Two series of [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine derivatives have been synthesized and evaluated for their antitumor activities. These compounds exhibit potent antiproliferative activities against A549 and H460 cells and c-Met kinase inhibitory activities. Five compounds are highly effective against A549 and H460 cells with IC50 values in 2.97-16.50 μM (the mean ± SD value of three independent determinations). Molecular docking is further performed to study the inhibitor-c-Met kinase interactions, and the results show that compound 3a is potently bound to the c-Met kinase with three hydrogen bonds, one π---π, and one CH---π interactions. Based on the preliminary results, it is deduced that compound 3a with potent c-Met kinase inhibitory activity may be a potential anticancer agent.

Background. Cuproptosis, a copper-dependent form of regulated cell death, has been repeatedly reported to be transcriptionally activated in atherosclerotic plaque, and cuproptosis- and copper-transport genes have been nominated as candidate biomarkers and therapeutic targets on the basis of descriptive expression studies. Whether genetically determined expression of these genes is causally related to atherosclerotic cardiovascular disease has not been tested. Methods. We first confirmed, across two independent carotid plaque transcriptomic cohorts (GSE43292 and GSE28829), that a panel of copper-metabolism and cuproptosis genes is concordantly dysregulated in plaque and that the copper importers track the degree of inflammatory-cell infiltration. We then performed two-sample cis-Mendelian randomization (MR) and Bayesian colocalization to test the causal effect of the genetically predicted expression of 11 cuproptosis/copper genes on coronary artery disease (CAD). Instruments were cis-eQTLs from whole-blood (eQTLGen, n = 31,684) and tibial artery (GTEx v8, n = 584); the outcome was CAD (CARDIoGRAMplusC4D/Aragam 2022; 181,522 cases, 1,165,690 participants, European ancestry). Large-artery atherosclerotic stroke (GIGASTROKE) was examined as a secondary outcome. LPL served as a positive control. The positive control was intended to validate the direction and harmonization of the MR pipeline, not to demonstrate that single-causal-variant colocalization must succeed at a known multi-signal locus such as LPL. Results. In plaque, copper-import genes (SLC31A2, SLC31A1) were upregulated and correlated strongly with myeloid/inflammatory infiltration (SLC31A2 vs. M1-macrophage r = +0.87), whereas the exporter ATP7B correlated inversely (r = −0.73). The positive control LPL showed the expected robust protective effect on CAD (IVW OR 0.90 per SD higher expression, 95% CI 0.87-0.93, P = 4.1 × 10 −12 ), validating the pipeline. None of the 11 cuproptosis/copper genes showed colocalization-supported causal evidence for CAD. Two genes reached nominal MR significance in single-instrument analyses (MTF1 OR 1.16, P = 2.7 × 10 −3 , DLAT OR 1.41, P = 2.2 × 10 −3 ,) but were not supported by colocalization (MTF1 PP.H4 = 4 × 10 −6 with PP.H3 = 0.9998; DLAT PP.H4 = 0.29), indicating linkage-disequilibrium confounding rather than causality. For well-instrumented genes (e.g. ATP7B, SLC31A2, FDX1), estimates were null and precise enough to exclude odds ratios larger than ≈1.05 per SD. Conclusions. Common cis-regulatory variation determining the baseline expression of cuproptosis/copper-transport genes in available eQTL tissues did not support a detectable causal effect on CAD risk. This does not exclude locally acquired plaque cuproptosis; rather, the reported upregulation of these genes in plaque is most consistent with a consequence or marker of established disease rather than a germline-encoded causal driver, and cautions against target nomination based on descriptive transcriptomics alone. Keywords: cuproptosis; atherosclerosis; coronary artery disease; Mendelian randomization; colocalization

Parkinson's disease (PD) patients cause substantial motor impairment in daily life, with approximately 40 % patients also exhibiting comorbid depression. Current therapy predominantly employs dopamine D2R/D3R agonists, whereas 5-HT1AR activation confers clinically validated antidepressant benefits. Therefore, in this study, we report the discovery of compound 22b, a D2R/D3R/5-HT1AR muti-target agonist, which demonstrates both enhanced antiparkinsonian and antidepressant-like activities. A new series of 2,6-Diamino-4,5,6,7-tetrahydrobenzothiazole derivatives were designed, synthesized, and evaluated for receptor activity and hERG inhibition. Among them, compound 22b showed potent agonistic activity at D2R (EC50 = 1.29 nM), D3R (EC50 = 1.05 nM) and 5-HT1AR (EC50 = 153.50 nM), with favorable metabolic stability (T1/2p.o. = 3.77 h), neuroprotective effects and blood-brain barrier permeability (B/P = 0.348-0.506). In vivo, 22b significantly improved total distance traveled in MPTP-induced PD mouse models at 3 mg/kg (s.c.) and depressive-like behaviors in forced swim test in mice at low doses (1 mg/kg p.o.). These findings highlight 22b as a promising candidate for future exploration aiming at treatment of depression and Parkinson's disease.

