Dihydromyricetin (DMY), one of the flavonoids in vine tea, exerts several pharmacological actions. However, it is not clear whether DMY has a protective effect on pressure overload-induced myocardial ...hypertrophy. In the present study, male C57BL/6 mice aging 8⁻10 weeks were subjected to transverse aortic constriction (TAC) surgery after 2 weeks of DMY (250 mg/kg/day) intragastric administration. DMY was given for another 2 weeks after surgery. Blood pressure, myocardial structure, cardiomyocyte cross-sectional area, cardiac function, and cardiac index were observed. The level of oxidative stress in the myocardium was assessed with dihydroethidium staining. Our results showed that DMY had no significant effect on the blood pressure. DMY decreased inter ventricular septum and left ventricular posterior wall thickness, relative wall thickness, cardiomyocyte cross-sectional areas, as well as cardiac index after TAC. DMY pretreatment also significantly reduced arterial natriuretic peptide (ANP), brain natriuretic peptide (BNP) mRNA and protein expressions, decreased reactive oxygen species production and malondialdehyde (MDA) level, while increased total antioxidant capacity (T-AOC), activity of superoxide dismutase (SOD), expression of sirtuin 3 (SIRT3), forkhead-box-protein 3a (FOXO3a) and SOD2, and SIRT3 activity in the myocardium of mice after TAC. Taken together, DMY ameliorated TAC induced myocardial hypertrophy in mice related to oxidative stress inhibition and SIRT3 pathway enhancement.
Mesenchymal stem cells (MSCs) are the most promising seed cells for cell therapy. Comparing the biological and transcriptome gene characteristics of MSCs from different sources provides an important ...basis for the screening of clinically used cells. The main purpose of this experiment was to establish methods for the isolation and culture of MSCs from five different canine sources, including adipose tissue, bone marrow, umbilical cord, amniotic membrane, and placenta, and compare biological and transcriptome characteristics of MSCs, in order to provide a basis for the clinical application of canine MSCs. MSCs were isolated from Chinese pastoral dogs, and the following experiments were performed: (1) the third, sixth, and ninth generations of cells were counted, respectively, and a growth curve was plotted to calculate the MSC population doubling time; (2) the expression of CD34 and CD44 surface markers was studied by immunofluorescence; (3) the third generation of cells were used for osteogenetic and adipogenic differentiation experiments; and (4) MSC transcriptome profiles were performed using RNA sequencing. All of the five types of MSCs showed fibroblast-like adherent growth. The cell surface expressed CD44 instead of CD34; the third-generation MSCs had the highest proliferative activity. The average population doubling time of adipose mesenchymal stem cells (AD-MSCs), placenta mesenchymal stem cells (P-MSCs), bone marrow mesenchymal stem cells (BM-MSCs), umbilical cord mesenchymal stem cells (UC-MSCs), and amniotic mesenchymal stem cells (AM-MSCs) were 15.8 h, 21.2 h, 26.2 h, 35 h, and 41.9 h, respectively. All five types of MSCs could be induced to differentiate into adipocytes and osteoblasts in vitro, with lipid droplets appearing after 8 days and bone formation occurring 5 days after AD-MSC induction. However, the multilineage differentiation for the remaining of MSCs was longer compared to that of the AD-MSCs. The MSC transcriptome profiles showed that AD-MSC and BM-MSCs had the highest homology, while P-MSCs were significantly different compared to the other four types of MSCs. All the isolated MSCs had the main biological characteristics of MSCs. AD-MSCs had the shortest time for proliferation, adipogenesis, and osteogenic differentiation.
Intravenous arsenic trioxide (ATO) has been adopted as the first‐line treatment for acute promyelocytic leukemia (APL). Another arsenic compound named the Realgar‐Indigo naturalis formula (RIF), an ...oral traditional Chinese medicine containing As4S4, has been shown to be highly effective in treating adult APL. In the treatment of pediatric APL, the safety and efficacy of RIF remains to be confirmed. This randomized, multicenter, and noninferiority trial was conducted to determine whether intravenous ATO can be substituted by oral RIF in the treatment of pediatric APL. From September 2011 to January 2017, among 92 patients who were 16 years old or younger with newly diagnosed PML‐RARa positive APL, 82 met eligible criteria and were randomly assigned to ATO (n = 42) or RIF (n = 40) group. The remaining 10 patients did not fulfilled eligible criteria because five did not accept randomization, four died and one had hemiplegia prior to arsenic randomization due to intracranial hemorrhage or cerebral thrombosis. Induction and consolidation treatment contained ATO or RIF, all‐trans‐retinoic acid and low intensity chemotherapy. End points included event‐free survival (EFS), adverse events and hospital days. After a median 3‐year follow‐up, the estimated 5‐year EFS was 100% in both groups, and adverse events were mild. However, patients in the RIF group had significantly less hospital stay than those in the ATO group. This interim analysis shows that oral RIF is as effective and safe as intravenous ATO for the treatment of pediatric APL, with the advantage of reducing hospital stay. Final trial analysis will reveal mature outcome data.
