosin, MMP-1 and TIMP-1 were assessed. RESULTS: LVGLS increased significantly in HFrEF patients at the third-month assessment compared to baseline (-8.6±2.3% vs. -9±2.5%, respectively; p<0.001), but there was no significant difference in LVEF (p=0.593). A substantial increase was observed in the left atrial ejection fraction (LAEF) compared to baseline values (36.3±9.4% vs. 42.1±8.7%, respectively; p<0.001), driven by a reduction in minimal LA volume [32.5 (19-96) ml vs. 32 (20-86) ml, respectively; p=0.018]. Compared to baseline evaluation, LA reservoir [13 (6-25) vs. 16.5 (2-26), respectively; p<0.001] and contraction strain (7.7±4.3 vs. 9.4±5.6, respectively; p=0.014) values were also enhanced at the third month. Between the baseline and the 3rd month, the patient group's LA conduit strain (p=0.122) and LA maximum volume (p=0.716) remained unchanged. Serum asprosin significantly increased (11.7±5.1 ng/mL vs. 14±9.4 ng/mL, respectively; p=0.032); however, no statistically significant alteration was detected in MMP (p=0.278) and TIMP-1 levels (p=0.401). CONCLUSIONS: SGLT-2i are associated with elevated levels of LVGLS, LAEF, LA contraction strain, and LA reservoir strain. SGLT-2i medications may improve plasma asprosin levels to boost energy metabolism, reduce oxidative stress and reactive oxygen radicals.

Asunto(s)

Antioxidantes , Ecocardiografía , Glucósidos , Insuficiencia Cardíaca , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Volumen Sistólico , Humanos , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/administración & dosificación , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/fisiopatología , Volumen Sistólico/efectos de los fármacos , Femenino , Masculino , Persona de Mediana Edad , Glucósidos/farmacología , Glucósidos/administración & dosificación , Glucósidos/uso terapéutico , Antioxidantes/farmacología , Antioxidantes/administración & dosificación , Estudios Prospectivos , Anciano , Compuestos de Bencidrilo/farmacología , Compuestos de Bencidrilo/administración & dosificación , Compuestos de Bencidrilo/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Estudios de Seguimiento , Inhibidor Tisular de Metaloproteinasa-1/sangre

RESUMEN

Steviol glycosides (SGs) are a class of high-potency noncalorie natural sweeteners made up of a common diterpenoid core and varying glycans. Thus, the diversity of glycans in composition, linkage, and isomerism results in the tremendous structural complexity of the SG family, which poses challenges for the precise identification and leads to the fact that SGs are frequently used in mixtures and their variances in biological activity remain largely unexplored. Here we show that a wild-type aerolysin nanopore can detect and discriminate diverse SG species through the modulable electro-osmotic flow effect at varied applied voltages. At low voltages, the neutral SG molecule was drawn and stuck in the pore entrance due to an energy barrier around R220 sites. The ensuing binding events enable the identification of the majority of SG species. Increasing the voltage can break the barrier and cause translocation events, allowing for the unambiguous identification of several pairs of SGs differing by only one hydroxyl group through recognition accumulation from multiple sensing regions and sites. Based on nanopore data of 15 SGs, a deep learning-based artificial intelligence (AI) model was created to process the individual blockage events, achieving the rapid, automated, and precise single-molecule identification and quantification of SGs in real samples. This work highlights the value of nanopore sensing for precise structural analysis of complex glycans-containing glycosides, as well as the potential for sensitive and rapid quality assurance analysis of glycoside products with the use of AI.

Asunto(s)

Aprendizaje Profundo , Diterpenos de Tipo Kaurano , Nanoporos , Diterpenos de Tipo Kaurano/química , Diterpenos de Tipo Kaurano/análisis , Glucósidos/química , Glucósidos/análisis , Glicósidos/química , Glicósidos/análisis