Relapsed/refractory (R/R) disease is a major hurdle to long‐term survival of acute myeloid leukemia (AML) patients treated with intensive cytarabine (AraC)‐based chemotherapy. R/R AML salvage treatment with venetoclax (VEN) + azacitidine (AZA) results in overall response rates between 20% and 60%, and responses are not durable, highlighting the need for new therapies. Here, we report elevated mTORC1 signaling in AraC‐resistant AML cell lines, primary AML patient samples, and patient‐derived xenograft (PDX) AML cells derived from patients at relapse postchemotherapy. The CDK9 inhibitor AZD4573 suppresses mTORC1 signaling and downregulates c‐MYC and MCL‐1, inducing AraC‐resistant AML cell death. AZD4573 in combination with VEN + AZA significantly increases AML cell death compared to any of the two‐drug combinations and suppresses AML progenitor cells but spares normal hematopoietic progenitor cells. The efficacy of this triple combination remains even with a 10‐fold reduction of VEN concentration. The roles of MCL‐1 and c‐MYC in the three‐drug combination were confirmed by knockdown. This study demonstrates that AZD4573 enhances the activity of VEN + AZA against AraC‐resistant AML by downregulating c‐MYC and MCL‐1 and to a lesser extent cellular respiration.

Tavapadon is a potent, selective G protein-biased partial agonist for the dopamine D1/D5 receptors, with positive experimental results in phase 3 trials for the treatment of Parkinson's disease (PD). This study aims to study the structure–activity relationship (SAR) of tavapadon to discover novel compounds with improved binding activity to D1/D5 receptors. In this work, a series of tavapadon derivatives were designed and synthesized based on the pharmacophores of tavapadon. Their binding activity to D1/D5 receptors was evaluated by determining in vitro median effect concentration (EC50). The binding mode was predicted by molecular docking. Our data showed that among those compounds, III-1 exhibited a similar binding pose to tavapadon at D1 dopamine receptors and demonstrated nanomolar potency for both D1 and D5 receptors. Compound III-1 is a potent partial agonist for the D1/D5 receptors, and may be a potent alternative to tavapadon for the treatment of PD in further study.

Chronic idiopathic constipation (CIC) is a prevalent gastrointestinal disorder with limited therapeutic options that balance efficacy and safety. Current therapies, such as the 5-HT4 receptor (5-HT4R) agonist prucalopride, demonstrate efficacy but are often associated with systemic side effects, highlighting the need for gut-restricted alternatives. Herein, we report for the first time the rational design and synthesis of gut-restricted bivalent agonists targeting mucosal 5-HT4R by integrating pharmacophores of prucalopride and tenapanor. Structural optimization, particularly of linker length and properties, led to the discovery of compound 4, which exhibited potent 5-HT4R agonistic activity, high selectivity, and favorable physicochemical properties. Preclinical studies demonstrated that compound 4 significantly enhanced whole-gut and colonic transit, increased fecal output and water content, while maintaining minimal systemic absorption, confirming its gut-restricted nature. These findings underscore the feasibility of gut-restricted 5-HT4R agonists as a novel therapeutic strategy for CIC and provide valuable insights into the development of safer, more effective treatments for gastrointestinal disorders.

BackgroundVenetoclax + azacitidine is a frontline treatment for older adult acute myeloid leukemia (AML) patients and a salvage therapy for relapsed/refractory patients who have been treated with intensive chemotherapy. While this is an important treatment option, many patients fail to achieve complete remission and of those that do, majority relapse. Leukemia stem cells (LSCs) are believed to be responsible for AML relapse and can be targeted through oxidative phosphorylation reduction. We previously reported that ONC213 disrupts oxidative phosphorylation and decreases Mcl-1 protein, which play a key role in venetoclax resistance. Here we investigated the antileukemic activity and underlying molecular mechanism of the combination of ONC213 + venetoclax against AML cells.MethodsFlow cytometry was used to determine drug-induced apoptosis. Protein level changes were determined by western blot. An AML cell line-derived xenograft mouse model was used to determine the effects of ONC213 + venetoclax on survival. A patient-derived xenograft (PDX) mouse model was used to determine drug effects on CD45+/CD34+/CD38-/CD123 + cells. Colony formation assays were used to assess drug effects on AML progenitor cells. Mcl-1 and Bax/Bak knockdown and Mcl-1 overexpression were used to confirm their role in the mechanism of action. The effect of ONC213 + venetoclax on mitochondrial respiration was determined using a Seahorse bioanalyzer.ResultsONC213 + venetoclax synergistically kills AML cells, including those resistant to venetoclax alone as well as venetoclax + azacitidine. The combination significantly reduced colony formation capacity of primary AML progenitors compared to the control and either treatment alone. Further, the combination prolonged survival in an AML cell line-derived xenograft model and significantly decreased LSCs in an AML PDX model.ConclusionsONC213 can resensitize VEN + AZA-resistant AML cells to venetoclax therapy and target LSCs ex vivo and in vivo.