AIM To determine whether fructo-oligosaccharide(FOS) affects visceral sensitivity, inflammation, and production of intestinal short-chain fatty acids(SCFA) in an irritable bowel syndrome(IBS) mouse ...model.METHODS Mice were randomly assigned to daily oral gavage of saline solution with or without FOS(8 g/kg body weight) for 14 d. Mice were further assigned to receive either daily one-hour water avoidance stress(WAS) or sham-WAS for the first 10 d. After 2 wk, visceral sensitivity was measured by abdominal withdrawal reflex in response to colorectal distension and mucosal inflammation was evaluated. Gas chromatography, real-time reverse transcription PCR, and immunohistochemistry assays were used to quantify cecal concentrations of SCFA, intestinal cytokine expression, and number of intestinal mast cells per high-power field(HPF), respectively.RESULTS Mice subjected to WAS exhibited visceral hypersensitivity and low-grade inflammation. Among mice subjected to WAS, FOS increased visceral hypersensitivity and led to higher cecal concentrations of acetic acid(2.49 ± 0.63 mmol/L vs 1.49 ± 0.72 mmol/L, P < 0.05), propionic acid(0.48 ± 0.09 mmol/L vs 0.36 ± 0.05 mmol/L, P < 0.01), butyric acid(0.28 ± 0.09 mmol/L vs 0.19 ± 0.003 mmol/L, P < 0.05), as well as total SCFA(3.62 ± 0.87 mmol/L vs 2.27 ± 0.75 mmol/L, P < 0.01) compared to saline administration. FOS also increased ileal interleukin(IL)-23 mR NA(4.71 ± 4.16 vs 1.00 ± 0.99, P < 0.05) and colonic IL-1β mR NA(2.15 ± 1.68 vs 0.88 ± 0.53, P < 0.05) expressions as well as increased mean mast cell counts in the ileum(12.3 ± 2.6 per HPF vs 8.3 ± 3.6 per HPF, P < 0.05) and colon(6.3 ± 3.2 per HPF vs 3.4 ± 1.2 per HPF, P < 0.05) compared to saline administration in mice subjected to WAS. No difference in visceral sensitivity, intestinal inflammation, or cecal SCFA levels was detected with or without FOS administration in mice subjected to sham-WAS.CONCLUSION FOS administration intensifies visceral hypersensitivity and gut inflammation in stress-induced IBS mice, but not in the control mice, and is also associated with increased intestinal SCFA production.
Introduction. Hypoglycemic drugs affect the bone quality and the risk of fractures in patients with type 2 diabetes mellitus (T2DM). We aimed to investigate the effects of glucagon-like peptide-1 ...receptor agonists (GLP-1RAs) and insulin on bone mineral density (BMD) in T2DM. Methods. In this single-blinded study, a total of 65 patients with T2DM were randomly assigned into four groups for 52 weeks: the exenatide group (n=19), dulaglutide group (n=19), insulin glargine group (n=10), and placebo (n=17). General clinical data were collected, and BMD was measured by dual-energy X-ray absorptiometry. Results. Compared with baseline, the glycosylated hemoglobin (HbA1c) decreased significantly in the exenatide (8.11±0.24% vs. 7.40±0.16%, P=0.007), dulaglutide (8.77±0.37% vs. 7.06±0.28%, P<0.001), and insulin glargine (8.57±0.24% vs. 7.23±0.25%, P<0.001) groups after treatment. In the exenatide group, the BMD of the total hip increased. In the dulaglutide group, only the BMD of the femoral neck decreased (P=0.027), but the magnitude of decrease was less than that in the placebo group; the BMD of L1-L4, femoral neck, and total hip decreased significantly (P<0.05) in the placebo group, while in the insulin glargine group, the BMD of L2, L4, and L1-4 increased (P<0.05). Compared with the placebo group, the BMD of the femoral neck and total hip in the exenatide group and the insulin glargine group were increased significantly (P<0.05); compared with the exenatide group, the BMD of L4 in the insulin glargine group was also increased (P=0.001). Conclusions. Compared with the placebo, GLP-1RAs demonstrated an increase of BMD at multiple sites of the body after treatment, which may not exacerbate the consequences of bone fragility. Therefore, GLP-1RAs might be considered for patients with T2DM. This trial is registered with ClinicalTrials.gov NCT01648582.
