Aim
To determine the overall efficacy of high‐ versus low‐dose sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors in patients with type 2 diabetes (T2D).
Material and Methods
A literature search ...using MEDLINE, EMBASE and the Cochrane Library was performed from 1 January 2006 to 23 September 2020. Random effects models were used to calculate mean differences (MDs) and pooled relative risk (RR). Prespecified subgroup analyses for each SGLT2 inhibitor, follow‐up and controls were performed. Leave‐one‐out sensitivity and meta‐regression analyses were conducted.
Results
A total of 51 randomized controlled trials involving 23 989 participants (weighted mean age, 58.9 years; men, 58.8%) were eligible for our meta‐analysis. For glycaemic regulation ability, a significant reduction in HbA1c (MD −0.080%, 95% confidence interval CI −0.100 to −0.060), fasting plasma glucose (MD −0.227 mmol/L, 95% CI −0.282 to −0.173) and postprandial plasma glucose (MD −0.834 mmol/L, 95% CI −1.268 to −0.400) levels was observed in the high‐dose SGLT2 inhibitor group. Treatment with high‐dose SGLT2 inhibitors enabled easier achievement of the target (HbA1c <7%) than low‐dose SGLT2 inhibitors (RR 1.148, 95% CI 1.104 to 1.193). High‐dose SGLT2 inhibitor‐based treatment resulted in more efficient regulation of body weight and blood pressure (body weight: MD −0.346 kg, 95% CI −0.437 to −0.254; systolic blood pressure: MD −0.583 mmHg, 95% CI −0.903 to −0.263; diastolic blood pressure: MD −0.352 mmHg, 95% CI −0.563 to −0.142). The results were similar in sensitivity analyses.
Conclusions
The overall efficacy of SGLT2 inhibitors, mainly canagliflozin, dapagliflozin and empagliflozin, was found to be dose dependent.
Chromosome translocation is a major cause of the onset and progression of diverse types of cancers. However, the mechanisms underlying this process remain poorly understood. Here, we identified a ...non-homologous end-joining protein, IFFO1, which structurally forms a heterotetramer with XRCC4. IFFO1 is recruited to the sites of DNA damage by XRCC4 and promotes the repair of DNA double-strand breaks in a parallel pathway with XLF. Interestingly, IFFO1 interacts with lamin A/C, forming an interior nucleoskeleton. Inactivating IFFO1 or its interaction with XRCC4 or lamin A/C leads to increases in both the mobility of broken ends and the frequency of chromosome translocation. Importantly, the destruction of this nucleoskeleton accounts for the elevated frequency of chromosome translocation in many types of cancer cells. Our results reveal that the lamin A/C-IFFO1-constituted nucleoskeleton prevents chromosome translocation by immobilizing broken DNA ends during tumorigenesis.
The aims of this work are to assess the clinical adverse events (AEs) of high-dose vs low-dose sodium-glucose cotransporter 2 inhibitors (SGLT2 inhibitors) in patients with type 2 diabetes mellitus ...(T2DM).
We searched MEDLINE, EMBASE, and Cochrane Library from January 1, 2006 to March 10, 2020, for identifying eligible randomized clinical trials (RCTs) that reported AEs by high-dose and low-dose SGLT2 inhibitors in T2DM patients. Random-effects models was used to obtain summary relative risks (RRs) with associated 95% CIs. Prespecified subgroup analyses according to individual SGLT2 inhibitors and follow-up duration, and leave-one-out sensitivity analysis were conducted.
A total of 51 RCTs involving 24 371 patients (12 208 received high-dose and 12 163 received low-dose SGLT2 inhibitors) were included. Overall, the heterogeneity among included studies was relatively low (I2 < 50% for each outcome). No significant differences between high-dose and low-dose SGLT2 inhibitors were observed for overall safety (including any AEs, serious AEs, AEs leading to discontinuation, and death) and specified safety (including infections and infestations, musculoskeletal disorders, gastrointestinal disorders, osmotic diuresis-related AEs, volume-related AEs, renal-related AEs, and metabolism and nutrition), except for a mild increase in risk for AEs related to study drugs (RR: 1.08; 95% CI, 1.01-1.16) that mainly derived from canagliflozin (RR: 1.17; 95% CI, 1.05-1.30). Subgroup analyses were consistent with the primary outcomes.
This study provided substantial evidence that AEs of SGLT2 inhibitors were not dose related.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors lowered the risk of cardiovascular events in patients with diabetes or heart failure (HF) with reduced ejection fraction, whether they directly ...promote cardiac function remains unclear. Therefore, we sought to determine whether SGLT2 inhibitors could improve left ventricular (LV) function in these patients.
A literature search was conducted using MEDLINE, EMBASE, and Cochrane Library databases from their inception to July 9, 2021. Randomized clinical trials and cohort studies that reported LV function-related variables were included.
