Search

Targeting receptor‐interacting protein kinase 1 (RIPK1) has emerged as a promising therapeutic stratagem for neurodegenerative disorders, particularly Alzheimer's disease (AD). A positron emission tomography (PET) probe enabling brain RIPK1 imaging can provide a powerful tool to unveil the neuropathology associated with RIPK1. Herein, the development of a new PET radioligand, [11C]CNY‐10 is reported, which may enable brain RIPK1 imaging. [11C]CNY‐10 is radiosynthesized with a high radiochemical yield (41.8%) and molar activity (305 GBq/µmol). [11C]CNY‐10 is characterized by PET imaging in rodents and a non‐human primate, demonstrating good brain penetration, binding specificity, and a suitable clearance kinetic profile. It is performed autoradiography of [11C]CNY‐10 in human AD and healthy control postmortem brain tissues, which shows strong radiosignal in AD brains higher than healthy controls. Subsequently, it is conducted further characterization of RIPK1 in AD using [11C]CNY‐10‐based PET studies in combination with immunohistochemistry leveraging the 5xFAD mouse model. It is found that AD mice revealed RIPK1 brain signal significantly higher than WT control mice and that RIPK1 is closely related to amyloid plaques in the brain. The studies enable further translational studies of [11C]CNY‐10 for AD and potentially other RIPK1‐related human studies. [ABSTRACT FROM AUTHOR]

The drive-stack design principle for the Tonpilz transducer aiming to transmit the acoustic signal in an ultra-wideband has been proposed [(2023). J. Acoust. Soc. Am. 154, 3709–3725], in which the design method is obtained and validated through simulation. This letter presents the experimental investigation of a fabricated transducer prototype and gives the measurement results of electroacoustic performance, including the electrical admittance, transmitting voltage response, directivity beam pattern, electroacoustic efficiency, and source level. The results indicate that the transducer can operate in the frequency band from 20 to 80 kHz without deep response notches within the band. [ABSTRACT FROM AUTHOR]

Liquid column resonance (LCR) transducers have been widely used in deep-sea acoustic applications because of their fluid-filled structures. Until now, studies of pipe resonance have generally been based on the plane acoustic wave equation, but for a vibrating object, the velocity is the primary focus instead of the pressure. Thus, the motion equation of a pipe resonance mode can be deduced based on the Navier–Stokes (N–S) equations. In this work, the velocity of an LCR transducer is obtained using the finite element model, and the velocity distribution inside the liquid column is examined. In addition, the radiating surface of the LCR transducer is identified and a simplified model of the radiation that consists of concave pistons and ring sources is proposed and verified. The theory behind the high mechanical quality (Q) value of the LCR transducer is explained through the radiation of the LCR transducer and the low viscosity of the water. This is also verified through a finite element model and measurements. Due to the high mechanical Q value and the low frequency of the LCR transducer, such measurements should be carried out in open-field water and the pulse should be long enough to achieve a steady state. [ABSTRACT FROM AUTHOR]

Background: Wrinkle formation is the most visible characteristic of facial aging. Radiofrequency (RF) technology is currently utilized to reduce facial wrinkles and contribute to skin rejuvenation. Objective: To analyze the efficacy and safety of a noninvasive, home‐based RF device applied for facial rejuvenation in Chinese people. Methods: A single‐center, open‐label, intraindividual controlled trial was performed on subjects who received an 8‐week treatment of the RF device. A total of 22 female individuals aged 25–60 years with Fitzpatrick skin type III–IV were enrolled. Efficacy of treatment was subjectively evaluated using the Fitzpatrick Wrinkle Classification Scale (FWCS) assessed by physician or overall satisfaction of subject with a 10‐point VAS, and objectively using the skin ultrasound examination as well as the 3D skin analysis system. Adverse event was recorded at each visit. Results: In comparison with the baseline, evaluator‐assessed FWCS scores showed significant improvement at 4 weeks (p < 0.005) and 8 weeks (p < 0.005) after treatment. All subjects reported different degrees of improvement in facial wrinkles after 8 weeks of treatment. The results of skin ultrasound examination revealed significant increase of the dermal thickness at week 8 (p < 0.05) as compared to the baseline. In addition, a significant decrease in the proportion and density of perioral wrinkles evaluated by the 3D skin analysis system was observed from baseline to week 4. The treatment was well‐tolerated, and no serious adverse event was observed. Conclusion: This noninvasive, home‐based RF device was effective in improving skin texture and elasticity with a safe and well‐tolerated treating procedure. [ABSTRACT FROM AUTHOR]

