OBJECTIVES: To explore the protective effect of vitexin-4 ″-O-glucoside (VOG) against acetaminophen-induced acute liver injury in mice and its underlying mechanism. METHODS: C57BL/6 mice were randomly divided into 4 groups: normal control group, model control group, low-dose group of VOG (30 mg/kg), and high-dose group of VOG (60 mg/kg). Acute liver injury was induced by intraperitoneal injection of acetaminophen (500 mg/kg). VOG was administrated by gavage 2 h before acetaminophen treatment in VOG groups. The protective effect of VOG against acute liver injury was evaluated by detecting alanine transaminase (ALT), aspartate transaminase (AST) levels and hematoxylin and eosin staining. The malondialdehyde (MDA) content, superoxide dismutase (SOD) and catalase (CAT) activity in liver were detected to evaluate the hepatic oxidative stress. The expression levels of tumor necrosis factor (TNF)-α, Il-1β, and Il-6 in liver were detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The expression levels of phosphorylated c-jun N-terminal kinase (JNK)/JNK, phosphorylated p38/p38, inositol-requiring enzyme 1 alpha (IRE-1α), X-box binding protein 1s (XBP1s), and glucose-regulated protein 78 (GRP78) in liver were detected by Western blotting. An endoplasmic reticulum stress model was established in AML-12 cells using tunicamycin. Cell viability was assessed using the CCK-8 assay, and the degree of cell damage was detected by lactate dehydrogenase (LDH) assay. The gene expression levels of Ire-1α, Xbp1s, and Grp78 in the cells were detected using qRT-PCR. RESULTS: In the animal experiments, compared with the model control group, VOG significantly improved plasma ALT and AST levels, liver MDA content, as well as SOD and CAT activities. VOG also reduced the expression levels of Tnf-α, Il-1β, and Il-6 in the liver, and improved protein phosphorylation levels of JNK and p38, as well as the protein expression levels of IRE-1α, XBP1s, and GRP78. In cell experiments, VOG pretreatment enhanced cell viability, reduced LDH release and decreased the mRNA expression of Ire-1α, Xbp1s, and Grp78. CONCLUSIONS VOG can suppress inflammation and oxidative stress, and alleviate acetaminophen-induced acute liver injury in mice by suppressing endoplasmic reticulum stress and modulating the MAPK signaling pathway.
Animals ; Endoplasmic Reticulum Chaperone BiP ; Mice ; Acetaminophen/adverse effects* ; Mice, Inbred C57BL ; Chemical and Drug Induced Liver Injury/prevention & control* ; Glucosides/therapeutic use* ; Oxidative Stress/drug effects* ; Male ; Apigenin/therapeutic use* ; Liver/drug effects* ; Tumor Necrosis Factor-alpha/metabolism* ; Endoplasmic Reticulum Stress/drug effects* ; X-Box Binding Protein 1 ; Endoribonucleases/metabolism* ; Interleukin-1beta/metabolism* ; Interleukin-6/metabolism* ; Protein Serine-Threonine Kinases

OBJECTIVE: To evaluate the protective effects of gentiopicroside (GPS) against reactive oxygen species (ROS)-induced NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation in endothelial cells, aiming to reduce atherosclerosis. METHODS: Eight-week-old male ApoE-deficient mice were randomly divided into 2 groups (n=10 per group): the vehicle group and the GPS treatment group. Both groups were fed a high-fat diet for 16 weeks. GPS (40 mg/kg per day) was administered by oral gavage to the GPS group, while the vehicle group received an equivalent volume of the vehicle solution. At the end of the treatment, blood and aortic tissues were collected for assessments of atherosclerosis, lipid profiles, oxidative stress, and molecular expressions related to NLRP3 inflammasome activation, ROS production, and apoptosis. Additionally, in