Supramolecular DNA nanogels through host-guest interaction for targeted drug delivery.

DNA hydrogels have been demonstrated with the advantages of good stability, easy modification, and extraordinary biocompatibility, which enables their great application prospects in biosensing, tissue engineering, and biomedicine. Based on the host-guest recognition properties of cucurbit[8]uril (CB[8]), we proposed a general method for constructing functional supramolecular DNA nanogels. Guest molecules have been conjugated into the DNA building units, which could be further crosslinked with CB[8] to construct supramolecular DNA nanogels. At the same time, the aptamer has also been modified into the hydrogel network to achieve cell targeting. These supramolecular DNA nanogels have been demonstrated with a controllable size and multiple stimuli responses, in addition to the excellent biocompatibility, stability and good targeting drug transport ability. Such a host-guest based strategy will provide a molecular library as a "toolbox" for the functionalization of DNA nanogels.

Reversible Control of Gene Expression by Guest-Modified Adenosines in a Cell-Free System via Host-Guest Interaction.

Gene expression technology has become an indispensable tool for elucidating biological processes and developing biotechnology. Cell-free gene expression (CFE) systems offer a fundamental platform for gene expression-based technology, in which the reversible and programmable control of transcription can expand its use in synthetic biology and medicine. This study shows that CFE can be controlled via the host-guest interaction of cucurbit[7]uril (CB[7]) with N6-guest-modified adenosines. These adenosine derivatives were conveniently incorporated into the DNA strand using a post-synthetic approach and formed a selective and stable base pair with complementary thymidine in DNA. Meanwhile, alternate addition of CB[7] and the exchanging guest molecule induced the reversible formation of a duplex structure through the formation and dissociation of a bulky complex on DNA. The kinetics of the reversibility was fine-tuned by changing the size of the modified guest moieties. When incorporated into a specific region of the T7 promoter sequence, the guest-modified adenosines enabled tight and reversible control of in vitro transcription and protein expression in the CFE system. This study marks the first utility of the host-guest interaction for gene expression control in the CFE system, opening new avenues for developing DNA-based technology, particularly for precise gene therapy and DNA nanotechnology.

The efficacy and safety of different Janus kinase inhibitors as monotherapy in rheumatoid arthritis: A Bayesian network meta-analysis.

OBJECTIVE: This study aims to evaluate the efficacy and safety of JAK inhibitors in the treatment of patients with RA. METHODS: The databases CNKI, VIP, Wanfang, CBM, and PubMed, Embase, Cochrane Library and Web of Science were searched to identify relevant randomized controlled trials (RCTs), all from the time of database creation to April 2024. Screening, data extraction, and risk of bias assessment (using Review Manager-5.3 software) were independently performed by at least two authors. The network meta-analysis was conducted using R 4.1.3 software. PROSPERO registration number: CRD42022370444. RESULTS: Thirty-three RCTs included 15,961 patients The experimental groups involved six JAK inhibitors (filgotinib, tofacitinib, decernotinib, baricitinib, upadacitinib and peficitinib) and 12 interventions (different doses of the six JAK inhibitors), and the control group involved adalimumab (ADA) and placebo. Compared with placebo, all JAK inhibitors showed a significant increase in efficacy measures (ACR20/50/70). Compared with ADA, only tofacitinib, low-dose decernotinib, and high-dose peficitinib showed a significant increase in ACR20/50/70. Decernotinib ranked first in the SUCRA ranking of ACR20/50/70. In terms of safety indicators, only those differences between low-dose filgotinib and high-dose upadacitinib, low-dose tofacitinib and high-dose upadacitinib were statistically significant. Low-dose filgotinib ranked first in the SUCRA ranking with adverse events as safety indicators. Only the efficacy and safety of tofacitinib ranked higher among different SUCRA rankings. CONCLUSION: Six JAK inhibitors have better efficacy than placebo. The superior efficacy of decernotinib and safety of low-dose filgotinib can be found in the SUCRA. However, there are no significant differences in safety between the different JAK inhibitors. Head-to-head trials, directly comparing one against each other, are required to provide more certain evidence.

Prediction of binding affinity and enthalpy of CB7 with alkaloids by attach-pull-release molecular dynamics simulations study.

