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The global incidence rate of nonalcoholic steatohepatitis (NASH) continues to rise. The pathogenesis of NASH is complex, and there is no effective clinical treatment. Previous study has shown that DEAD box protein 5 (DDX5) can significantly alleviate the NASH process in mice. This study screened the natural product library of the research group and found that the active compound hypercalin B (HB) in Hypericum beanii N. Robson, a traditional Chinese medicine, can upregulate the expression of DDX5 protein in a dose-dependent manner. In this study, an in vitro model of NASH stimulated by palmitic acid (PA) and an animal model of NASH induced by the methionine- and choline-deficient diet (MCD) were constructed. Different concentrations of HB were used to investigate the effect and mechanism of HB in alleviating NASH progression. All animal experiments in this paper were approved by the Ethics Committee of China Pharmaceutical University (NO: 2021-02-003). In vitro model results showed that HB significantly reduced the intracellular lipid deposition induced by free fatty acid (FFA). Animal experiments showed that HB improved liver injury by significantly reducing lipid accumulation in the liver of NASH mice, and reducing serum aspartate transaminase (AST) and alanine transaminase (ALT) levels. Moreover, HB could inhibit liver inflammation by reducing the mRNA levels of liver pro-inflammatory cytokines including interleukin 6 (IL-6), interleukin 1β (IL-1β), and tumor necrosis factor α (TNFα). Further research showed that HB could reduce the phosphorylation level of the mechanical target of rapamycin (mTOR) and reduce the expression of sterol regulatory element binding protein 1 (SREBP1) and fatty acid synthase (FASN), thereby improving lipid metabolism and alleviating NASH progression, and the effects of HB against NASH were dependent on DDX5. In conclusion, HB can improve lipid metabolism and inhibit inflammatory activation by suppressing mTORC1 pathway via upregulating DDX5 protein, and showed promising anti-NASH activity in vitro and in vivo.
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Two new type B polycyclic polyprenylated acylphloroglucinols (PPAPs) (1 and 2) and a known biogenetic precursor hyperbeanol Q (3) were isolated from the root extract of Hypericum beanii, a medicinal plant widespread in southwest China. Their chemical structures were elucidated by 1D/2D NMR and HRESIMS data analysis, and absolute configurations were determined through detailed electric circular dichroism (ECD) analysis including ECD exciton chirality, Mo
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Objective Blood-brain barrier(BBB)may stop over 95%of the drugs delivered from entering the brain.This study aimed to establish a BBB model in vitro,detect the ability of the nano drug delivery system to penetrate the BBB,and observe its effect on angiogenesis and neuron cell proliferation after cerebral infarction. Methods A BBB model was established in vitro and the penetrability of PHRO through the BBB was detected by transwell assay.PBS,Rg1,and PHRO were placed in the upper chamber,and the content of Rg1 in the lower chamber was measured by HPLC.The effect of PHRO on angiogenesis was assessed with the in vitro tube formation model and the expression levels of the angiogenesis -related genes VEGFA and Dll4 determined by real time fluorescence quantitative PCR.Brain endothelial cells were incubated with 10 μL PBS(the control group),10 μmol/L Rg1(the Rg1 group),and PHRO(containing 10 μmol/L Rg1,the PHRO group)for 24 hours,and the SH5Y cells incubated the same way in the three groups for 72 hours.The effects of PHRO on the proliferation and apoptosis of the SH5Y cells were detected by MTT assay and flow cytometry respectively.The SH5Y cells were treated with 10 μL PBS(the PBS con-trol group),1 mmol/L Na2S2O4(the hypoxia-induction group),1 mmol/L Na2S2O4plus 10 μmol/L Rg1(the hypoxia-induction +Rg1 group),and 1 mmol/LNa2S2O4plus PHRO(including10 μmol/L Rg1,the hypoxia-induction +PHRO group), respectively. Results The content of Rg1 was 3.18%in the Rg1 group,28.8%in the PHRO group,and 0 in the control group.The angiogenesis of endothelial cells was markedly increased in the Rg 1 group as compared with the control(P<0.05), and even more significantly in the PHRO than in the Rg1 group(P<0.05).In comparison with the control group,the expressions of VEGFA and Dll 4 and the prolif-eration of the SH5Y cells were remarkably elevated in the Rg 1 group(P<0.05)and even more significantly in the PHRO than in the Rg1 group(P<0.05).The apoptosis rate of neurons was the lowest in PBS control(1.2%)and the highest in the hypoxia-induction group(21.6%),decreased to 13.14%and 8.25%in the hypoxia-induction +Rg1 and hypoxia-induction +PHRO group,respectively. Conclusion PHRO nanomedicine could penetrate the blood-brain barrier in vitro, promote angiogenesis and neuronal proliferation, reduce the apoptosis of neurons under hypoxia,and up-regulate the expressions of angiogenesis-related genes.