vitro experiments on human aortic endothelial cells treated with oxidized low-density lipoprotein (ox-LDL) were conducted to evaluate the effects of GPS on NLRP3 inflammasome activation, pyroptosis, apoptosis, and ROS production, specifically examining the role of the sirtuin 1 (SIRT1)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. SIRT1 and Nrf2 inhibitors were used to confirm the pathway's role. RESULTS: GPS treatment significantly reduced atherosclerotic lesions in the en face aorta (P<0.01), as well as in the thoracic and abdominal aortic regions, and markedly decreased sinus lesions within the aortic root (P<0.05 or P<0.01). Additionally, GPS reduced oxidative stress markers and proinflammatory cytokines, including interleukin (IL)-1 β and IL-18, in lesion areas (P<0.05, P<0.01). In vitro, GPS inhibited ox-LDL-induced NLRP3 activation, as evidenced by reduced NLRP3 (P<0.01), apoptosis-associated speck-like protein containing a CARD, cleaved-caspase-1, and cleaved-gasdermin D expressions (all P<0.01). GPS also decreased ROS production, apoptosis, and pyroptosis, with the beneficial effects being significantly reversed by SIRT1 or Nrf2 inhibitors. CONCLUSION GPS exerts an antiatherogenic effect by inhibiting ROS-dependent NLRP3 inflammasome activation via the SIRT1/Nrf2 pathway.
NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Reactive Oxygen Species/metabolism* ; Iridoid Glucosides/therapeutic use* ; NF-E2-Related Factor 2/metabolism* ; Animals ; Atherosclerosis/metabolism* ; Inflammasomes/drug effects* ; Male ; Sirtuin 1/metabolism* ; Signal Transduction/drug effects* ; Humans ; Endothelial Cells/pathology* ; Mice ; Oxidative Stress/drug effects* ; Apoptosis/drug effects* ; Lipoproteins, LDL ; Mice, Inbred C57BL

OBJECTIVES: To assess the therapeutic effect of aucubin in mice with knee osteoarthritis (KOA) and investigate the underlying mechanism. METHODS: Sixty C57BL/6J mice were randomized equally into sham operation group, KOA model group, glucosamine (positive control) treatment group, and low-, medium-, and high-dose aucubin treatment groups (2, 4, and 8 mg/kg, respectively). KOA mouse models were established by transection of the anterior cruciate ligament (ACL), and the treatment was initiated on day 1 postoperatively and administered weekly for 8 weeks. Safranin O-fast green staining, immunohistochemistry, and microCT were used to evaluate the changes in cartilage pathology, inflammatory protein expression, and subchondral bone volume fraction (BV/TV). The expression levesl of COL2, SOX9, p-P65, IL-1β and MMP13 proteins in the cartilage tissues were detected using Western blotting. In a chondrocyte model with IL-1β treatment for mimicking KOA, the effect of aucubin on chondrogenic differentiation was observed with Alcian blue and Safranin O staining, and cellular COL2, SOX9 and TNF‑α mRNA expressions were detected with RT-qPCR. RESULTS: Compared with those in the model group, the mouse models receiving aucubin treatment showed significantly upregulated COL2 and SOX9 protein levels and downregulated p-P65, IL-1β and MMP13 expressions in the cartilage tissues. In the IL-1β-induced chondrocyte model, aucubin treatment significantly upregulated the mRNA expressions of SOX9 and COL2 but lowered the mRNA expression of TNF-α. Alcian blue and Safranin O staining confirmed that aucubin promoted the synthesis of cartilage extracellular matrix and enhanced chondrogenic differentiation of the cells. CONCLUSIONS Aucubin can effectively alleviate KOA in mice by inhibiting NF‑κB-mediated cartilage inflammation, promoting cartilage matrix synthesis, and improving subchondral bone microstructure.
