Effectiveness of acceptance and commitment therapy in people with type 2 diabetes mellitus: A systematic review and meta-analysis.

BACKGROUND: Acceptance and commitment therapy (ACT) is a psychotherapy technique, which promotes psychological flexibility and enables patients to change behaviors based on value-directed goals. However, the beneficial effects of ACT on glycemic control, self-care behaviors, acceptance of diabetes, self-efficacy, and psychological burden are still unclear among patients with type 2 diabetes mellitus (T2DM). AIMS: This study aimed to systematically synthesize scientific evidence to determine the effectiveness of ACT among patients with T2DM on glycemic control, self-care behaviors, acceptance of diabetes, self-efficacy, and psychological burden and identify the optimal characteristics of effective interventions. METHODS: Nine electronic databases were searched to identify eligible studies of randomized controlled trials from inception to June 2023. Two reviewers independently assessed the study eligibility, extracted the data, and performed the quality appraisal using the Cochrane Risk of Bias 2 Tool. The meta-analysis was conducted using Review Manager 5.3. The certainty of the evidence was rated using the Grading of Recommendations Assessment, Development, and Evaluation system. RESULTS: Ten studies involving 712 participants were included. ACT demonstrated significant improvements on patients' glycemic control (mean difference [MD]: 0.95%; p < .001), self-care behaviors (MD: 1.86; p = .03), diabetes acceptance (MD: 7.80; p < .001), self-efficacy (standardized mean difference [SMD]: 1.04; p < .001), anxiety (SMD: -1.15; p = .006), and depression (SMD: -1.10; p = .04). However, favorable but nonsignificant improvements were found in diabetes distress. Subgroup analyses demonstrated that ACT offered more than five sessions using individualized format, with theoretical underpinnings and professional input from multidisciplinary therapists are recommended to yield better results on glycemic control and self-care behaviors. LINKING EVIDENCE TO ACTION: Acceptance and commitment therapy could generate beneficial effectiveness on glycemic control, self-care behaviors, acceptance of diabetes, self-efficacy, anxiety, and depression among patients with T2DM. Large-scale trials with rigorous design and representative samples are warranted to strengthen the current evidence.

Focus on Radiation Protection Improves Both Correct Behavior and Procedural Performance During Simulation-Based Training - A Randomized Comparison.

BACKGROUND: To explore whether simulation-based endovascular training with focus on radiation safety could improve correct behavior without jeopardizing the learning of procedural skills. METHODS: Twenty-four residents without previous endovascular experience completed 10 clinical scenarios on a virtual-reality endovascular simulator with software for peripheral endovascular interventions. Participants were randomized to receive feedback (n = 12) or not (n = 12) on radiation protection (RP) performance after each case. Expert assessments were done at the first, second, fourth, seventh, and 10th case on RP and endovascular skills (ES). Automatic simulator metrics on procedure time, contrast dose, handling errors, and estimated radiation exposure to patient and operator were registered. Outcome metrics were analyzed by two-way mixed analysis of variance pairwise comparisons with independent t-tests. Correlations were explored using Pearson's r for internal consistency reliability. RESULTS: The RP performance was similar in both groups at their first attempt (P = 0.61), but the feedback group significantly outperformed the control group over time (P < 0.001 for all comparisons). The feedback group was however slower to learn the ES at start (P = 0.047 at second performance), but after 7 attempts no difference was shown (P = 0.59). The feedback group used more time (19.5 vs. 15.3 min; P = 0.007) but less contrast (60 vs. 100 mL; P < 0.001). The number of errors was the same in both groups, but all metrics regarding radiation exposure favored the feedback group (P-values from 0.001 to 0.008). CONCLUSIONS: Simulation-based training (SBT) is effective to acquire basic endovascular intervention skills and concurrently learn RP behavior when feedback on radiation culture is provided.

Discovery of Proline-Based p300/CBP Inhibitors Using DNA-Encoded Library Technology in Combination with High-Throughput Screening.

E1A binding protein (p300) and CREB binding protein (CBP) are two highly homologous and multidomain histone acetyltransferases. These two proteins are involved in many cellular processes by acting as coactivators of a large number of transcription factors. Dysregulation of p300/CBP has been found in a variety of cancers and other diseases, and inhibition has been shown to decrease Myc expression. Herein, we report the identification of a series of highly potent, proline-based small-molecule p300/CBP histone acetyltransferase (HAT) inhibitors using DNA-encoded library technology in combination with high-throughput screening. The strategy of reducing ChromlogD and fluorination of metabolic soft spots was explored to improve the pharmacokinetic properties of potent p300 inhibitors. Fluorination of both cyclobutyl and proline rings of 22 led to not only reduced clearance but also improved cMyc cellular potency.