Hematopoietic stem cell (HSC)-independent lymphopoiesis has been elucidated in murine embryos. However, our understanding regarding human embryonic counterparts remains limited. Here, we demonstrated the presence of human yolk sac-derived lymphoid-biased progenitors (YSLPs) expressing CD34 , IL7R , LTB , and IRF8 at Carnegie stage 10, much earlier than the first HSC emergence. The number and lymphopoietic potential of these progenitors were both significantly higher in the yolk sac than the embryo proper at this early stage. Importantly, single-cell/bulk culture and CITE-seq have elucidated the tendency of YSLP to differentiate into innate lymphoid cells and dendritic cells. Notably, lymphoid progenitors in fetal liver before and after HSC seeding displayed distinct transcriptional features, with the former closely resembling those of YSLPs. Overall, our data identified the origin, potential, and migratory dynamics of innate lymphoid-biased multipotent progenitors in human yolk sac before HSC emergence, providing insights for understanding the stepwise establishment of innate immune system in humans. [Display omitted] • Progenitors with non-NK lymphoid potential exist in human yolk sac before HSC onset • Human yolk sac lymphoid progenitors before HSC emergence show ILC and DC potential • ILC potential before HSC onset is stronger in human yolk sac than in embryo proper • Early fetal liver lymphoid progenitors share characteristics with those from yolk sac Liu et al. demonstrated the presence of yolk sac-derived lymphoid progenitors expressing IL7R and IRF8 well before HSC emergence in human embryos, which showed differentiation bias toward innate lymphoid cells and dendritic cells. They shared transcriptional profiles with lymphoid progenitors in the fetal liver before HSC colonization. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the diagnostic accuracy of liver dual-layer spectral-detector CT (SDCT) derived parameters of liver parenchyma for grading steatosis with reference to magnetic resonance imaging-based proton density fat fraction (MRI-PDFF). Methods: Altogether, 320 consecutive subjects who underwent MRI-PDFF and liver SDCT examinations were recruited and prospectively enrolled from four Chinese hospital centers. Participants were classified into normal (n = 152), mild steatosis (n = 110), and moderate/severe(mod/sev) steatosis (n = 58) groups based on MRI-PDFF. SDCT liver parameters were evaluated using conventional polychromatic CT images (CTpoly), virtual mono-energetic images at 40 keV (CT40kev), the slope of the spectral attenuation curve (λ), the effective atomic number (Zeff), and liver to spleen attenuation ratio (L/S ratio). Linearity between SDCT liver parameters and MRI-PDFF was examined using Spearman correlation. Cutoff values for SDCT liver parameters in determining steatosis grades were identified using the area under the receiver-operating characteristic curve analyses. Results: SDCT liver parameters demonstrated a strong correlation with PDFF, particularly Zeff (rs = −0.856; p < 0.001). Zeff achieved an area under the curve (AUC) of 0.930 for detecting the presence of steatosis with a sensitivity of 89.4%, a specificity of 82.4%, and an AUC of 0.983 for detecting mod/sev steatosis with a sensitivity of 93.1%, a specificity of 93.5%, the corresponding cutoff values were 7.12 and 6.94, respectively. Zeff also exhibited good diagnostic performance for liver steatosis grading in subgroups, independent of body mass index. Conclusion: SDCT liver parameters, particularly Zeff, exhibit excellent diagnostic accuracy for grading steatosis. Critical relevance statement: Dual-layer SDCT parameter, Zeff, as a more convenient and accurate imaging biomarker may serve as an alternative indicator for MRI-based proton density fat fraction, exploring the stage and prognosis of liver steatosis, and even metabolic risk assessment. Key Points: Liver biopsy is the standard for grading liver steatosis, but is limited by its invasive nature. The diagnostic performance of liver steatosis using SDCT-Zeff outperforms conventional CT parameters. SDCT-Zeff accurately and noninvasively assessed the grade of liver steatosis. [ABSTRACT FROM AUTHOR]