Host-guest complex has attracted much attention because of their fantastic capability. Accurate prediction of their binding affinity and enthalpy is essential to the rational design of guest molecules. The attach-pull-release (APR) method proposed by Henriksen et al. (J. Chem. Theory Comput., 2015, 11:4377.) shows good prediction capability of binding affinity especially for host-guest system. In order to further evaluate the performance of APR method in practice, we have conducted the calculations on the macrocycle cucurbit [7]urils (CB7) encapsulated with four structurally similar alkaloids (berberine, coptisine, epiberberine and palmatine) with two force fields (GAFF and GAFF2) and three water models (TIP3P, SPC/E and OPC). Compared to the experimental data, the calculation by the combination of GAFF2 and SPC/E force field presents the best performance, of which the Pearson correlation coefficients (R2) is 0.95, and the root-mean-square-deviation is 3.04 kcal/mol. While the predictions from GAFF force field all overestimated the binding affinity, suggesting a systematic error may be involved. Comparison of calculation also indicates that the accuracy of prediction was susceptible to the combination of force field. Therefore, it would be necessary to repeat the simulation with different combination of force fields in practice.

Towards the Fifth Pillar for the Treatment of Heart Failure with Reduced Ejection Fraction: Vericiguat in Older and Complex Patients.

Heart failure with reduced ejection fraction (HFrEF) represents an emerging epidemic, particularly affecting frail, older, and multimorbid patients. Current therapy for the management of HFrEF includes four different classes of disease-modifying drugs, commonly referred to as 'four pillars', which target the neurohormonal system that is overactivated in HF and contributes to its progression. These classes of drugs include ß-blockers, inhibitors of the renin-angiotensin-aldosterone system, mineralocorticoid receptor antagonists, and sodium-glucose co-transporter-2 (SGLT2) inhibitors. Unfortunately, these agents cannot be administered as frequently as needed to older patients because of poor tolerability and comorbidities. In addition, although these drugs have dramatically increased the survival expectations of patients with HF, their residual risk of rehospitalization and death at 5 years remains considerable. Vericiguat, a soluble guanylate cyclase (sGC) stimulator, was reported to exert beneficial effects in patients with worsening HF, including older subjects, reducing the rate of both hospitalizations and deaths, with limited adverse effects and drug interaction. In this narrative review, we present the current state of art on vericiguat, with a particular focus on elderly and frail patients.

Cucurbit[7]uril-based host-guest complexes for improving bioavailability and reducing side effects of piroxicam.

Piroxicam (PX) is a nonsteroidal anti-inflammatory drug (NSAID) commonly associated with gastrointestinal (GI) injuries, including dyspepsia, heartburn, inflammation, bleeding, ulceration, and life-threatening perforation. The ß-cyclodextrin (ß-CD)-based PX formulation (PX@CD) has been shown to reduce gastric side effects by improving PX's solubility and dissolution rates. However, the solubility of PX can only be increased to a limited extent by ß-CD, due to the low binding constant between PX and ß-CD (∼100 M-1). As a result, adverse reactions such as epigastric pain and pyrosis are still commonly reported. Cucurbit[7]uril (CB[7]) is a synthetic macrocyclic host compound that binds strongly to various drugs. In this study, we demonstrated that CB[7] forms complexes with PX in the gastric acid environment with a binding constant approximately 70 times higher than that between ß-CD and PX. The PX@CB[7] inclusion complexes exhibited rapid dissolution rates in the gastric environment. In addition, PX@CB[7] showed significantly higher oral bioavailability and maximum concentration (Cmax) compared to PX and PX@CD (1:2.5), resulting in improved anti-inflammatory effects in both mouse and rat models. Moreover, PX@CB[7] (1:2.5) had the least adhesion to the gastric mucosa and caused the mildest gastric side effects in rat models when compared to PX, PX@CD (1:2.5), and PX@CB[7] (1:1). Lastly, CB[7] demonstrated good oral biocompatibility in a subacute toxicity evaluation study. These findings indicate that CB[7] could be used as an excipient to improve treatment effectiveness and decrease adverse reactions in orally administered formulations with a favorable safety profile.

Clinical Pharmacokinetic and Pharmacodynamic Profile of Vericiguat.