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As the monotherapy of available analgesics is usually accompanied by serious side effects or limited efficacy in the management of chronic pain, multimodal analgesia is widely used to ...achieve improved benefit-to-risk ratios in clinic. Drug-drug salts are extensively researched to optimize the physicochemical properties of active pharmaceutical ingredients (APIs) and achieve clinical benefits compared with individual APIs or their combination. New drug-drug salt crystals metformin-ibuprofen (MET-IBU) and metformin-naproxen (MET-NAP) were prepared from metformin (MET) and two poorly water-soluble anti-inflammatory drugs (IBU and NAP) by the solvent evaporation method. The structures of these crystals were confirmed by single crystal and powder X-ray diffraction, Hirshfeld surface, Fourier transform infrared spectroscopy and thermal analysis. Both MET-IBU and MET-NAP showed significantly improved solubility and intrinsic dissolution rate than the pure IBU or NAP. The stability test indicated that MET-IBU and MET-NAP have excellent physical stability under stressing test (10 days) and accelerated conditions (3 months). Moreover, isobolographic analysis suggested that MET-IBU and MET-NAP exerted potent and synergistic antinociceptive effects in λ-Carrageenan-induced inflammatory pain in mice, and both of them had an advantage in rapid pain relief. These results demonstrated the potential of MET-IBU and MET-NAP to achieve synergistic antinociceptive effects by developing drug-drug salt crystals.
The prognosis of childhood acute lymphoblastic leukemia (ALL) is optimistic with a 5-year event-free survival (EFS) rate of 70-85%. However, the major causes of mortality are chemotherapy toxicity, ...infection and relapse. The Guangdong (GD)-2008-ALL collaborative protocol was carried out to study the effect of reduced intensity on treatment related mortality (TRM) based on Berlin-Frankfurt-Münster (BFM) 2002 backbone treatment. The study was designed to elucidate whether the reduced intensity is effective and safe for children with ALL.
The clinical data were obtained from February 28, 2008 to June 30, 2016. A total of 1765 childhood ALL cases from 9 medical centers were collected and data were retrospectively analyzed. Patients were stratified into 3 groups according to bone marrow morphology, prednisone response, age, genotype, and karyotype information: standard risk (SR), intermediate risk (IR) and high risk (HR). For SR group, daunorubicin was decreased in induction IA while duration was reduced in Induction Ib (2 weeks in place of 4 weeks). Doses for CAM were same in all risk groups - SR patients received one CAM, others got two CAMs.
The 5-year and 8-year overall survival (OS), event-free survival (EFS) and cumulative incidence of relapse (CIR) were 83.5±0.9% and 83.1±1.0%, 71.9±1.1% and 70.9±1.2%, and 19.5±1.0% and 20.5±1.1%, respectively. The 2-year treatment-related mortality (TRM) was 5.2±0.5%. The 5-year and 8-year OS were 90.7±1.4% and 89.6±1.6% in the SR group, while the 5-year and 8-year EFS were 81.5±1.8% and 80.0±2.0%. In the SR group, 74 (15.2%) patients measured minimal residual disease (MRD) on Day 15 and Day 33 of induction therapy. Among them, 7 patients (9.46%) were MRD positive (≥ 0.01%) on Day 33. The incidence of relapse in the MRD Day 33 positive group (n=7) was 28.6%, while in the MRD Day 33 negative group (n=67) was 7.5% (p=0.129).
The results of GD-2008-ALL protocol are outstanding for reducing TRM in childhood ALL in China with excellent long term EFS. This protocol provided the evidence for further reducing intensity of induction therapy in the SR group according to the risk stratification. MRD levels on Day 15 and Day 33 are appropriate indexes for stratification.