In our ongoing work to create potential antifungal agents, we synthesized and tested a group of C1-substituted acylhydrazone β-carboline analogues 9a–o and 10a–o for their effectiveness against Valsa mali, Fusarium solani, Fusarium oxysporum, and Fusarium graminearum. Their compositions were analyzed using different spectral techniques, such as 1H/13C NMR and HRMS, with the structure of 9l being additionally confirmed through X-ray diffraction. The antifungal evaluation showed that, among all the target β-carboline analogues, compounds 9n and 9o exhibited more promising and broad-spectrum antifungal activity than the commercial pesticide hymexazol. Several intriguing findings regarding structure–activity relationships (SARs) were examined. In addition, the cytotoxicity test showed that these acylhydrazone β-carboline analogues with C1 substitutions exhibit a preference for fungi, with minimal harm to healthy cells (LO2). The reported findings provide insights into the development of β-carboline analogues as new potential antifungal agents. [ABSTRACT FROM AUTHOR]

Multidrug resistance (MDR) remains the most difficult problem facing conventional chemotherapy for cancers. Astragalus membranaceus is a historically traditional Chinese medicine. One of its bioactive components, formononetin, exhibits antitumor effects on various cancers. However, the effects of formononetin on MDR cancers have not been evaluated. Therefore, we investigated the defense's effects of formononetin on MDR. We used rhodamine 123 and doxorubicin efflux assays to analyze the inhibition kinetics of P-glycoprotein (P-gp) mediated-efflux. Cell viability was detected by sulforhodamine B assay, and the synergistic effects of formononetin combined with chemotherapeutic agents were further calculated using CompuSyn software. Molecular docking was performed with iGEMDOCK. We discovered that formononetin considerably induced oxidative stress and the disruption of mitochondrial membrane potential in MDR cancer cells. Furthermore, formononetin inhibits the P-gp efflux function by ATPase stimulation and the uncompetitive inhibition of P-gp-mediated effluxes of rhodamine 123 and doxorubicin. The molecular docking model indicates that formononetin may bind to P-gp by strong hydrogen bonds at Arginine (Arg) 489 and Glutamine (Gln) 912. Formononetin exhibits significant synergistic effects with vincristine and doxorubicin toward MDR cancer cells, and it synergistically suppressed tumor growth in vivo with paclitaxel. These results suggest that formononetin should be seen as a potential candidate for the adjuvant therapy of MDR cancers. [ABSTRACT FROM AUTHOR]

Melanoma clinical outcomes emerge from incompletely understood genetic mechanisms operating within the tumor and its microenvironment. Here, we used single-cell RNA-based spatial molecular imaging (RNA-SMI) in patient-derived archival tumors to reveal clinically relevant markers of malignancy progression and prognosis. We examined spatial gene expression of 203,472 cells inside benign and malignant melanocytic neoplasms, including melanocytic nevi and primary invasive and metastatic melanomas. Algorithmic cell clustering paired with intratumoral comparative two-dimensional analyses visualized synergistic, spatial gene signatures linking cellular proliferation, metabolism, and malignancy, validated by protein expression. Metastatic niches included up-regulation of CDK2 and FABP5, which independently predicted poor clinical outcome in 473 patients with melanoma via Cox regression analysis. More generally, our work demonstrates a framework for applying single-cell RNA-SMI technology toward identifying gene regulatory landscapes pertinent to cancer progression and patient survival. [ABSTRACT FROM AUTHOR]

Background: Osteoprotegerin (OPG) is supposed to participate in the development of atherosclerosis and cardio-cerebrovascular disease. However, the results of research on relationship between OPG and ischemic stroke (IS) are controversial. Therefore, we carried out the first systematic review and meta-analysis to evaluate prognostic effect of osteoprotegerin in patients with IS. Methods: We comprehensively searched databases of PubMed, Embase, and the Cochrane Library through 21 August 2023 to identify observational studies that evaluated effect of OPG on poor functional outcome (modified Rankin Scale [mRS] Score of 3–6) and mortality in patients with IS. Adjusted odds ratios (aOR) with a 95% confidence interval (CI) of each included study were used as much as possible to assess the pooled effect. Results: Five studies that enrolled 4,506 patients in total fulfilled our inclusion criteria. Three studies were included in the pooled analysis for each endpoint since one of the included studies had provided data on poor functional outcome as well as mortality. OPG was neither associated with poor functional outcome (aOR 1.29, 95% CI 0.90–1.85) nor with mortality (aOR 1.57, 95% CI 0.90–2.74) in patients with IS. Conclusions: There is insufficient evidence to demonstrate the correlation between OPG and mortality or poor functional outcome in IS patients. OPG cannot be applied to predict worse neurological function in IS patients based on the current evidence. [ABSTRACT FROM AUTHOR]