Vericiguat is an oral soluble guanylate cyclase stimulator and enhances the cyclic guanosine monophosphate pathway independently of nitric oxide as well as synergistically in normal- and low-nitric oxide conditions. This review describes the pharmacokinetic and pharmacodynamic profile of vericiguat and summarizes the effect of vericiguat on cardiac electrophysiology and population pharmacokinetic/pharmacodynamic relationships. Vericiguat demonstrates virtually complete absorption and increased exposure with food. Vericiguat has high oral bioavailability when taken with food (93.0%) with dose-proportional pharmacokinetics in healthy volunteers. Vericiguat has slightly less than dose-proportional pharmacokinetics with a slight decrease in bioavailability at higher doses in patients with heart failure (HF) with reduced ejection fraction (HFrEF). Vericiguat is a low-clearance drug, with a half-life of approximately 20 h in healthy volunteers and 30 h in patients with HFrEF. Most drug metabolism is achieved by glucuronidation. Vericiguat has pharmacodynamic effects as expected from its pharmacological mechanism of action (i.e., relaxation of the smooth muscles in the vasculature leading to changes in hemodynamics). In the VICTORIA trial (NCT02861534), which enrolled patients with HFrEF, no meaningful exposure-response relationships for the incidence of symptomatic hypotension or syncope were evident. There were no significant imbalances in the incidence of undesirable hemodynamic-related effects (symptomatic hypotension and syncope) in subgroups with HFrEF defined by sex, age, race, and renal impairment. In addition, most patients achieved the 10-mg target dose per the blood pressure-guided titration regimen. No dose adjustments due to body weight, age, sex, race, or hepatic/renal impairment are necessary in adult patients with HFrEF. Observed and predicted changes in vericiguat exposure when co-administered with perpetrator drugs were small and not clinically meaningful. In addition, vericiguat has low potential as a perpetrator to affect exposure and/or pharmacodynamic effects of drugs commonly prescribed in patients with heart failure; therefore, no dose adjustment of these drugs is required in patients taking vericiguat. There is limited experience on the combined use of vericiguat with long-acting nitrates in patients with HFrEF. The ongoing VICTOR trial (NCT05093933), which is investigating vericiguat in patients with HFrEF, permits the co-administration of long-acting nitrates. Combined use of vericiguat and phosphodiesterase type-5 inhibitors has not been studied in patients with HFrEF and is therefore not recommended because of the potential increased risk for symptomatic hypotension. Vericiguat was not associated with electrophysiological abnormalities in preclinical and clinical studies up to the approved dose of 10 mg at steady state. Vericiguat is approved for the treatment of recently decompensated patients with worsening HFrEF. Vericiguat's safety and efficacy profile in patients with HFrEF will be further characterized by the VICTOR trial (NCT05093933) in adults without recent decompensation and in a pediatric population with HF due to left ventricular systolic dysfunction (VALOR trial, NCT05714085).

Supramolecular assembly activated single-molecule phosphorescence resonance energy transfer for near-infrared targeted cell imaging.

Pure organic phosphorescence resonance energy transfer is a research hotspot. Herein, a single-molecule phosphorescence resonance energy transfer system with a large Stokes shift of 367 nm and near-infrared emission is constructed by guest molecule alkyl-bridged methoxy-tetraphenylethylene-phenylpyridines derivative, cucurbit[n]uril (n = 7, 8) and ß-cyclodextrin modified hyaluronic acid. The high binding affinity of cucurbituril to guest molecules in various stoichiometric ratios not only regulates the topological morphology of supramolecular assembly but also induces different phosphorescence emissions. Varying from the spherical nanoparticles and nanorods for binary assemblies, three-dimensional nanoplate is obtained by the ternary co-assembly of guest with cucurbit[7]uril/cucurbit[8]uril, accompanying enhanced phosphorescence at 540 nm. Uncommonly, the secondary assembly of ß-cyclodextrin modified hyaluronic acid and ternary assembly activates a single intramolecular phosphorescence resonance energy transfer process derived from phenyl pyridines unit to methoxy-tetraphenylethylene function group, enabling a near-infrared delayed fluorescence at 700 nm, which ultimately applied to mitochondrial targeted imaging for cancer cells.

Structure-Based Design of a Potent and Selective YTHDC1 Ligand.