Animals ; Mice, Inbred C57BL ; Mice ; Osteoarthritis, Knee/drug therapy* ; Signal Transduction/drug effects* ; NF-kappa B/metabolism* ; Iridoid Glucosides/therapeutic use* ; SOX9 Transcription Factor/metabolism* ; Chondrocytes/drug effects* ; Male ; Interleukin-1beta/metabolism* ; Matrix Metalloproteinase 13/metabolism* ; Collagen Type II/metabolism* ; Disease Models, Animal

OBJECTIVES: Patients with heart failure with reduced ejection fraction (HFrEF) often require diuretics during hospitalization to alleviate fluid retention and improve prognosis. However, the diuretic efficacy and renal impact of dapagliflozin in this population remain unclear. This study aims to investigate the effects of dapagliflozin on diuresis and renal function in hospitalized patients with HFrEF. METHODS: This retrospective analysis included clinical data from 200 hospitalized HFrEF patients treated at Xiangya Hospital of Central South University between January 2021 and September 2022. Patients were divided into 2 groups based on whether they received dapagliflozin: a standard treatment group (n=120) and a dapagliflozin treatment group (n=80). The following were compared between the 2 groups during hospitalization: The 24-hour average difference of liquid intake and output during the first 5 days, urine output, cumulative urine output, diuretic efficiency, estimated glomerular filtration rate (eGFR), N-terminal pro B-type natriuretic peptide (NT-proBNP), hospitalization costs, drug costs, and cost-effectiveness ratio (C/E). RESULTS: 1) Primary outcome: The 24-hour average difference of liquid intake and output during the first 5 days was significantly higher in the dapagliflozin treatment group than in the standard treatment group (P<0.05). 2) Secondary outcomes: The 24-hour average urine volume, cumulative urine volume and diuretic efficiency in the first 5 days of dapagliflozin treatment group were higher than those in the standard treatment group, and the differences were statistically significant (all P<0.05). Among patients with impaired renal function on admission [eGFR between 45 and 90 mL/(min·1.73 m²)], the change in eGFR after treatment was significantly smaller in the dapagliflozin treatment group (P<0.05). For patients with normal renal function on admission [eGFR >90 mL/(min·1.73 m²)], the difference in eGFR changes between 2 groups was not significant (P>0.05). NT-proBNP decreased more in the dapagliflozin treatment group than in the standard treatment group during hospitalization (P<0.05). 3) Other indicators: The length of hospital stay was longer in the dapagliflozin treatment group. However, discharge systolic blood pressure, drug costs, and hospitalization costs were all higher in the standard group, though differences were not statistically significant (all P>0.05). The C/E was more favorable in the dapagliflozin treatment group (425.36 vs. 476.67). CONCLUSIONS In hospitalized patients with chronic HFrEF, dapagliflozin treatment increased 24-hour average difference of liquid intake and output and total urine output, reduced NT-proBNP levels, and showed a milder decline in eGFR in those with pre-existing renal impairment. Discharge blood pressure, drug costs, and hospital stay were not significantly affected. While standard therapy may offer better short-term clinical benefits, dapagliflozin demonstrated a superior short-term cost-effectiveness profile.