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<p><b>OBJECTIVE</b>To compare the efficacy and safety of BD regimen combined with cyclophosphamide(CTX) and pirarubicin chemotherapy(P-CAD) for patients with relapse/refractory multiple myeloma(MM).</p><p><b>METHODS</b>Twenty-eight cases of relapse/refractory MM were enrolled in a group of P-CAD regimen, 36 cases of relapse/retractory MM treated with BD were used as controls. The therapeutic efficacy and adverse reactions of 2 regimens for patients with relapse/retractory MM were compared and analyzed.</p><p><b>RESULTS</b>The overall response rate (CR+NCR+PR+MR) of the 28 cases treated with P-CAD regimen was 85.7%, and the response rate (CR+PR) was 75.0%. The median progression-free survival time were 16.1 months, and the average survival time were 30.6 months, while the overall response rate of the 36 patients treated with BD regimen was 63.9%, and the response rate was 55.6%. The median progression-free survival time were 13.7 months, and the average survival time were 26.7 months. The adverse reactions of 2 groups included gastrointestinal reactions, peripheral neuropathy, fatigue, skin rashes, leucopenia and thrombocytopenia, and they were all well tolerated.</p><p><b>CONCLUSION</b>BD regimen combined with cyclophosphamide and pirarubicin chemotherapy can improve the response rate of patients with relapse/refractory multiple myeloma, and shows the trend of prolonging PFS and survival times. Patients were well tolerated, and this regimen is a new choice in treatment of relapse/refractory MM.</p>
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<p><b>OBJECTIVE</b>To observe the effects of aerobic exercise on cardiac output during exercise in patients with chronic heart failure (CHF).</p><p><b>METHODS</b>A total of 50 CHF patients (echocardiography measured left ventricular ejection fraction < 0.49) were enrolled in the study and randomly divided into aerobic exercise group (n = 25) and control group (n = 25). Cardiopulmonary exercise testing (CPET) was performed. Patients of aerobic exercise group underwent aerobic exercise according to aerobic exercise prescription and exercise intensity is decided by anaerobic threshold before 10 J/s (1 minute before) of the oxygen consumption. After 6 supervised aerobic exercise training sessions in the hospital, patients were asked to perform the home-based aerobic exercise training. Patients in control group were required to maintain daily physical activities. CPET were reviewed 3 months later.</p><p><b>RESULTS</b>Cardiac output (CO), peak CO, peak cardiac power output (peak CPO), resting heart rate (HR), heart rate at AT (HRAT), HR peak, resting mean arterial pressure (MAP), peak MAP at baseline were similar between aerobic exercise group and control [(4.2 ± 2.0) L/min vs. (3.3 ± 1.0) L/min, (6.2 ± 2.7) L/min vs. (5.2 ± 1.8) L/min, (1.8 ± 2.9) L/min vs. (2.0 ± 1.8) L/min, (1.3 ± 0.5) J/s vs. (1.2 ± 0.5) J/s, (76.8 ± 13.5) beats/min vs. (73.4 ± 11.9) beats/min, (91.5 ± 11.3) beats/min vs. (92.6 ± 12.4) beats/min, (106.0 ± 12.9) beats/min vs. (108.3 ± 17.4) beats/min, (80.8 ± 9.9) mm Hg (1 mm Hg = 0.133 kPa) vs. (87.6 ± 13.3) mm Hg, (98.8 ± 12.4) mm Hg vs. (102.7 ± 13.9) mm Hg, all P > 0.05]. Compared to baseline, CO, peak CO, peak CPO, HR, HRAT, HR peak, MAP, peak MAP after 3 months were similar between aerobic exercise group and control (all P > 0.05). The differences between baseline and 3 months later expressed as ΔCO, Δpeak CO, Δpeak CPO, ΔHR, ΔHRAT, ΔHR peak, ΔMAP, Δpeak MAP were also similar between aerobic exercise group and control group [(-0.7 ± 2.4) L/min vs. (0.7 ± 2.0) L/min, (1.1 ± 2.6) L/min vs. (1.4 ± 2.1) L/min, (0.1 ± 3.7) L/min vs. (-0.2 ± 2.5) L/min, (0.2 ± 1.0) J/s vs. (0.2 ± 0.5) J/s, (-0.4 ± 7.6) beats/min vs. (1.9 ± 9.9) beats/min, (3.4 ± 11.3) beats/min vs. (-2.8 ± 7.6) beats/min, (8.9 ± 14.5) beats/min vs. (3.7 ± 14.4) beats/min, (1.5 ± 12.8) mm Hg vs. (-1.3 ± 11.1) mm Hg, (6.4 ± 18.9) mm Hg vs. (1.3 ± 12.3) mm Hg, all P > 0.05].</p><p><b>CONCLUSION</b>Three months aerobic exercise training did not improve cardiac output and related parameters during exercise in this cohort patients with CHF.</p>