N6-Adenosine methylation (m6A) is a prevalent post-transcriptional modification of mRNA, with YTHDC1 being the reader protein responsible for recognizing this modification in the cell nucleus. Here, we present a protein structure-based medicinal chemistry campaign that resulted in the YTHDC1 inhibitor 40, which shows an equilibrium dissociation constant (Kd) of 49 nM. The crystal structure of the complex (1.6 Å resolution) validated the design. Compound 40 is selective against the cytoplasmic m6A-RNA readers YTHDF1-3 and YTHDC2 and shows antiproliferative activity against the acute myeloid leukemia (AML) cell lines THP-1, MOLM-13, and NOMO-1. For the series of compounds that culminated into ligand 40, the good correlation between the affinity in the biochemical assay and antiproliferative activity in the THP-1 cell line provides evidence of YTHDC1 target engagement in the cell. The binding to YTHDC1 in the cell is further supported by the cellular thermal shift assay. Thus, ligand 40 is a tool compound for studying the role of YTHDC1 in AML.

Long-term safety of fezolinetant in Chinese women with vasomotor symptoms associated with menopause: the phase 3 open-label MOONLIGHT 3 clinical trial.

OBJECTIVE: We aimed to assess long-term safety and tolerability of fezolinetant, a nonhormonal neurokinin 3 receptor antagonist, among Chinese women with vasomotor symptoms associated with menopause participating in the MOONLIGHT 3 trial. METHODS: In this phase 3 open-label study, women in menopause aged 40-65 years received fezolinetant 30 mg once daily for 52 weeks. The primary endpoint was frequency and severity of treatment-emergent adverse events (TEAEs), assessed at every visit through week 52 and one follow-up visit at week 55. RESULTS: Overall, 150 women were enrolled (mean age, 54 years) and 105 completed treatment. The frequency of TEAEs was 88.7%. Most TEAEs were mild (63.3%) or moderate (22.7%). The most common TEAE was upper respiratory tract infection (16.0%), followed by dizziness, headache, and protein urine present (10.7% each). There was no clinically relevant change (mean ± standard deviation) in endometrial thickness (baseline, 2.95 ± 1.11 mm; week 52, 2.94 ± 1.18 mm). Alanine aminotransferase and/or aspartate aminotransferase levels >3 times the upper limit of normal were reported in 1.4% of women; no Hy's Law cases occurred. CONCLUSIONS: Fezolinetant 30 mg once daily was generally safe and well tolerated over a 52-week period among women in China with vasomotor symptoms associated with menopause.ClinicalTrials.gov Identifier: NCT04451226.

Cucurbit[8]uril-based supramolecular theranostics.

Different from most of the conventional platforms with dissatisfactory theranostic capabilities, supramolecular nanotheranostic systems have unparalleled advantages via the artful combination of supramolecular chemistry and nanotechnology. Benefiting from the tunable stimuli-responsiveness and compatible hierarchical organization, host-guest interactions have developed into the most popular mainstay for constructing supramolecular nanoplatforms. Characterized by the strong and diverse complexation property, cucurbit[8]uril (CB[8]) shows great potential as important building blocks for supramolecular theranostic systems. In this review, we summarize the recent progress of CB[8]-based supramolecular theranostics regarding the design, manufacture and theranostic mechanism. Meanwhile, the current limitations and corresponding reasonable solutions as well as the potential future development are also discussed.

Analysis of omarigliptin forced degradation products by ultra-fast liquid chromatography, mass spectrometry, and in vitro toxicity assay.

Omarigliptin (OMG) is an antidiabetic drug indicated for the treatment of type 2 diabetes mellitus. Forced degradation studies are practical experiments to evaluate the stability of drugs and to establish degradation profiles. Herein, we present the investigation of the degradation products (DPs) of OMG formed under various stress conditions. OMG was subjected to hydrolytic (alkaline and acidic), oxidative, thermal, and photolytic forced degradation. A stability-indicating ultra-fast liquid chromatography method was applied to separate and quantify OMG and its DPs. Five DPs were adequately separated and detected in less than 6 min, while other published methods detected four DPs. MS was applied to identify and obtain information on the structural elucidation of the DPs. Three m/z DPs confirmed previously published research, and two novel DPs were described in this paper. The toxicity of OMG and its DPs were investigated for the first time using in vitro cytotoxicity assays, and the sample under oxidative conditions presented significant cytotoxicity. Based on the results from forced degradation studies, OMG was found to be labile to hydrolysis, oxidation, photolytic, and thermal stress conditions. The results of this study contribute to the quality control and stability profile of OMG.