Streptococcus suis is one of the most common zoonotic pathogens, in humans and can cause meningitis, endocarditis, arthritis and sepsis. Human cases of Streptococcus suis infection have been reported worldwide, and most of those cases occurred in Asia. Hearing loss is the most common sequela of Streptococcus suis meningitis. Streptococcus suis infection complicated with acute cerebral infarction has rarely been reported. Therefore, to provide a reference for this disease, we reported a case of acute multiple brain infarctions associated with Streptococcus suis infection. In our report, a 69yearold male patient had Streptococcus suis meningitis and sepsis, which were associated with multiple acute cerebral infarctions in the pons and bilateral frontotemporal parietal occipital lobes. After treatment, the patient exhibited cognitive impairment, dyspraxia and irritability. There are limited case reports of cerebral infarction associated with Streptococcus suis infection, and further research is needed to determine the best treatment method. [ABSTRACT FROM AUTHOR]

Biochar application can alleviate the adverse effects of saline-alkali stress on crops. However, the long-term effects of one-off biochar application on soil physicochemical properties, salt concentration, nutrient availability, soil enzyme activities, and rice yield under highly saline-alkali paddy soils remain unclear. Here, a 6-year paddy field study was conducted in a saline-alkali paddy field using two nitrogen application levels (0 and 225 kg ha−1) and four biochar application rates [0 (T0), 1.5% (T1.5), 3.0% (T3.0), and 4.5% (T4.5) biochar, w/w]. The results showed that compared with T0, the bulk density (BD) under T1.5, T3.0, and T4.5 treatments significantly decreased by 11.21%, 16.33%, and 25.57%, while total porosity (Tp) and saturated hydraulic conductivity (Ks) increased by 19.15–27.34% and 3217.78–5539.83%, respectively. Biochar consistently improved soil macro-aggregates, mean weight diameter (MWD), and the percentage of water-stable aggregates (PWSA) over the years. Additionally, one-off application of biochar continuously reduced the soil Na+ concentration, Na+/K+ ratio, Na+/Ca2+ ratio, saturated paste extract (ECe), exchangeable sodium percentage (ESP), and sodium adsorption ratio (SARe). However, it reduced the pH in 2021 and 2022 only. It enhanced the concentration of K+, Ca2+, Mg2+, and cation exchange capacity (CEC) over the 6-year study, indicating its longer-term positive impact. Furthermore, the one-off biochar application, especially under high application rate treatments (T3.0 and T4.5), significantly and continuously improved nutrient availability and soil enzyme activities. However, alkali-hydrolysable nitrogen (AN) decreased in the initial year of biochar application. The grain yield of T1.5, T3.0, and T4.5 surpassed that of T0 by 116.38%, 141.24%, and 145.20%, respectively. Notably, the rice yield reached its peak with the treatment of 3.0% (w/w) in all 6 years of study period. These findings offered new perspectives on repairing and improving soil quality and production ability of highly saline-alkali paddy soils. Highlights: A long-term (6-year), one-off application of biochar was conducted in a highly saline-alkali paddy field. Biochar consistently decreased soil BD, increased Tp, Ks, and improved soil aggregates. Biochar showed a sustained ability to alleviate saline-alkali stress. The continuous improvement of soil functions acted on the increase of rice yield. [ABSTRACT FROM AUTHOR]