We report a case of transcatheter paravalvular leak (PVL) closure assisted by three-dimensional (3D) printing and intracardiac echocardiography (ICE) in a patient with complex valvular history. A 70-year-old male manifested acute exacerbation of dyspnea, accompanied by orthopnea and nocturnal paroxysmal respiratory distress. Echocardiographic evaluation revealed severe aortic PVL. After multidisciplinary heart team evaluation, transcatheter aortic PVL closure was selected as the preferred therapeutic strategy. The preoperative assessment of PVL location, size, and morphology using 3D printing technology accurately guided the interventional position and the selection of the occluder size and the successful completion of closed treatment under local anesthesia, which was assisted by intracardiac echocardiography to ensure the safety and smoothness of the procedure.

BACKGROUND:This study aimed to provide a thorough overview of research hotspots in mitophagy in osteoarthritis through a bibliometric analysis approach. METHODS:A comprehensive literature search was conducted on the Web of Science Core Collection on September 9, 2024. Key metrics were calculated using Microsoft Excel 2019, and bibliometric analysis and visualization were performed with VOSviewer 1.6.20, CiteSpace 6.3.R1, and R 4.3.3. RESULTS:The analysis covered 259 articles published between 2008 and 2024, involving 1679 authors from 924 institutions across 41 countries, indicating growing interest in mitophagy research related to osteoarthritis. Wenzhou Medical University emerged as the most prolific institution with 25 articles. The journal Osteoarthritis and Cartilage was a leading venue, showing high citation metrics and an impact factor of 7.2. The most cited article was "Pesticides and human chronic diseases: Evidence, mechanisms, and perspectives" from Toxicology and Applied Pharmacology. The keyword "apoptosis" was the most frequently used, along with significant terms like "oxidative stress" and "mitochondrial dysfunction." Keyword burst analysis indicated intensified focus on "mammalian target of rapamycin" and "cell death." CONCLUSION:This bibliometric analysis highlights a growing interest in mitophagy in osteoarthritis research, emphasizing its potential as a therapeutic target and signaling future advancements in this field.

FMS-like tyrosine kinase 3 (FLT3) mutations occur in approximately one third of acute myeloid leukemia (AML) patients. FLT3-Internal tandem duplication (FLT3-ITD) mutations are the most common FLT3 mutations and are associated with a poor prognosis. Gilteritinib is a FLT3 inhibitor that is US FDA approved for treating adult patients with relapsed/refractory AML and a FLT3 mutation. While gilteritinib monotherapy has improved patient outcome, few patients achieve durable responses. Combining gilteritinib with venetoclax (VEN) appears to make further improvements, though early results suggest that patients with prior exposure to VEN fair much worse than those without prior exposure. MRX-2843 is a promising inhibitor of FLT3 and MERTK. We recently demonstrated that MRX-2843 is equally potent as gilteritinib in FLT3-ITD AML cell lines in vitro and primary patient samples ex vivo. In this study, we investigated the combination of VEN and MRX-2843 against FLT3-ITD AML cells. We found that VEN synergistically enhances cell death induced by MRX-2843 in FLT3-mutated AML cell lines and primary patient samples. Importantly, we found that VEN synergistically enhances cell death induced by MRX-2843 in FLT3-ITD AML cells with acquired resistance to cytarabine (AraC) or VEN+AraC. VEN and MRX-2843 significantly reduce colony-forming capacity of FLT3-ITD primary AML cells. Mechanistic studies show that MRX-2843 decreases Mcl-1 and c-Myc protein levels via transcriptional regulation and combined MRX-2843 and VEN significantly decreases oxidative phosphorylation in FLT3-ITD AML cells. Our findings highlight a promising combination therapy against FLT3-ITD AML, supporting further in vitro and in vivo testing.