Selection Method of DNA-Encoded Chemical Library for Irreversible Covalent Binders.

Compounds acting through irreversible covalent interactions with therapeutic targets represent an important mechanism of drug action. Here I describe a selection method for DNA-encoded libraries to discover irreversible covalent binders to target proteins. This method offers an enabling tool in drug discovery for therapeutic targets that may be undruggable for reversible inhibition.

Label-free LC-MS based assay to characterize small molecule compound binding to cells.

Study of small molecule binding to live cells provides important information on the characterization of ligands pharmacologically. Here we developed and validated a label-free, liquid chromatography-mass spectrometry (LC-MS) based cell binding assay, using centrifugation to separate binders from non-binders. This assay was applied to various target classes, with particular emphasis on those for which protein-based binding assay can be difficult to achieve. In one example, to study a G protein coupled receptor (GPCR), we used one antagonist as probe and multiple other antagonists as competitor ligands. Binding of the probe was confirmed to be specific and saturable, reaching a fast equilibrium. Competition binding analysis by titration of five known ligands suggested a good correlation with their inhibition potency. In another example, this assay was applied to an ion channel target with its agonists, of which the determined binding affinity was consistent with functional assays. This versatile method allows quantitative characterization of ligand binding to cell surface expressed targets in a physiologically relevant environment.

Orthogonality catastrophe and quantum speed limit for spin chain at finite temperature.

We present an interesting relationship between the orthogonality catastrophe (OC) and the quantum speed limit (QSL) for a spin chain with uniform nearest neighbour couplings perturbed by an impurity spin. We thoroughly study the catastrophic QSL that specifies a bound on the evolution time between the initial and final states and in this respect, link it to the emerging OC effect. It is found that the speed of state evolution subtle but fundamental, and the bound characterized by QSL shows the same behaviours as the OC effect in the thermodynamic limit. It allows us to reveal some universal properties, in particular finite temperature effects. Significantly, the threshold of temperature and system size is clearly demonstrated for the QSL under finite temperature.

The development of highly potent and selective small molecule correctors of Z α1-antitrypsin misfolding.

α1-antitrypsin deficiency is characterised by the misfolding and intracellular polymerisation of mutant α1-antitrypsin protein within the endoplasmic reticulum (ER) of hepatocytes. Small molecules that bind and stabilise Z α1-antitrypsin were identified via a DNA-encoded library screen. A subsequent structure based optimisation led to a series of highly potent, selective and cellular active α1-antitrypsin correctors.

Development of a small molecule that corrects misfolding and increases secretion of Z α1 -antitrypsin.

Severe α1 -antitrypsin deficiency results from the Z allele (Glu342Lys) that causes the accumulation of homopolymers of mutant α1 -antitrypsin within the endoplasmic reticulum of hepatocytes in association with liver disease. We have used a DNA-encoded chemical library to undertake a high-throughput screen to identify small molecules that bind to, and stabilise Z α1 -antitrypsin. The lead compound blocks Z α1 -antitrypsin polymerisation in vitro, reduces intracellular polymerisation and increases the secretion of Z α1 -antitrypsin threefold in an iPSC model of disease. Crystallographic and biophysical analyses demonstrate that GSK716 and related molecules bind to a cryptic binding pocket, negate the local effects of the Z mutation and stabilise the bound state against progression along the polymerisation pathway. Oral dosing of transgenic mice at 100 mg/kg three times a day for 20 days increased the secretion of Z α1 -antitrypsin into the plasma by sevenfold. There was no observable clearance of hepatic inclusions with respect to controls over the same time period. This study provides proof of principle that "mutation ameliorating" small molecules can block the aberrant polymerisation that underlies Z α1 -antitrypsin deficiency.

DNA-Encoded Library Technology-Based Discovery, Lead Optimization, and Prodrug Strategy toward Structurally Unique Indoleamine 2,3-Dioxygenase-1 (IDO1) Inhibitors.

