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.
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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 , HumanosRESUMEN
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.
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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 , MasculinoRESUMEN
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.
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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 fármacosRESUMEN
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.
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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 , MasculinoAsunto(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/farmacologíaRESUMEN
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.
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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 MembranaRESUMEN
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.
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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 , MutaciónRESUMEN
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.
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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/químicaRESUMEN
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.
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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 C57BLRESUMEN
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 ABTSâ¢+ 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.
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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 , PolifenolesRESUMEN
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.
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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/sangreRESUMEN
BACKGROUND: Right ventricular (RV) fibrosis is an important pathological change that occurs during the development of right heart failure (RHF) induced by pulmonary hypertension (PH). Dapagliflozin (DAPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has been shown to play a major role in left heart failure, but it is unclear whether it has a positive effect on RHF. This study aimed to clarify the effect of DAPA on PH-induced RHF and investigate the underlying mechanisms. METHODS: We conducted experiments on two rat models with PH-induced RHF and cardiac fibroblasts (CFs) exposed to pathological mechanical stretch or transforming growth factor-beta (TGF-ß) to investigate the effect of DAPA. RESULTS: In vivo, DAPA could improve pulmonary hemodynamics and RV function. It also attenuated right heart hypertrophy and RV fibrosis. In vitro, DAPA reduced collagen expression by increasing the production of matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9). Additionally, DAPA was found to reduce reactive oxygen species (ROS) levels in CFs and the right heart in rats. Similar to DAPA, the ROS scavenger N-acetylcysteine (NAC) exerted antifibrotic effects on CFs. Therefore, we further investigated the mechanism by which DAPA promoted collagen degradation by reducing ROS levels. CONCLUSIONS: In summary, we concluded that DAPA ameliorated PH-induced structural and functional changes in the right heart by increasing collagen degradation. Our study provides new ideas for the possibility of using DAPA to treat RHF.
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Compuestos de Bencidrilo , Colágeno , Fibrosis , Glucósidos , Insuficiencia Cardíaca , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno , Animales , Glucósidos/farmacología , Glucósidos/uso terapéutico , Compuestos de Bencidrilo/farmacología , Compuestos de Bencidrilo/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Especies Reactivas de Oxígeno/metabolismo , Ratas , Colágeno/metabolismo , Masculino , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Metaloproteinasa 9 de la Matriz/metabolismo , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/patología , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Metaloproteinasa 2 de la Matriz/metabolismo , Modelos Animales de EnfermedadRESUMEN
Alzheimer's disease (AD) is closely associated with the neurotoxic effects of amyloid-ß (Aß), leading to synaptic damage, neuronal loss and cognitive dysfunction. Previous in vitro studies have demonstrated the potential of corilagin to counteract Aß-induced oxidative stress, inflammatory injury, and ß-site amyloid precursor protein cleaving enzyme-1 (BACE1) activity in Aß production. However, the in vivo protective effects of corilagin on Alzheimer's disease remain unexplored. The purpose of this study was to investigate the protective effects of corilagin on APP/PS1 mice and the underlying mechanisms. The cognitive function of the mice was assessed by step-through passive avoidance and Morris water maze tests. Nissl staining was used to evaluate neuronal damage in the hippocampus. ELISA and Western blotting analyses were used to determine the associated protein expression. Transmission electron microscopy was utilized to observe the synaptic ultrastructure of hippocampal neurons. Golgi staining was applied to assess dendritic morphology and dendritic spine density in hippocampal pyramidal neurons. Immunohistochemistry and Western blotting were performed to examine the expression of synaptic-associated proteins. The results showed that corilagin improves learning and memory in APP/PS1 mice, reduces hippocampal neuron damage, inhibits BACE1 and reduces Aß generation. It also improves synaptic plasticity and the expression of synaptic-associated proteins. Corilagin effectively reduces Aß generation by inhibiting BACE1, ultimately reducing neuronal loss and enhancing synaptic plasticity to improve synaptic transmission. This study sheds light on the potential therapeutic role of corilagin in Alzheimer's disease.