Pogostemon cablin Benth (PCB) is a well-known traditional Chinese medicine that has been used for treatment of many ailments for several centuries. In presently, the chemical profiling and quality ...control study of PCB has mainly concentrated on the volatile fractions. However, the non-volatile chemical profile of PCB was still unclear. In this study, 73 non-volatile constituents (i.e., 33 flavonoids, 21 organic acids, 9 phenylpropanoids, 4 sesquiterpenes, 3 alkaloids, and 3 other types of compounds) were identified and characterized in PCB using high performance liquid chromatography coupled with quadruple time-of-flight tandem mass spectrometry (HPLC-Q-TOF-MS). Meanwhile, to assess PCB samples, an established HPLC-Q-TOF-MS fingerprint was combined with multivariate statistical analysis that included similarity analysis (SA), hierarchical cluster analysis (HCA), principal component analysis (PCA), and orthogonal partial least squares-discriminant analysis (OPLS-DA). The PCB samples could be classified into two groups (herbal decoction pieces and processed medicinal materials), and acteoside, isoacteoside, 4′,6-Dihydroxy-5,7-dimethoxyflavone, pachypodol and pogostone were screened as the potential chemical markers that attributed classification. In addition, nine representative components (pachypodol, vicenin-2, apigenin, rhamnocitrin, acteoside, isoacteoside, chlorogenic acid, azelaic acid and pogostone) in PCB were simultaneously determined by using an ultra-high-performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry (UPLC-QQQ-MS/MS). This study is the first to describe the chemical profile of PCB using liquid chromatography tandem mass spectrometry, which would improve our understanding of the substance basis of PCB and is helpful to the PCB further quality evaluation.
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•The non-volatile chemical profile of Pogostemon cablin Benth (PCB) was revealed for the first time using HPLC-Q-TOF-MS.•An established HPLC-Q-TOF-MS fingerprint of PCB combined with the multivariate statistical analysis used to assess PCB samples.•A quick and sensitive UPLC-QQQ-MS/MS method was established and used to simultaneously quantify nine representative components in the PCB samples.•Five components were screened and identified as the potential chemical markers for the classification of herbal decoction pieces and processed medicinal materials of PCB.
An online condensation system was designed to separate coal tar during cooling process. Traditional method use room temperature ammonia water to cool hot pyrolysis gas by quenching for tar ...collection, and then follow by dehydration and distillation process for tar separation. This method will cause a lot of wastewater, repetitive energy cost and make system far more complex. On the basis of applying cleaner production idea, we put forward this online indirect heat exchange separation system, which can separate while cooling. The system consist of two high temperature oil bath and a cold trap as three condensers to realize an online cooling separation. 120, 240 ℃ is selected temperature for two oil bath as cut points for light, middle and heavy coal tar fraction. −20 ℃ is selected temperature for cold trap for a complete condensation. The results showed that this system give a high yield of the light fraction tar, which has a higher commercial value. In addition, the influence of pyrolysis temperature for tar separation was also examined for this system.
Realgar-Indigo naturalis formula (RIF), an oral traditional Chinese medicine mainly containing Realgar (As
S
), is highly effective in treating adult acute promyelocytic leukemia (APL). However, the ...treatment efficacy and safety of RIF have not been verified in pediatric patients. SCCLG-APL group conducted a multicenter randomized non-inferiority trial to determine whether intravenous arsenic trioxide (ATO) can be substituted by oral RIF in treating pediatric APL. Of 176 eligible patients enrolled, 91 and 85 were randomized to ATO and RIF groups, respectively. Patients were treated with the risk-adapted protocol. Induction, consolidation, and 96-week maintenance treatment contained all-trans-retinoic acid and low-intensity chemotherapy, and either ATO or RIF. The primary endpoint was 5-year event-free survival (EFS). The secondary endpoints were adverse events and hospital days. After a median 6-year follow-up, the 5-year EFS was 97.6% in both groups. However, the RIF group had significantly shorter hospital stays and lower incidence of infection and tended to have less cardiac toxicity. All 4 relapses occurred within 1.5 years after completion of maintenance therapy. No long-term arsenic retentions were observed in either group. Substituting oral RIF for ATO maintains treatment efficacy while reducing hospitalization and adverse events in treating pediatric APL patients, which may be a future treatment strategy for APL.
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