Humans ; Benzhydryl Compounds/pharmacology* ; Glucosides/pharmacology* ; Retrospective Studies ; Male ; Female ; Heart Failure/physiopathology* ; Hospitalization ; Middle Aged ; Aged ; Glomerular Filtration Rate/drug effects* ; Diuretics/therapeutic use* ; Kidney/drug effects* ; Natriuretic Peptide, Brain/blood* ; Stroke Volume ; Peptide Fragments/blood* ; Diuresis/drug effects*

OBJECTIVE: To investigate the therapeutic effects of total glucosides of paeony (TGP) on psoriasis based on the immunomodulatory effect of dermal mesenchymal stem cells (DMSCs). METHODS: A total of 30 male BALB/c mice were divided into 6 groups (n=5 in each) by a random number table method, including control, psoriasis model (model, 5% imiquimod cream 42 mg/d), low-, medium- and high-dose TGP (50, 100, and 200 mg/kg, L, M-, and H-TGP, respectively), and positive control group (2.5 mg/kg acitretin). After 14 days of continuous administration, the skin's histopathological changes, apoptosis, secretion of inflammatory cytokines, and proportion of regulatory T cells (Treg) and T helper cell 17 (Th17) were evaluated using hematoxylin-eosin (HE) staining, TdT-mediated dUTP nick end labeling staining, enzyme-linked immunosorbent assay, and flow cytometry, respectively. DMSCs were further isolated from the skin tissues of normal and psoriatic mice, and the cell morphology, phenotype, and cycle were observed. Furthermore, TGP was used to treat psoriatic DMSCs to analyze the effects on the DMSCs immune regulation. RESULTS: TGP alleviated skin pathological injury, reduced epidermis layer thickness, inhibited apoptosis, and regulated the secretion of inflammatory cytokines and the proportion of Treg and Th17 in the skin tissues of psoriatic mice (P<0.05 or P<0.01). There was no significant difference in cell morphology and phenotype between control and psoriatic DMSCs (P>0.05), however, more psoriatic DMSCs remained in G₀/G₁ phase compared with the normal DMSCs (P<0.01). TGP treatment of psoriatic DMSCs significantly increased cell viability, decreased apoptosis, relieved inflammatory response, and inhibited the expression of toll-like receptor 4 and P65 (P<0.05 or P<0.01). CONCLUSION TGP may exert a good therapeutic effect on psoriasis by regulating the immune imbalance of DMSCs.
Male ; Animals ; Mice ; Psoriasis/drug therapy* ; Cytokines ; Glucosides/therapeutic use* ; Mesenchymal Stem Cells ; Mice, Inbred BALB C ; Paeonia

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. It is known that aucubin (AU) exerts anti-inflammatory activity, but its effects and mechanisms in RA are unclear. This study investigated the anti-inflammatory effects and mechanisms of AU in vivo and in vitro. Human fibroblast-like synoviocyte cells from patients with RA (HFLS-RA), RAW264.7 cells, and MC3T3-E1 cells were used to evaluate the effects of AU on migration, invasion, apoptosis, osteoclast differentiation and production. Immunofluorescence was used to observe nuclear translocation of nuclear factor (NF)-κB, the double luciferase reporter gene method was used to observe NF-κB-p65 activity in AU-treated MC3T3-E1 cells. RT-qPCR was used to measure expression of bone metabolism and inflammation-related genes, and western blot was used to measure bone metabolism and NF-κB protein expression levels. Collagen-induced arthritis (CIA) rat model was used for pharmacodynamics study. Arthritis indexes were measured in the ankle and knee, histological staining and Micro-computed tomography were performed on the ankle joints. Also, inflammatory factor gene expression and the levels of NF-κB-related proteins were detected as in vitro. AU effectively inhibited HFLS-RA cell migration and invasion, promoted apoptosis, and inhibited RAW264.7 cell differentiation into osteoclasts, as well as inhibited NF-κB-p65 activity in MC3T3-E1 cells. Notably, AU significantly reduced the gene expression levels of three cell-related inflammatory factors and bone metabolism factors, effectively inhibited the expression of p-Iκκα β, p-IκBα, and p-p65 proteins. In vivo, AU relieved joint inflammation, reduced related inflammatory factors, and inhibited NF-κB signaling. It could be used to treat RA-related synovial inflammation and bone destruction through the NF-κB pathway.