Cost-utility analysis of add-on vericiguat for the treatment of chronic heart failure with reduced ejection fraction in China.

OBJECTIVE: This study aimed to evaluate the cost-utility of the addition of vericiguat for treating chronic heart failure (CHF) in China from the healthcare payer's perspective. METHODS: A Markov model was built to estimate the cost and utility of treating CHF using vericiguat plus standard treatment (vericiguat group) vs. standard treatment alone (standard treatment group). The clinical parameters (mortality of cardiovascular and hospitalization rate of HF) were calculated according to the VICTORIA clinical trial. The HF cost and utility data were obtained from the literature published in China. One-way sensitivity analysis and probability sensitivity analysis were performed. RESULTS: According to the 13-year model, vericiguat was more expensive (155599.07 CNY vs. 259396.83 CNY) and more effective (4.41 QALYs vs. 4.54 QALYs). The incremental cost-utility ratio (ICUR) was 802389.27 CNY per QALY. One-way sensitivity analysis revealed that cardiovascular mortality in the two groups was the parameter that had the greatest impact on the results. The GDP per capita in 2022 in China was 85,700 CNY. The probability sensitivity analysis (PSA) showed that the probability of vericiguat being cost-effective was only 41.7% at the willingness-to-pay (WTP) threshold of 3 times GDP per capita (257,100 CNY). CONCLUSIONS: In China, the treatment of CHF with vericiguat is not cost-effective. The drug price could decrease to 145.8 CNY, which could be considered cost-effective.

Practical Three-Component Regioselective Synthesis of Drug-Like 3-Aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnolines as Potential Non-Covalent Multi-Targeting Inhibitors To Combat Neurodegenerative Diseases.

Neurodegenerative diseases (NDs) are one of the prominent health challenges facing contemporary society, and many efforts have been made to overcome and (or) control it. In this research paper, we described a practical one-pot two-step three-component reaction between 3,4-dihydronaphthalen-1(2H)-one (1), aryl(or heteroaryl)glyoxal monohydrates (2a-h), and hydrazine monohydrate (NH2NH2•H2O) for the regioselective preparation of some 3-aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnoline derivatives (3a-h). After synthesis and characterization of the mentioned cinnolines (3a-h), the in silico multi-targeting inhibitory properties of these heterocyclic scaffolds have been investigated upon various Homo sapiens-type enzymes, including hMAO-A, hMAO-B, hAChE, hBChE, hBACE-1, hBACE-2, hNQO-1, hNQO-2, hnNOS, hiNOS, hPARP-1, hPARP-2, hLRRK-2(G2019S), hGSK-3ß, hp38α MAPK, hJNK-3, hOGA, hNMDA receptor, hnSMase-2, hIDO-1, hCOMT, hLIMK-1, hLIMK-2, hRIPK-1, hUCH-L1, hPARK-7, and hDHODH, which have confirmed their functions and roles in the neurodegenerative diseases (NDs), based on molecular docking studies, and the obtained results were compared with a wide range of approved drugs and well-known (with IC50, EC50, etc.) compounds. In addition, in silico ADMET prediction analysis was performed to examine the prospective drug properties of the synthesized heterocyclic compounds (3a-h). The obtained results from the molecular docking studies and ADMET-related data demonstrated that these series of 3-aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnolines (3a-h), especially hit ones, can really be turned into the potent core of new drugs for the treatment of neurodegenerative diseases (NDs), and/or due to the having some reactionable locations, they are able to have further organic reactions (such as cross-coupling reactions), and expansion of these compounds (for example, with using other types of aryl(or heteroaryl)glyoxal monohydrates) makes a new avenue for designing novel and efficient drugs for this purpose.

Vericiguat suppresses ventricular tachyarrhythmias inducibility in a rabbit myocardial infarction model.