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Enfermedad de Alzheimer , Secretasas de la Proteína Precursora del Amiloide , Péptidos beta-Amiloides , Precursor de Proteína beta-Amiloide , Disfunción Cognitiva , Glucósidos , Hipocampo , Taninos Hidrolizables , Ratones Transgénicos , Plasticidad Neuronal , Animales , Plasticidad Neuronal/efectos de los fármacos , Péptidos beta-Amiloides/metabolismo , Taninos Hidrolizables/farmacología , Taninos Hidrolizables/uso terapéutico , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , Ratones , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Glucósidos/farmacología , Glucósidos/uso terapéutico , Masculino , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Presenilina-1/genética , Modelos Animales de Enfermedad , Ácido Aspártico Endopeptidasas/metabolismo , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Cognición/efectos de los fármacosRESUMEN
Liver fibrosis is a pathological process that endangers human health, for which effective treatments remain elusive to date. Paeoniflorin (PAE), a pineane-type monoter penoid compound from the traditional Chinese medicine PaeoniaeRubra Radix, and metformin (MET), an oral biguanide hypoglycemic agent, both demonstrate anti-inflammatory and hepatoprotective effects. In current work, we first discovered that the combined treatment of PAE and MET synergistically inhibited the progression of liver fibrosis in two different animal models: therapeutic and preventive. This therapeutic effect is evidenced by a reduction in the expression levels of liver fibrosis markers and an improvement in histopathological characteristics. Mechanistic exploration further revealed that this combination therapy downregulated the expression of TGF-ß1 and p-Smad2, while upregulating Smad7 expression in both models. Importantly, we also found that this combinatorial approach significantly reduced hepatotoxicity and nephrotoxicity in both models. Our findings suggest an effective combination therapy for liver fibrosis and provide the possibility of therapeutic improvement for patients with liver fibrosis.
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Sinergismo Farmacológico , Glucósidos , Cirrosis Hepática , Metformina , Monoterpenos , Animales , Monoterpenos/farmacología , Monoterpenos/uso terapéutico , Monoterpenos/administración & dosificación , Glucósidos/farmacología , Glucósidos/uso terapéutico , Glucósidos/administración & dosificación , Metformina/farmacología , Metformina/uso terapéutico , Metformina/administración & dosificación , Ratones , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/patología , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/metabolismo , Masculino , Progresión de la Enfermedad , Ratones Endogámicos C57BL , Quimioterapia Combinada , Factor de Crecimiento Transformador beta1/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Proteína Smad2/metabolismo , Modelos Animales de EnfermedadRESUMEN
BACKGROUND AND OBJECTIVE: The objective of this study was to investigate the potential of salidroside (SAL) (a major active compound in Rhodiola rosea L.) in regulating osteoclast differentiation and function by modulating the HIF-1α pathway and its downstream target genes. METHODS: The expression of HIF-1α and its downstream target genes was examined at both mRNA and protein levels in osteoclasts treated with SAL. Immunofluorescence analysis was performed to assess the nuclear translocation and transcriptional activity of HIF-1α in response to SAL. MTT, flow cytometry, qPCR, TRAP staining and bone resorption assays were used to evaluate the potential effect of salidroside on osteoclasts. RESULTS: SAL enhanced the expression of HIF-1α and its downstream target genes in osteoclasts. Immunofluorescence analysis confirmed the facilitation of HIF-1α nuclear translocation and transcriptional activity by SAL. In addition, SAL enhanced osteoclast viability, differentiation and bone resorption activity in an autocrine manner through HIF-1α/VEGF, IL-6 and ANGPTL4 pathways. CONCLUSION: SAL promotes osteoclast proliferation, differentiation and bone resorption through HIF-1α/VEGF, IL-6 and ANGPTL4 pathways.
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Glucósidos , Subunidad alfa del Factor 1 Inducible por Hipoxia , Osteoclastos , Osteogénesis , Fenoles , Glucósidos/farmacología , Fenoles/farmacología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Osteoclastos/efectos de los fármacos , Animales , Ratones , Osteogénesis/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Células RAW 264.7 , Interleucina-6/metabolismo , Interleucina-6/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Resorción Ósea , Transducción de Señal/efectos de los fármacos , Proteína 4 Similar a la Angiopoyetina/metabolismo , Proteína 4 Similar a la Angiopoyetina/genética , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacosRESUMEN
BACKGROUND: Traumatic brain injury (TBI) could induce multiple forms of cell death, ferroptosis, a novel form of cell death distinct from apoptosis and autophagy, plays an important role in disease progression in TBI. Therapies targeting ferroptosis are beneficial for recovery from TBI. Paeoniflorin (Pae) is a water-soluble monoterpene glycoside and the active ingredient of Paeonia lactiflora pall. It has been shown to exert anti-inflammatory and antioxidant effects. However The effects and mechanisms of paeoniflorin on secondary injury after TBI are unknown. PURPOSE: To investigate the mechanism by which Pae regulates ferroptosis after TBI. METHODS: The TBI mouse model and cortical primary neurons were utilized to study the protective effect of paeoniflorin on the brain tissue after TBI. The neuronal cell ferroptosis model was established by treating cortical primary neurons with erastin. Liproxstatin-1(Lip-1) was used as a positive control drug. Immunofluorescence staining, Nissl staining, biochemical analyses, pharmacological analyses, and western blot were used to evaluate the effects of paeoniflorin on TBI. RESULTS: Pae significantly ameliorated neuronal damage after TBI, inhibited mitochondrial damage, increased glutathione peroxidase 4 (GPX4) activity, decreased malondialdehyde (MDA) production, restored neurological function and inhibited cerebral edema. Pae promotes the degradation of P53 in the form of proteasome, promotes its ubiquitination, and reduces the stability of P53 by inhibiting its acetylation, thus alleviating the P53-mediated inhibition of cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11) by P53. CONCLUSION: Pae inhibits ferroptosis by promoting P53 ubiquitination out of the nucleus, inhibiting P53 acetylation, and modulating the SLC7A11-GPX4 pathway.