Animals ; Anti-Inflammatory Agents/therapeutic use* ; Arthritis, Experimental ; Arthritis, Rheumatoid/drug therapy* ; Cells, Cultured ; Humans ; Inflammation/pathology* ; Iridoid Glucosides ; NF-kappa B/metabolism* ; Rats ; X-Ray Microtomography

Objective: To evaluate the impact of empagliflozin on peak oxygen uptake (VO₂peak) in patients with heart failure with mildly reduced ejection fraction (HFmrEF). Methods: In this randomized controlled trial, consecutive HFmrEF patients admitted to the Department of Cardiology of China-Japan Friendship Hospital from September 2019 to October 2020 were screened, and randomly assigned to empagliflozin group (EG) or conventional group (CG) using a random number table. The enrolled patients were treated according to the guidelines, and patients in the empagliflozin group received additional empagliflozin (10 mg, once a day, orally) on top of the conventional treatment. The primary end points were VO₂peak at 6 months after treatment, and the secondary end points included other parameters of cardiopulmonary exercise test (CPET), 6-minute walking distance, N-terminal B-type pro-natriuretic peptide (NT-proBNP) level, and Kansas City Cardiomyopathy Questionnaire (KCCQ) score. Results: A total of 112 patients were included (mean age 69 (57, 78) years, 84 male (75.0%)). There were 55 cases in CG group and 57 cases in EG group. There were no significant differences in baseline data including age, sex, body mass index, left ventricular ejection fraction, systolic blood pressure, heart rate, estimated glomerular filtration rate, glycosylated hemoglobin, hemoglobin, NT-proBNP, daily dose of tolasemi, combined medication, CPET parameters, the proportion of New York Heart Association heart function Ⅲ/Ⅳ, history of coronary heart disease, history of hypertension, history of diabetes (all P>0.05). At 6 months after treatment, VO₂peak was significantly higher in EG group than in CG group(P=0.023). VE/VCO₂ slope was significantly lower in EG group than in CG group(P=0.034). Oxygen uptake efficiency slope was significantly higher in EG group than in CG group(P=0.038). The level of NT-proBNP was significantly lower in EG group than in CG group(P=0.020). Six-minute walking distance was significantly higher in EG group than in CG group(P=0.037). KCCQ score was significantly higher in EG group than in CG group(P=0.048). Exercise oscillatory ventilation decreased in both groups (1 case in each group, P>0.05). Conclusion: Empagliflozin can significantly improve VO₂peak in patients with HFmrEF.
Aged ; Benzhydryl Compounds ; Glucosides ; Heart Failure/drug therapy* ; Humans ; Male ; Natriuretic Peptide, Brain ; Oxygen/therapeutic use* ; Peptide Fragments ; Stroke Volume/physiology* ; Ventricular Dysfunction, Left ; Ventricular Function, Left

OBJECTIVE: To study the clinical effect and mechanism of total glucosides of paeony (TGP) in the adjuvant therapy for children with Henoch-Schönlein purpura nephritis (HSPN). METHODS: Sixty-four HSPN children with moderate proteinuria were divided into a TGP treatment group ( RESULTS: Compared with the healthy children before treatment, the children with HSPN had higher proportion of Tfh cells and expression levels of IL-21 and IL-4 ( CONCLUSIONS TGP has a marked clinical effect in the treatment of HSPN and can reduce the inflammatory response of the kidney and exert a protective effect on the kidney by inhibiting the proliferation of Tfh cells and downregulating the expression of IL-21 and IL-4 in plasma.