BACKGROUND: The VICTORIA trial demonstrated a significant decrease in cardiovascular events through vericiguat therapy. This study aimed to assess the potential mechanisms responsible for the reduction of cardiovascular events with vericiguat therapy in a rabbit model of myocardial infarction (MI). METHODS: A chronic MI rabbit model was created through coronary artery ligation. Following 4 weeks, the hearts were harvested and Langendorff perfused. Subsequently, electrophysiological examinations and dual voltage-calcium optical mapping studies were conducted at baseline and after administration of vericiguat at a dose of 5 µmol/L. RESULTS: Acute vericiguat therapy demonstrated a significant reduction in premature ventricular beat burden and effectively suppressed ventricular arrhythmic inducibility. The electrophysiological influences of vericiguat therapy included an increased ventricular effective refractory period, prolonged action potential duration, and accelerated intracellular calcium (Cai) homeostasis, leading to the suppression of action potential and Cai alternans. The pacing-induced ventricular arrhythmias exhibited a reentrant pattern, attributed to fixed or functional conduction block in the peri-infarct zone. Vericiguat therapy effectively mitigated the formation of cardiac alternans as well as the development of reentrant impulses, providing additional anti-arrhythmic benefits. CONCLUSIONS: In the MI rabbit model, vericiguat therapy demonstrates anti-ventricular arrhythmia effects. The vericiguat therapy reduces ventricular ectopic beats, inhibiting the initiation of ventricular arrhythmias. Furthermore, the therapy successfully suppresses cardiac alternans, preventing conduction block and, consequently, the formation of reentry circuits.

Vericiguat improves cardiac function and microcirculation of a male patient with Fabry disease: A case report.

Fabry disease (FD) is a rare X chromosome-linked disorder and can be easily misdiagnosed. Here, we report the case of a 69-year-old male patient with FD who developed heart failure and showed extremely high pulmonary artery pressure. His initial symptom was recurrent atrial fibrillation. The left and right atrial inner diameters were large, and the ventricular wall was thick. Gene analysis which showed GLA c.215T>C p.Met72Thr mutation and single photon emission computed tomography indicated the diagnosis of FD with coronary microvascular dysfunction. The patient was prescribed anti-heart failure drugs, including vericiguat. Following the treatment, his heart function and microvascular perfusion significantly improved, which might be due to the beneficial effects of vericiguat.

Two Iron(II), α-Ketoglutarate-Dependent Enzymes Encoded by the PPZ Gene Cluster of Metarhizium majus Enable Production of 8-Hydroxyperamine.

Entomopathogenic fungus Metarhizium majus contains the nine-gene PPZ cluster, with ppzA, encoding a peramine-producing nonribosomal peptide synthetase, as the central component. In this work, the roles of two α-ketoglutarate, iron-dependent oxygenases encoded by the PPZ genes ppzC and ppzD were elucidated. PpzD was found to produce both trans-4-hydroxy-l-proline and trans-3-hydroxy-l-proline in a 13.1:1 ratio, yielding a key precursor for peramine biosynthesis. PpzC was found to act directly on peramine, yielding the novel analogue 8-hydroxyperamine.

Supermolecular Confined Silicon Phosphorescence Nanoprobes for Time-Resolved Hypoxic Imaging Analysis.

Room temperature phosphorescence (RTP) nanoprobes play crucial roles in hypoxia imaging due to their high signal-to-background ratio (SBR) in the time domain. However, synthesizing RTP probes in aqueous media with a small size and high quantum yield remains challenging for intracellular hypoxic imaging up to present. Herein, aqueous RTP nanoprobes consisting of naphthalene anhydride derivatives, cucurbit[7]uril (CB[7]), and organosilicon are reported via supermolecular confined methods. Benefiting from the noncovalent confinement of CB[7] and hydrolysis reactions of organosilicon, such small-sized RTP nanoprobes (5-10 nm) exhibit inherent tunable phosphorescence (from 400 to 680 nm) with microsecond second lifetimes (up to ∼158.7 µs) and high quantum yield (up to ∼30%). The as-prepared RTP nanoprobes illustrate excellent intracellular hypoxia responsibility in a broad range from ∼0.1 to 21% oxygen concentrations. Compared to traditional fluorescence mode, the SBR value (∼108.69) of microsecond-range time-resolved in vitro imaging is up to 2.26 times greater in severe hypoxia (<0.1% O2), offering opportunities for precision imaging analysis in a hypoxic environment.