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Lesiones Traumáticas del Encéfalo , Ferroptosis , Glucósidos , Monoterpenos , Proteína p53 Supresora de Tumor , Glucósidos/farmacología , Ferroptosis/efectos de los fármacos , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Lesiones Traumáticas del Encéfalo/metabolismo , Animales , Monoterpenos/farmacología , Proteína p53 Supresora de Tumor/metabolismo , Acetilación , Ratones , Masculino , Neuronas/efectos de los fármacos , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Paeonia/química , Fármacos Neuroprotectores/farmacologíaRESUMEN
BACKGROUND: Although blood flow is restored after treatment of myocardial infarction (MI), myocardial ischemia and reperfusion (I/R) can cause cardiac injury, which is a leading cause of heart failure. Gastrodin (GAS) exerts protective effects against brain, heart, and kidney I/R. However, its pharmacological mechanism in myocardial I/R injury (MIRI) remains unclear. PURPOSE: GAS regulates autophagy in various diseases, such as acute hepatitis, vascular dementia, and stroke. We hypothesized that GAS could repair mitochondrial damage and regulate autophagy to protect against MIRI. STUDY DESIGN: Male C57BL/6 mice and H9C2 cells were subjected to I/R and hypoxia-reoxygenation (H/R) injury after GAS administration, respectively, to assess the impact of GAS on cardiomyocyte phenotypes, heart, and mitochondrial structure and function. The effect of GAS on cardiac function and mitochondrial structure in patients undergoing cardiac surgery has been observed in clinical practice. METHODS: The effects of GAS on cardiac structure and function, mitochondrial structure, and expression of related molecules in an animal model of MIRI were evaluated using immunohistochemical staining, enzyme-linked immunosorbent assay (ELISA), transmission electron microscopy, western blotting, and gene sequencing. Its effects on the morphological, molecular, and functional phenotypes of cardiomyocytes undergoing H/R were observed using immunohistochemical staining, real-time quantitative PCR, and western blotting. RESULTS: GAS significantly reduces myocardial infarct size and improves cardiac function in MIRI mice in animal models and increases cardiomyocyte viability and reduces cardiomyocyte damage in cellular models. In clinical practice, myocardial injury was alleviated with better cardiac function in patients undergoing cardiac surgery after the application of GAS; improvements in mitochondria and autophagy activation were also observed. GAS primarily exerts cardioprotective effects through activation of the PINK1/Parkin pathway, which promotes mitochondrial autophagy to clear damaged mitochondria. CONCLUSION: GAS can promote mitophagy and preserve mitochondria through PINK1/Parkin, thus indicating its tremendous potential as an effective perioperative myocardial protective agent.
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Alcoholes Bencílicos , Glucósidos , Ratones Endogámicos C57BL , Mitofagia , Daño por Reperfusión Miocárdica , Miocitos Cardíacos , Proteínas Quinasas , Ubiquitina-Proteína Ligasas , Animales , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Alcoholes Bencílicos/farmacología , Glucósidos/farmacología , Mitofagia/efectos de los fármacos , Masculino , Ubiquitina-Proteína Ligasas/metabolismo , Ratones , Miocitos Cardíacos/efectos de los fármacos , Proteínas Quinasas/metabolismo , Línea Celular , Modelos Animales de Enfermedad , Humanos , Miocardio/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Cardiotónicos/farmacologíaRESUMEN
A previous study showed that high-glucose (HG) conditions induce mitochondria fragmentation through the calcium-mediated activation of extracellular signal-regulated kinase 1/2 (ERK 1/2) in H9C2 cells. This study tested whether empagliflozin could prevent HG-induced mitochondria fragmentation through this pathway. We found that exposing H9C2 cells to an HG concentration decreased cell viability and increased cell apoptosis and caspase-3. Empagliflozin could reverse the apoptosis effect of HG stimulation on H9C2 cells. In addition, the HG condition caused mitochondria fragmentation, which was reduced by empagliflozin. The expression of mitochondria fission protein was upregulated, and fusion proteins were downregulated under HG stimulation. The expression of fission proteins was decreased under empagliflozin treatment. Increased calcium accumulation was observed under the HG condition, which was decreased by empagliflozin. The increased expression of ERK 1/2 under HG stimulation was also reversed by empagliflozin. Our study shows that empagliflozin could reverse the HG condition, causing a calcium-dependent activation of the ERK 1/2 pathway, which caused mitochondria fragmentation in H9C2 cells.