We report the discovery of a novel indoleamine 2,3-dioxygenase-1 (IDO1) inhibitor class through the affinity selection of a previously unreported indole-based DNA-encoded library (DEL). The DEL exemplar, spiro-chromane 1, had moderate IDO1 potency but high in vivo clearance. Series optimization quickly afforded a potent, low in vivo clearance lead 11. Although amorphous 11 was highly bio-available, crystalline 11 was poorly soluble and suffered disappointingly low bio-availability because of solubility-limited absorption. A prodrug approach was deployed and proved effective in discovering the highly bio-available phosphonooxymethyl 31, which rapidly converted to 11 in vivo. Obtaining crystalline 31 proved problematic, however; thus salt screening was performed in an attempt to circumvent this obstacle and successfully delivered greatly soluble and bio-available crystalline tris-salt 32. IDO1 inhibitor 32 is characterized by a low calculated human dose, best-in-class potential, and an unusual inhibition mode by binding the IDO1 heme-free (apo) form.

Predictors of primary patency after percutaneous balloon angioplasty for stenosis of Brescia-Cimino hemodialysis arteriovenous fistula.

OBJECTIVE: Percutaneous transluminal balloon angioplasty (PTA) is recommended as the first choice to treat stenosis of Brescia-Cimino arteriovenous fistulas (B-C AVFs). The ability to predict which B-C AVFs are at risk for recurrent stenosis post-PTA would allow closer monitoring of patients, and possibly result in surgical intervention rather than repeat PTA. The purpose of this study was to identify predictive factors of primary patency after PTA in B-C AVFs. METHODS: Patients diagnosed with B-C AVF primary stenosis and treated by PTA between November 2013 and March 2018 were included in the study. Patient and stenotic lesion characteristics and PTA procedure factors were included in the analysis. The Kaplan-Meier method was used to analyze the primary patency rate. Cox proportional hazard regression analysis was used to identify factors predictive of decreased primary patency. RESULTS: 74 patients (35 males, 39 females) with a mean age of 61.68 ± 11.44 years (range, 36-84 years) were included in the study. The mean B-C AVF age was 16.34 ± 12.93 months (range, 2-84 months), and the median primary patency time was 7.79 ± 0.48 months. Cox proportional hazard regression analysis revealed stenosis location at the inflow artery [hazard ratio (HR)=3.83, 95% confidence interval (CI): 1.46-10.09] or anastomosis (HR = 1.90, 95% CI: 1.09-3.32), dilation >2 times during PTA (HR = 2.30, 95% CI: 1.22-4.34), and residual stenosis >30% (HR = 2.42, 95% CI: 1.26-4.63) were significantly associated with decreased patency. CONCLUSION: In conclusion, the primary patency rate of PTA for B-C AVF dysfunction is reduced by dilation >2 times, residual stenosis >30%, and stenosis located at the inflow artery or anastomosis. These results may help in tailoring surveillance programs, multiple PTA, or a proximal re-anastomosis surgery in patients with AVF dysfunction. ADVANCES IN KNOWLEDGE: A number of studies have been conducted to examine the predictors of primary patency after PTA, however, no definitive conclusions have been reached. Our study revealed that stenosis location at the inflow artery or anastomosis, dilation >2 times during PTA, and residual stenosis >30% were the predictors of primary patency after PTA, which may help in tailoring surveillance programs, multiple PTA, or a proximal re-anastomosis surgery in patients with arteriovenous fistulas dysfunction.

Oxidative Degradation of Dimethyl Phthalate (DMP) by the Fe(VI)/H2O2 Process.

This study investigates the degradation of dimethyl phthalate (DMP) with hydrogen peroxide and ferrate (Fe(VI)) under various reaction conditions. The results showed that the optimum conditions for dimethyl phthalate removal from water were as follows: (a) pH 7.0 and (b) the original molar ratio of [Fe(VI)]/[H2O2]/[DMP] equal to 10:2:1. Under the optimum conditions, the degradation rate of DMP can reach 89.7% in 360 min. Furthermore, 2,5-dihydroxybenzaldehyde, isophthalic acid, 2-ethylhexanol, oxalic acid, 2,6-dihydroxybenzoic acid, 2,6-dihydroxybenzaldehyde, 2,5-dihydroxybenzoic acid, and monomethyl phthalate were identified as the degradation intermediates, and degradation pathways were proposed.

DNA-Encoded Macrocyclic Peptide Library.

DNA-encoded library technology (ELT) is a cutting-edge enabling technology platform for drug discovery. Here we describe how to design and synthesize a macrocyclic DNA-encoded library; how to perform selection, sequencing, and data analysis to identify potential active peptides; and how to synthesize off-DNA peptides to confirm activity. This approach provides an effective tool for pharmaceutical research based on peptides.

Development of a Selection Method for Discovering Irreversible (Covalent) Binders from a DNA-Encoded Library.