Abstract Eradication of acute myeloid leukemia (AML) is therapeutically challenging; many patients succumb to AML despite initially responding to conventional treatments. Here, we showed that the imipridone ONC213 elicits potent antileukemia activity in a subset of AML cell lines and primary patient samples, particularly in leukemia stem cells, while producing negligible toxicity in normal hematopoietic cells. ONC213 suppressed mitochondrial respiration and elevated α-ketoglutarate by suppressing α-ketoglutarate dehydrogenase (αKGDH) activity. Deletion of OGDH, which encodes αKGDH, suppressed AML fitness and impaired oxidative phosphorylation, highlighting the key role for αKGDH inhibition in ONC213-induced death. ONC213 treatment induced a unique mitochondrial stress response and suppressed de novo protein synthesis in AML cells. Additionally, ONC213 reduced the translation of MCL1, which contributed to ONC213-induced apoptosis. Importantly, a patient-derived xenograft from a relapsed AML patient was sensitive to ONC213 in vivo. Collectively, these findings support further development of ONC213 for treating AML. Significance: In AML cells, ONC213 suppresses αKGDH, which induces a unique mitochondrial stress response, and reduces MCL1 to decrease oxidative phosphorylation and elicit potent antileukemia activity. See related commentary by Boët and Sarry, p. 950

The majority of acute myeloid leukemia (AML) patients respond to intensive induction therapy, consisting of cytarabine (AraC) and an anthracycline, though more than half experience relapse. Relapsed/refractory (R/R) AML patients are difficult to treat, and their clinical outcomes remain dismal. Venetoclax (VEN) in combination with azacitidine (AZA) has provided a promising treatment option for R/R AML, though the overall survival (OS) could be improved (OS ranges from 4.3 to 9.1 months). Overexpression of c-Myc is associated with chemoresistance in AML. Histone deacetylase (HDAC) inhibitors have been shown to suppress c-Myc and enhance the antileukemic activity of VEN, as well as AZA, though combination of all three has not been fully explored. In this study, we investigated the HDAC inhibitor, panobinostat, in combination with VEN + AZA against AraC-resistant AML cells. Panobinostat treatment downregulated c-Myc and Bcl-xL and upregulated Bim, which enhanced the antileukemic activity of VEN + AZA against AraC-resistant AML cells. In addition, panobinostat alone and in combination with VEN + AZA suppressed oxidative phosphorylation and/or glycolysis in AraC-resistant AML cells. These findings support further development of panobinostat in combination with VEN + AZA for the treatment of AraC-resistant AML.

Self-adhesion and conductivity are the key factors to ensure the high performance of hydrogel-based wearable electronics. In this paper, a method of amylopectin (Amy) tackifying hydrogel is proposed. Amy was introduced into poly(acrylamide-2-acrylamide-2-methylpropane sulfonic acid) (P(AAm-AMPS)) polymer networks to prepare hydrogel conductors with excellent flexibility, self-adhesion and compliance. As a rigid network, Amy can improve the mechanical properties of hydrogels through the hydrogen bond interaction between networks, so as to achieve repeated deformation and stretching. In addition, the dendritic hydroxyl structure of Amy can provide more physical adhesion, which makes the hydrogel have strong adhesion to various solid substrates. Based on the ion transport behavior close to organisms, tensile properties and skin stickiness, hydrogel sensors exhibit significant strain sensitivity (gauge factor = 5.47), fast response, negligible hysteresis and operational durability, which are conducive to the accurate identification of continuous whole body motion signals and motion states. It is worth noting that hydrogel conductors can also be assembled into epidermal electrodes for real -time and highquality acquisition of electrocardiogram (ECG) and electromyogram (EMG) electrophysiological signals. It is believed that the simple design concept will provide a new vision for the development of multi-functional wearable electronic devices.

Patient characteristics for AML cell lines

Table S1 shows patient characteristics and Figure S1 shows preliminary efficacy results

In search of novel neuroprotective agents with higher potency and lower hERG liability, a series of novel Fenazinel derivatives were designed and synthesized, among which compounds 8m–o containing amide moiety exhibited good neuroprotective effects in vitro and in vivo. Especially, the representative compound 8o showed lower activity in a patch clamp hERG K+ ion channel screen and could be considered as a lead compound for further development. These findings provided an alternative approach to the development of drugs more potent than Fenazinel for the intervention of ischemic stroke.

AbstractBackground:It is unclear whether socioeconomic factors causally affect cardiovascular disease risk. Utilizing data from comprehensive genetic associated studies of socioeconomic status (SES) and myocardial infarction (MI), we employed two-sample mendelian randomization (MR) analysis to determine the causality between SES and MI.Method:The genetic summary level data of SES and MI were acquired from various genome-wide association studies (GWAS) studies. We first identified instrumental variables of the socioeconomic determinants and then investigated the causality between instrumental variables and MI. The primary method employed to evaluate this causation was the conventional inverse variance weighted (IVW). Sensitivity analysis was used to assess the underlying heterogeneity and pleiotropy.Results:Age of full-time education has a reverse causal relationship with MI (OR 0.57, 95 percent CI 0.38-0.87, p=0.0096). There is a potential causal association between self-reported household income and the incidence of MI (OR 0.41, 95 percent CI 0.32-0.52, p=8.82×10-14). Additionally, Hard physical work is significantly associated with a higher risk of MI (OR 1.79, 95 percent CI 1.02-3.13, p= 0.042).Conclusions:The idea that low SES levels might raise the incidence of MI is supported by this MR study.