Subject(s)
Aged , Female , Humans , Male , Middle Aged , Blood Pressure , Cardiac Output , Exercise , Exercise Therapy , Heart Failure , Therapeutics , Heart Rate , Oxygen ConsumptionABSTRACT
<p><b>OBJECTIVE</b>To screen the gene GATA4 for novel mutations associated with congenital atrial septal defect (ASD).</p><p><b>METHODS</b>The clinical data and peripheral venous blood specimen from 85 unrelated subjects with congenital ASD were collected and analyzed in contrast to 200 healthy individuals. The coding exons and the exon/intron boundaries of GATA4 gene were amplified by polymerase chain reaction and sequenced using the di-deoxynucleotide chain termination procedure. The obtained sequences were aligned with those publicized in GenBank with the help of programme BLAST to identify the sequence variations. The software Clustal W was applied to analysis of the conservation of altered amino acids.</p><p><b>RESULTS</b>Three novel heterozygous missense GATA4 mutations were identified in 3 of 85 ASD patients, respectively. Namely, the triplet substitutions of ATG for GTG at codon 267, GCC for ACC at codon 354, and CAA for CCA at codon 407, predicting the conversions of valine into methionine at amino acid residue 267 (V267M), threonine into alanine at amino acid residue 354 (T354A), and proline into glutamine at amino acid residue 407 (P407Q), were identified. No mutation was detected in 200 healthy controls. A cross-species alignment of GATA4 encoded protein sequences showed that the valine at amino acid residue 267 and proline at amino acid residue 407 were completely conserved evolutionarily.</p><p><b>CONCLUSION</b>Three novel heterozygous missense GATA4 mutations were identified in patients with congenital ASD, which reveals new molecular etiology responsible for ASD, and contributes to the early prophylaxis and therapy for ASD.</p>
Subject(s)
Humans , Base Sequence , Case-Control Studies , DNA Mutational Analysis , GATA4 Transcription Factor , Genetics , Genetic Testing , Heart Septal Defects, Atrial , Genetics , Mutation, MissenseABSTRACT
<p><b>OBJECTIVE</b>To investigate the possible association between the glutamate-cysteine ligase catalytic subunit gene (GCLC) C-129T and modifier subunit gene (GCLM) G-23T polymorphisms with coronary heart disease (CHD) in Chinese population.</p><p><b>METHODS</b>GCLC C-129T and GCLM G-23T genotypes were determined in 212 CHD patients and 218 healthy individuals using a PCR-based restriction fragment length polymorphism (RFLP) method. Odds ratio (OR) for CHD and 95% confidence interval (CI) from unconditional logistic regression models were used to evaluate relative risks.</p><p><b>RESULTS</b>The T allele of the GCLC C-129T polymorphism was more frequently found in CHD cases than in controls (P < 0.01) and individuals with GCLC-129T allele had a significantly higher risk for CHD (OR = 2.38, 95% CI: 1.25 - 4.54) as compared to individuals with the -129C allele. When compared with CC homozygote, CT heterozygote had a 2.14-fold higher risk for CHD (95% CI: 1.08 - 4.24, P < 0.05) and carriers of the-129T allele (CT or TT genotype) also had a similarly 2.28-fold higher risk for CHD (95% CI: 1.16 - 4.49, P < 0.05). In contrast, the frequency of T allele of the GCLM G-23T polymorphism was lower in CHD patients than that of controls (0.174 vs. 0.264) and individuals with the GCLM-23T allele had a significantly lower risk for CHD (OR = 0.59, 95% CI: 0.42 - 0.82, P < 0.01) as compared to the -23G allele. When compared with GG homozygote, the OR of CHD for GT heterozygote was 0.71 (95% CI: 0.47 - 1.08, P > 0.05), for TT homozygote was 0.18 (95% CI: 0.06 - 0.55, P < 0.01), and for carriers of the -23T allele (GT or TT genotype) was 0.61 (95% CI: 0.42 - 0.92, P < 0.05).</p><p><b>CONCLUSION</b>The GCLC C-129T polymorphism may be one of the genetic risk factor while the GCLM G-23T polymorphism may be one of the genetic protective factors for CHD in this Chinese population.</p>