Thirteen studies comprising 1437 patients (830 SGLT2 inhibitor-treated and 607 non-SGLT2 inhibitor-treated patients) and representing 7 randomized controlled trials with 640 individuals and 6 cohort studies with 797 individuals were included in this meta-analysis. LV regression LV mass (LVM), LV ejection fractions (LVEF), LV volumes LV end-diastolic volumes and systolic volumes (LVEDV and LVESV, respectively, and LV diastolic function mitral inflow E velocity to tissue Doppler e' ratio, E/e' and left atrial volume index (LAVI) were all significantly improved in patients treated with SGLT2 inhibitors (weighted mean differences, 95% CI, LVM: -6.319 g, -10.850 to -1.789; LVEF: 2.458%, 0.693 to 4.224; LVEDV: -9.134 mL, -15.808 to -2.460; LVESV: -8.440 mL, -15.093 to -1.787; LAVI: -2.791 mL/m2, -.554 to -1.027; E/e': -1.567, -2.440 to -0.698). Subgroup analysis further confirmed the improvement of LV function mainly in patients with HF or those receiving empagliflozin treatment.
Treatment with SGLT2 inhibitors can significantly improve LV function in patients with or without diabetes (especially those with HF or undergoing empagliflozin treatment).
Although synonymous single nucleotide variants (sSNVs) do not alter the protein sequences, they have been shown to play an important role in human disease. Distinguishing pathogenic sSNVs from ...neutral ones is challenging because pathogenic sSNVs tend to have low prevalence. Although many methods have been developed for predicting the functional impact of single nucleotide variants, only a few have been specifically designed for identifying pathogenic sSNVs.
In this work, we describe a computational model, IDSV (Identification of Deleterious Synonymous Variants), which uses random forest (RF) to detect deleterious sSNVs in human genomes. We systematically investigate a total of 74 multifaceted features across seven categories: splicing, conservation, codon usage, sequence, pre-mRNA folding energy, translation efficiency, and function regions annotation features. Then, to remove redundant and irrelevant features and improve the prediction performance, feature selection is employed using the sequential backward selection method. Based on the optimized 10 features, a RF classifier is developed to identify deleterious sSNVs. The results on benchmark datasets show that IDSV outperforms other state-of-the-art methods in identifying sSNVs that are pathogenic.
We have developed an efficient feature-based prediction approach (IDSV) for deleterious sSNVs by using a wide variety of features. Among all the features, a compact and useful feature subset that has an important implication for identifying deleterious sSNVs is identified. Our results indicate that besides splicing and conservation features, a new translation efficiency feature is also an informative feature for identifying deleterious sSNVs. While the function regions annotation and sequence features are weakly informative, they may have the ability to discriminate deleterious sSNVs from benign ones when combined with other features. The data and source code are available on website http://bioinfo.ahu.edu.cn:8080/IDSV .
This study exhibits a highly H
2
S-selective gas sensor based on copper oxide nanosheets (CuO-NSs) material. CuO-NSs are fabricated by a simple and economical method. CuO-NSs are decorated by gold ...nanoparticles (AuNPs) and used to detect H
2
S at room temperature. The AuNPs decorated CuO sensor has responses of 36.55% to 69.67% at 0.1 to 0.5 ppm of H
2
S while the pure sensor has responses from 4.77% to 13.37%. It can be seen that AuNPs can enhance H
2
S sensing responses five to nine times higher than pure one. The sensor also shows high H
2
S selectivity against NH
3
, SO
2
and volatile organic compounds (VOCs). The beneficial effect of AuNPs allow the H
2
S detection of CuO material down to ppb and even lower level, which make it possible to be applied in environmental applications and portable devices.
We aim to evaluate the efficacy and tolerability of Janus kinase inhibitors (JAKi) as monotherapy and in combination with methotrexate (MTX) in active rheumatoid arthritis (RA).
Medline, EMBASE, and ...Cochrane Library were systematically searched to identify relevant randomized controlled trials (RCTs). Pooled analysis was conducted using random-effects model, along with the risk difference (RD) and 95% confidence intervals (CIs).
Three RCTs, including 2,290 patients, were included. JAKi (tofacitinib, baricitinib, and filgotinib) plus MTX displayed a higher proportion of patients meeting the American College of Rheumatology (ACR) criteria than JAKi alone at week 52 (ACR20 RD 0.032; 95% CI -0.027 to 0.091; ACR50 RD 0.050; 95% CI 0.003 to 0.097; ACR70 RD 0.056; 95% CI 0.012 to 0.100). Similar results were observed for ACR20/50/70 at week 24. No significant difference was found between two regimens for the proportion of patients achieving Health Assessment Questionnaire disability index (HAQ-DI) improvement ≥ 0.22 at weeks 24 and 52. Regarding low disease activity and remission achievement, JAKi in combination with MTX, contributed higher response rates than JAKi alone at weeks 24 and 52. Compared with JAKi monotherapy, combination therapy had a higher risks of treatment-emergent adverse events (TEAEs) and adverse events (AEs) leading to study discontinuation.