DNA-encoded libraries (DELs) have been broadly applied to identify chemical probes for target validation and lead discovery. To date, the main application of the DEL platform has been the identification of reversible ligands using multiple rounds of affinity selection. Irreversible (covalent) inhibition offers a unique mechanism of action for drug discovery research. In this study, we report a developing method of identifying irreversible (covalent) ligands from DELs. The new method was validated by using 3C protease (3CP) and on-DNA irreversible tool compounds (rupintrivir derivatives) spiked into a library at the same concentration as individual members of that library. After affinity selections against 3CP, the irreversible tool compounds were specifically enriched compared with the library members. In addition, we compared two immobilization methods and concluded that microscale columns packed with the appropriate affinity resin gave higher tool compound recovery than magnetic beads.

MiR-140-3p is Involved in In-Stent Restenosis by Targeting C-Myb and BCL-2 in Peripheral Artery Disease.

AIM: In-Stent Restenosis (ISR) is the major reason for recurrent ischemia and amputation after endovascular treatment of Peripheral Artery Disease (PAD). Our previous study demonstrated that miR-140-3p is significantly down-regulated in PAD arteries. However, expression and function of miR-140-3p in ISR of human PAD are currently unclear.The aim of this study is to determine the miR-140-3p expression and its regulative role in ISR of PAD. METHODS: The RNA level was determined by quantitative real-time polymerase chain Reaction (qRT-PCR) and in situ hybridization. Primary cultured ASMCs were isolated from human femoral arterial of the healthy donors or ISR patients. Cell proliferation was determined by Edu incorporation and CCK-8 assay. Apoptosis was determined by Annexin-Ⅴ/PI Double-Staining assay and TUNEL assay. A rat carotid artery balloon angioplasty model was used to investigate the effect of miR-140-3p on restenosis. RESULTS: MiR-140-3p was significantly down-regulated in PAD and ISR arteries than normal arteries. Primary cultured ISR ASMCs exhibited elevated proliferation and down-regulated miR-140-3p than normal ASMCs. Transfection of miR-140-3p mimic attenuated PDGF-BB-induced proliferation in cultured ASMCs and induced apoptosis. Luciferase reporter assay indicated that miR-140-3p transfection significantly down-regulated C-Myb and BCL-2 in ISR ASMCs by targeting to their 3'-UTRs. MiR-140-3p transfection induced anti-proliferation and apoptosis in ASMCs, which were ameliorated by over-expression of C-Myb or BCL-2. Moreover, the animal study showed that miR-140-3p can reduce restenosis following angioplasty via targeting C-Myb and BCL-2. CONCLUSIONS: The result suggests that miR-140-3p regulates ASMC function via targeting C-Myb and BCL-2 in the process of ISR in PAD. The novel findings may offer a hopeful therapeutic target for human PAD.

Design and Application of a DNA-Encoded Macrocyclic Peptide Library.

A DNA-encoded macrocyclic peptide library was designed and synthesized with 2.4 × 1012 members composed of 4-20 natural and non-natural amino acids. Affinity-based selection was performed against two therapeutic targets, VHL and RSV N protein. On the basis of selection data, some peptides were selected for resynthesis without a DNA tag, and their activity was confirmed.

Encoded library technology screening of hepatitis C virus NS4B yields a small-molecule compound series with in vitro replicon activity.

To identify novel antivirals to the hepatitis C virus (HCV) NS4B protein, we utilized encoded library technology (ELT), which enables purified proteins not amenable to standard biochemical screening methods to be tested against large combinatorial libraries in a short period of time. We tested NS4B against several DNA-encoded combinatorial libraries (DEL) and identified a single DEL feature that was subsequently progressed to off-DNA synthesis. The most active of the initial synthesized compounds had 50% inhibitory concentrations (IC50s) of 50 to 130 nM in a NS4B radioligand binding assay and 300 to 500 nM in an HCV replicon assay. Chemical optimization yielded compounds with potencies as low as 20 nM in an HCV genotype 1b replicon assay, 500 nM against genotype 1a, and 5 µM against genotype 2a. Through testing against other genotypes and genotype 2a-1b chimeric replicons and from resistance passage using the genotype 1b replicon, we confirmed that these compounds were acting on the proposed first transmembrane region of NS4B. A single sequence change (F98L) was identified as responsible for resistance, and it was thought to largely explain the relative lack of potency of this series against genotype 2a. Unlike other published series that appear to interact with this region, we did not observe sensitivity to amino acid substitutions at positions 94 and 105. The discovery of this novel compound series highlights ELT as a valuable approach for identifying direct-acting antivirals to nonenzymatic targets.