Summary: Black wolfberry (Lycium ruthenicum Murr.) contains various bioactive metabolites represented by flavonoids, which are quite different among production regions. However, the underlying regulation mechanism of flavonoid biosynthesis governing the bioactivity of black wolfberry remains unclear.Presently, we compared the bioactivity of black wolfberry from five production regions. Multi‐omics were performed to construct the regulation network associated with the fruit bioactivity. The detailed regulation mechanisms were identified using genetic and molecular methods.Typically, Qinghai (QH) fruit exhibited higher antioxidant and anti‐inflammatory activities. The higher medicinal activity of QH fruit was closely associated with the accumulation of eight flavonoids, especially Kaempferol‐3‐O‐rutinoside (K3R) and Quercetin‐3‐O‐rutinoside (rutin). Flavonoid biosynthesis was found to be more active in QH fruit, and the upregulation of LrFLS, LrCHS, LrF3H and LrCYP75B1 caused the accumulation of K3R and rutin, leading to high medicinal bioactivities of black wolfberry. Importantly, transcription factor LrMYB94 was found to regulate LrFLS, LrCHS and LrF3H, while LrWRKY32 directly triggered LrCYP75B1 expression. Moreover, LrMYB94 interacted with LrWRKY32 to promote LrWRKY32‐regulated LrCYP75B1 expression and rutin synthesis in black wolfberry. Transgenic black wolfberry overexpressing LrMYB94/LrWRKY32 contained higher levels of K3R and rutin, and exhibited high medicinal bioactivities. Importantly, the LrMYB94/LrWRKY32‐regulated flavonoid biosynthesis was light‐responsive, showing the importance of light intensity for the medicinal quality of black wolfberry.Overall, our results elucidated the regulation mechanisms of K3R and rutin synthesis, providing the basis for the genetic breeding of high‐quality black wolfberry. [ABSTRACT FROM AUTHOR]

Ginseng (Panax ginseng Meyer) has long been consumed as a medicinal or functional food in East Asia. It is available as dried white ginseng (WG) and steamed red ginseng (RG), which might differ in ginsenoside profiles. We compared ginsenoside types of RG and WG using UPLC‐MS/MS and evaluated how they biologically affected heart of healthy rats by recording electrocardiography, measuring biochemical indicators, analyzing cardiac tissue slides, and Ca2+ signaling pathways. About 25 and 29 ginsenosides were detected in WG and RG, respectively, and the total ginsenoside content of RG contained was nearly 1.8 times higher than that of WG. Among them, ginsenoside Rg4, ginsenoside Rg6, ginsenoside Rh4, ginsenoside Rk1, ginsenoside Rg5, and protopanaxadiol were detected only in RG, while 20(R)‐ginsenoside Rg2 was detected only in WG. Male SD rats treated by intraperitoneal injection of WG or RG extracts were similar to the control in terms of electrocardiography and heart histology, indicating that both may not significantly affect the rats' myocardial function. However, WG and RG may induce mild cardiac injury resulting in increased cardiac collagen and creatine kinase levels. In addition, upregulated p‐CaMKII and PPARδ and downregulated SERCA2a for WG and RG treatments were further associated with increased cardiac contractility. In general, RG had less effect on the heart of healthy rats than WG, which may be due to RG having a high proportion of low‐polar ginsenosides. [ABSTRACT FROM AUTHOR]

Dianhong Black Tea, a fermented tea containing various bioactive ingredients, has been found to have a significant role in alleviating alcoholic liver injury (ALI). One of its main unique components, Dianhong Black Tea volatile substances (DBTVS), may have potential anti‐ALI effects. However, its effects and underlying molecular mechanisms are still unknown. In this study, we aimed to investigate the potential of DBTVS as an anti‐ALI agent using alcohol‐fed rats. We assessed the effect of DBTVS on ALI by analyzing serum transaminase and lipid levels, as well as conducting hematoxylin–eosin and oil red O staining. Additionally, GC‐MS was used to detect the components of DBTVS, while transcriptome, proteomics analysis, Western blot, and molecular docking were employed to uncover the underlying mechanisms. Our results demonstrated that DBTVS significantly reduced serum ALT and AST levels and improved lipid metabolism disorders. Moreover, we identified 14 components in DBTVS, with five of them exhibiting strong binding affinity with key proteins. These findings suggested that DBTVS could be a promising agent for the prevention and treatment of ALI. Its potential therapeutic effects may be attributed to its ability to regulate lipid metabolism through the PPAR signaling pathway. [ABSTRACT FROM AUTHOR]