JAKi combined with MTX demonstrated superiority to JAKi monotherapy in terms of ACR responses, low disease activity and remission achievement. The two regimens presented comparable physical functioning measured by HAQ-DI improvement and similar tolerability, except for high risks of TEAEs and AEs leading to study discontinuation in combination therapy.
https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42021288907.
COVID-19 is a global health problem caused by SARS-CoV-2, which has led to over 600 million infections and 6 million deaths. Developing novel antiviral drugs is of pivotal importance to slow down the ...epidemic swiftly. In this study, we identified five azo compounds as effective antiviral drugs to SARS-CoV-2, and mechanism study revealed their targets for impeding viral particles’ ability to bind to host receptors. Direct Blue 53, which displayed the strongest inhibitory impact, inhibited five mutant strains at micromole. In vitro, mechanism study demonstrated Direct Blue 53 inhibited viral infection through interaction with the spike of SARS-CoV-2. And 25 mg/kg/d compound treatment showed 50% or 60% survival protection against lethal Delta or Omicron BA.2 infection in vivo. Taken together, our results demonstrate that azo compounds with dimethyl-biphenyl-diyl-bis(azo)bis structure may be promising anti-SARS-CoV-2 drug candidates, which provide practicable therapies with the aid of structural optimizations and further research.
•Azo compounds, especially Direct Blues, significantly inhibited wild type and mutants SARS-CoV-2 infection in vitro.•Direct Blue 53 disturbed SARS-CoV-2 infection through directly interacting with Spike glycoprotein.•Direct Blue 53 showed robust antiviral effect on both human small airway epithelial cells and K18-ACE2 C57BL/6 mice infected by SARS-CoV-2, and displayed slight toxicity at high dose in vivo.
Four pairs of neolignan enantiomers (±)-1− (±)-4 with a distinctive isochroman moiety, including seven undescribed compounds, were isolated and identified from the fruits of Crataegus pinnatifida. ...Structural characterization of these compounds was established through comprehensive spectroscopic analyses, as well as quantum chemical calculations of ECD and NMR data. The preliminary bioassay displayed that compounds (+)-2 and (±)-3 exerted protective activities against H2O2-induced human neuroblastoma SH-SY5Y cells compared with the positive control. These bioactive compounds could be potential candidates for further pharmaceutical applications.
Four pairs of neolignan enantiomers with a distinctive isochroman moiety, including seven undescribed compounds (±)-1− (±)-3 and (−)-4, were isolated from Crataegus pinnatifida. Some of them exerted potential protective activities against H2O2-induced SH-SY5Y cells. Display omitted
•Four pairs of neolignan enantiomers were isolated from Crataegus pinnatifida.•All isolates were separated by chiral resolution.•All isolates possess a distinctive isochroman unit.•(+)-2 and (±)-3 exerted protective activity against H2O2-induced SH-SY5Y cells.
To evaluate the efficacy and safety of ertugliflozin in patients with type 2 diabetes.
MEDLINE, EMBASE, and Cochrane Library were searched (July 31, 2021) for phase II/III randomized clinical trials, ...which reported the efficacy and safety of ertugliflozin. Continuous variables were calculated as weighted mean difference (WMD) and associated 95% confidence intervals (CIs); dichotomous data were expressed as risk ratios (RRs) with 95% CIs.
Nine randomized clinical trials including 5638 type 2 diabetes patients were included. For efficacy, ertugliflozin significantly reduced HbA1c (%) (WMD -0.452%; 95% CI -0.774 to -0.129), fasting plasma glucose (FPG) (WMD -0.870 mmol/L; 95% CI -1.418 to -0.322), body weight (WMD -1.774 kg; 95% CI -2.601 to -0.946), and blood pressure levels (systolic blood pressure: WMD -2.572 mmHg; 95% CI -3.573 to -1.571 and diastolic blood pressure: WMD -1.152 mmHg; 95% CI -2.002 to -0.303) compared with placebo and other hypoglycaemic agents. Compared with placebo, ertugliflozin was superior in reducing HbA1c (%) (WMD -0.641%) and FPG (WMD -1.249 mmol/L). And compared with active agents, ertugliflozin also could decrease HbA1c by 0.215% and FPG by 0.266 mmol/L. The interactive effect between different controls was significant (
of 0.039). For safety, similar to other sodium-glucose cotransporter type-2 inhibitors, ertugliflozin mainly increased the risk of genital mycotic infection (RR: 4.004; 95% CI 2.504-6.402). There was no significant difference in the incidence of any adverse events (AEs), AEs related to study drug, serious AEs, deaths, and discontinuations due to AEs. Results were consistent with the most primary outcomes in subgroups analysis and sensitivity analysis.
Ertugliflozin was relatively effective and tolerated in patients with type 2 diabetes compared with placebo or other hypoglycaemic agents, except for a high risk of genital mycotic infection.
(ClinicalTrials.gov), identifier (CRD42020206356).
PDF