Child ; Glucosides/therapeutic use* ; Humans ; Nephritis ; Paeonia ; Prospective Studies ; Purpura, Schoenlein-Henoch/drug therapy*

The efficacy of gastrodin as a Chinese herbal medicine extract in the treatment of tension-type headache has been confirmed. This paper systematically reviewed the efficacy and safety of gastrodin in the treatment of tension-type headache, aiming to provide a new choice for the treatment of this disease. In this study, four Chinese databases, four English databases and two trial registries were searched from the date of establishment to September 2020. The related randomized controlled trials(RCTs) were screened out according to the predetermined criteria. The bias risk assessment tool developed by Cochrane collaboration was used to evaluate the quality of the reports. RevMan 5.4.1 was used for Meta-analysis, and GRADE system for the evidence-based evaluation on the quality of outcome indicators. A total of 177 articles were retrieved and 8 articles were finally included for analysis, with a total sample size of 1 091 cases, which included 565 cases in the treatment group and 526 cases in the control group. The overall quality of included stu-dies was not high. The results of Meta-analysis are as follows:(1)In terms of headache frequency, gastrodin group was better than wes-tern medicine group(MD=-2.90, 95%CI[-3.76,-2.03], P<0.000 01).(2)In terms of number of abnormal blood vessels in TCD, gastrodin group was better than western medicine group(MD=-88.96, 95%CI[-102.36,-75.55], P<0.000 01).(3)In terms of effective rate, gastrodin group was better than western medicine group(RR=1.47, 95%CI[1.29, 1.68], P<0.000 01). The results of subgroup analysis are as follows:(1)Effective rate based on age, for the patients upper age limit 40-46 years old, gastro-din group was better than western medicine group(RR=1.69, 95%CI[1.50, 1.90], P<0.000 01); for the patients upper age limit 55-60 years old, gastrodin group was better than western medicine group(RR=1.27, 95%CI[1.16, 1.38], P<0.000 01).(2)Effective rate based on dosage form, both the gastrodin capsules and injection groups were better than western medicine group(RR_(capsules)=1.42, 95%CI[1.08, 1.88], P=0.01; RR_(injection)=1.50, 95%CI[1.26, 1.77], P<0.000 01). GRADE evaluation showed that the above outcomes had low quality of evidence. Only one article detailed the occurrence of adverse reactions and thus the present study cannot make a positive conclusion on the safety of gastrodin in the treatment of tension-type headache. The small number and low quality of the included reports affected the reliability of the results. In the future, more high-quality randomized controlled trails are needed to improve the evaluation on the efficacy and safety of gastrodin in the treatment of tension-type headache.
Adult ; Benzyl Alcohols/therapeutic use* ; Drugs, Chinese Herbal/adverse effects* ; Glucosides ; Humans ; Middle Aged ; Reproducibility of Results ; Tension-Type Headache

OBJECTIVE: To investigate the effect and mechanism of glucosides of chaenomeles speciosa (GCS) on ischemia/reperfusion-induced brain injury in mouse model. METHODS: Fifty 8-week C57BL/C mice were randomly divided into five groups with 10 in each group:sham group, model group, GCS 30 mg/kg group, GCS 60 mg/kg group and GCS 90 mg/kg group, and the GCS was administrated by gavage (once a day) for 14 d. HE staining was performed to investigate the cell morphology; the Zea-Longa scores were measured for neurological activity; TUNEL staining was performed to investigate the cell apoptosis; ELISA was used to detected the oxidative stress and inflammation; Western Blot was performed to investigate the key pathway and neurological functional molecules. RESULTS: Compared with the sham group, the brain tissues in model group were seriously damaged, presenting severe cell apoptosis, oxidative stress and inflammation, associated with increased NF-κB P65 and TNF-α levels as well as decreased myelin associate glycoprotein (MAG) and oligodendrocyte-myelin glycoprotein (OMgp)levels (all <0.01). Compared with the model group, the brain tissues in GCS groups were ameliorated, and cell apoptosis, oxidative stress and inflammation were inhibited, associated with decreased NF-κB P65 and TNF-α levels as well as increased MAG and OMgp levels (all <0.01), which were more markedly in GCS 60 mg/kg group. CONCLUSIONS GCS can inhibit the NF-κB P65 and TNF-α, reduce the oxidative stress and inflammation, decrease the cell apoptosis in mouse ischemia/reperfusion-induced brain injury model, and 60 mg/kg GCS may be the optimal dose.
Animals ; Brain ; drug effects ; Brain Injuries ; drug therapy ; Gene Expression Regulation ; drug effects ; Glucosides ; pharmacology ; therapeutic use ; Mice ; Mice, Inbred C57BL ; NF-kappa B ; genetics ; Oxidative Stress ; drug effects ; Plant Extracts ; pharmacology ; Random Allocation ; Rosaceae ; chemistry ; Tumor Necrosis Factor-alpha ; genetics