Involvement of MicroRNA-133a in the Development of Arteriosclerosis Obliterans of the Lower Extremities via RhoA Targeting.

AIM: RhoA is a critical factor in regulating the proliferation and migration of arterial smooth muscle cells (ASMCs) in patients with arteriosclerosis obliterans (ASO). RhoA is modulated by microRNA-133a (miR-133a) in cardiac myocytes and bronchial smooth muscle cells. However, the relationship between miR-133a and RhoA with respect to the onset of ASO in the lower extremities is uncertain. METHODS: We employed in situ hybridization (ISH) and immunohistochemistry (IHC) to detect the location of miR-133a and RhoA in ASO clinical samples, respectively. 5-ethynyl-2'-deoxyuridine (EdU), cell counting kit-8 (CCK-8), Transwell and wound closure assays were utilized to determine the features of human ASMC (HASMC) proliferation and migration. The expression of miR-133a in the HASMCs was assessed using quantitative real-time PCR (qRT-PCR), while that of RhoA was examined via qRT-PCR and Western blotting. RESULTS: We found miR-133a and RhoA to be primarily located in the ASMCs of ASO. miR-133a was significantly downregulated in the ASO tissues and proliferating HASMCs. In contrast, RhoA was upregulated in the ASO samples. The proliferation and migration of HASMCs was markedly promoted by the downregulation of miR-133a and inhibited by the upregulation of miR-133a. The Luciferase assay confirmed that RhoA was a direct target of miR-133a. The upregulation of miR-133a in the HASMCs decreased the RhoA expression at the protein level. Inversely, the downregulation of miR-133a increased the RhoA protein expression. Of note, the overexpression of RhoA in the HASMCs attenuated the anti-proliferative and anti-migratory effects of miR-133a. CONCLUSIONS: Our data indicate that miR-133a regulates the functions of HASMCs by targeting RhoA and may be involved in the pathogenesis of ASO. These findings may lead to the development of potential therapeutic targets for ASO of the lower extremities.

Application of encoded library technology (ELT) to a protein-protein interaction target: discovery of a potent class of integrin lymphocyte function-associated antigen 1 (LFA-1) antagonists.

The inhibition of protein-protein interactions remains a challenge for traditional small molecule drug discovery. Here we describe the use of DNA-encoded library technology for the discovery of small molecules that are potent inhibitors of the interaction between lymphocyte function-associated antigen 1 and its ligand intercellular adhesion molecule 1. A DNA-encoded library with a potential complexity of 4.1 billion compounds was exposed to the I-domain of the target protein and the bound ligands were affinity selected, yielding an enriched small-molecule hit family. Compounds representing this family were synthesized without their DNA encoding moiety and found to inhibit the lymphocyte function-associated antigen 1/intercellular adhesion molecule-1 interaction with submicromolar potency in both ELISA and cell adhesion assays. Re-synthesized compounds conjugated to DNA or a fluorophore were demonstrated to bind to cells expressing the target protein.

Review article: high-throughput affinity-based technologies for small-molecule drug discovery.

High-throughput affinity-based technologies are rapidly growing in use as primary screening methods in drug discovery. In this review, their principles and applications are described and their impact on small-molecule drug discovery is evaluated. In general, these technologies can be divided into 2 groups: those that detect binding interactions by measuring changes to the protein target and those that detect bound compounds. Technologies detecting binding interactions by focusing on the protein have limited throughput but can reveal mechanistic information about the binding interaction; technologies detecting bound compounds have very high throughput, some even significantly higher than current high-throughput screening technologies, but offer limited information about the binding interaction. In addition, the appropriate use of affinity-based technologies is discussed. Finally, nanotechnology is predicted to generate a significant impact on the future of affinity-based technologies.

Use of cryopreserved transiently transfected cells in high-throughput pregnane X receptor transactivation assay.

Cryopreserved, transiently transfected HepG2 cells were compared to freshly transfected HepG2 cells for use in a pregnane X receptor (PXR) transactivation assay. Assay performance was similar for both cell preparations; however, cryopreserved cells demonstrated less interassay variation. Validation with drugs of different PXR activation potencies and efficacies demonstrated an excellent correlation (r(2) > 0.95) between cryopreserved and fresh cells. Cryopreservation did not change the effect of known CYP3A4 inducers that have poor cell permeability, indicating that cryopreservation had little effect on membrane permeability. In addition, cryopreserved HepG2 cells did not exhibit enhanced susceptibility to cytotoxic compounds compared to transiently transfected control cells. The use of cryopreserved cells enables this assay to run with enhanced efficiency.