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Apoptosis , Compuestos de Bencidrilo , Calcio , Glucosa , Glucósidos , Sistema de Señalización de MAP Quinasas , Mitocondrias , Apoptosis/efectos de los fármacos , Compuestos de Bencidrilo/farmacología , Glucósidos/farmacología , Glucosa/metabolismo , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Calcio/metabolismo , Animales , Ratas , Línea Celular , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Dinámicas Mitocondriales/efectos de los fármacos , Caspasa 3/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/metabolismoRESUMEN
During the development of animal organs, various adverse stimuli or toxic environments can induce oxidative stress and delay ovarian development. Paeoniflorin (PF), the main active ingredient of the traditional Chinese herb Paeonia lactiflora Pall., has protective effects on various diseases by preventing oxidative stress. However, the mechanism by which PF attenuates oxidative damage in mouse ovaries remains unclear. We evaluated the protective effects of PF on ovaries in an H2O2-induced mouse oxidative stress model. The H2O2-induced mouse ovarian oxidative stress model was used to explore the protective effect of PF on ovarian development. Histology and follicular development were observed. We then detected related indicators of cell apoptosis, oxidative stress, and autophagy in mouse ovaries. We found that PF inhibited H2O2-induced ovarian cell apoptosis and ferroptosis and promoted granulosa cell proliferation. PF prevented oxidative stress by increasing nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression levels. In addition, the autophagic flux of ovarian cells was activated and was accompanied by increased lysosomal biogenesis. Moreover, PF-mediated autophagy was involved in clearing mitochondria damaged by H2O2. Importantly, PF administration significantly increased the number of primordial follicles, primary follicles, secondary follicles, and antral follicles. PF administration improved ovarian sizes compared with the H2O2 group. The present study suggested that PF administration reversed H2O2-induced ovarian developmental delay and promoted follicle development. PF-activated mitophagy is crucial for preventing oxidative stress and improving mitochondrial quality.
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Glucósidos , Peróxido de Hidrógeno , Mitofagia , Ovario , Estrés Oxidativo , Animales , Femenino , Estrés Oxidativo/efectos de los fármacos , Glucósidos/farmacología , Ratones , Ovario/efectos de los fármacos , Ovario/metabolismo , Mitofagia/efectos de los fármacos , Peróxido de Hidrógeno/metabolismo , Monoterpenos/farmacología , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Hemo-Oxigenasa 1/metabolismo , Proliferación Celular/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Células de la Granulosa/efectos de los fármacos , Células de la Granulosa/metabolismoRESUMEN
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have a variety of cardiovascular and renoprotective effects and have been developed as novel agents for the treatment of heart failure. However, the beneficial mechanisms of SGLT2i on cardiac tissue need to be investigated further. In this study, we established a mouse model of acute myocardial infarction (AMI) using coronary artery constriction surgery and investigated the role of dapagliflozin (DAPA) in protecting cardiomyocytes from hypoxic injury induced by AMI. In vitro experiments were done using hypoxic cultured H9c2 ventricular cells to verify this potential mechanism. Expression of the SIRT family and related genes and proteins was verified by qPCR, Western blotting and immunofluorescence staining, and the intrinsic potential mechanism of cardiomyocyte death due to AMI and hypoxia was comprehensively investigated by RNA sequencing. The RNA sequencing results of cardiomyocytes from AMI mice showed that the SIRT family may be mainly involved in the mechanisms of hypoxia-induced cardiomyocyte death. In vitro hypoxia-induced ventricular cells showed the role of dapagliflozin in conferring resistance to hypoxic injury in cardiomyocytes. It showed that SIRT1/3/6 were downregulated in H9c2 cells in a hypoxic environment, and the addition of dapagliflozin significantly increased the gene and protein expression of SIRT1, 3 and 6. We then verified the underlying mechanisms induced by dapagliflozin in hypoxic cardiomyocytes using RNA-seq, and found that dapagliflozin upregulated the hypoxia-induced gene downregulation, which includes ESRRA, EPAS1, AGTRAP, etc., that associated with SIRTs-related and apoptosis-related signaling to prevent H9c2 cell death. This study provides laboratory data for SGLT2i dapagliflozin treatment of AMI and confirms that dapagliflozin can be used to treat hypoxia-induced cellular necrosis in cardiomyocytes, in which SIRT1 and SIRT3 may play an important role. This opens up further opportunities for SGLT2i in the treatment of heart disease.