Drug-induced liver injury (DILI) poses a severe threat to public health. Endoplasmic reticulum (ER) stress contributes significantly to DILI pathogenesis, with peroxynitrite (ONOO−) identified as a pivotal indicator. However, the temporal and spatial fluctuations of ONOO− associated with ER stress in the pathogenesis of DILI remain unclear. Herein, a novel ER-specific near-infrared (NIR) probe (QM-ONOO) with aggregation-induced emission (AIE) features for monitoring ONOO− fluctuations in DILI was elaborately constructed. QM-ONOO exhibited excellent ER-targeting specificity, a large Stoke's shift, and a low detection limit (26.9 nM) toward ONOO−. QM-ONOO performed well in imaging both exogenous and endogenous ONOO− in HepG2 cells. Furthermore, molecular docking calculations validated the ER-targeting mechanism of QM-ONOO. Most importantly, using this probe allowed us to intuitively observe the dynamic fluctuations of ONOO− during the formation and remediation processes of DILI in the acetaminophen (APAP)-induced mouse model. Consequently, this work provides a promising tool for in-depth research of ONOO− associated pathological processes in DILI. [Display omitted] • An endoplasmic reticulum-targeted NIR fluorescent probe with aggregation-induced emission features was developed for ONOO−. • The multifunctional probe can detect ONOO− selectively and sensitively with fluorescence changes at 620 nm. • The fluorescence probe can image ER-associated ONOO− with low biotoxicity in cells. • The probe can monitor the fluctuations of ONOO− in the APAP-induced mouse model of DILI. [ABSTRACT FROM AUTHOR]

Although the combination of chemotherapy and radiotherapy has increased the survival rate of patients with nasopharyngeal carcinoma (NPC), certain patients do not respond well to the treatment and have a poor prognosis. Therefore, novel therapeutic drugs and strategies to improve prognosis of patients with NPC are required. As certain plant extracts can suppress the viability of cancer cells, the present study investigated whether oligonol, a polyphenolic compound primarily found in lychee fruit, exerts anticancer activities in NPC cells. MTT, ELISA and immunoblotting were performed to investigate cell survival, cytokeratin-18 fragment release, and the expression of apoptosis and autophagy markers, respectively. Oligonol decreased the viability of NPC-TW01 and NPC/HK1NPC cell lines. Oligonol increased the protein expression of several apoptosis markers, including cleaved caspase-8 and -3, cleaved PARP and cytokeratin 18 fragment. Moreover, it also increased expression of autophagy markers Beclin 1 and LC3-II, as well as LC3-II/LC3-I ratio in both NPC cell lines. Furthermore, treatment with autophagy inhibitors 3-methyladenine or LY294002 significantly increased oligonol-induced viability inhibition in NPC-TW01 cells. Combined treatment of oligonol + LY294002 reduced LC3-II expression and the LC3II/LC3I ratio while increasing cleaved caspase-8 and -3, cleaved PARP and cytokeratin 18 fragment expression in NPC-TW01 cells. These findings indicated autophagy inhibitors could enhance viability inhibition and apoptotic effects induced by oligonol in NPC cells. [ABSTRACT FROM AUTHOR]

DNA repair allows the survival of cancer cells. Therefore, the development of DNA repair inhibitors is a critical need for sensitizing cancers to chemoradiation. Sae2CtIP has specific functions in initiating DNA end resection, as well as coordinating cell cycle checkpoints, and it also greatly interacts with the DDR at different levels. In this study, we demonstrated that corylin, a potential sensitizer, causes deficiencies in DNA repair and DNA damage checkpoints in yeast cells. More specifically, corylin increases DNA damage sensitivity through the Sae2-dependent pathway and impairs the activation of Mec1-Ddc2, Rad53-p and γ-H2A. In breast cancer cells, corylin increases apoptosis and reduces proliferation following Dox treatment by inhibiting CtIP. Xenograft assays showed that treatment with corylin combined with Dox significantly reduced tumor growth in vivo. Our findings herein delineate the mechanisms of action of corylin in regulating DNA repair and indicate that corylin has potential long-term clinical utility as a DDR inhibitor. [Display omitted] • Corylin inhibits DNA repair and DNA damage checkpoints in the SSA system. • Corylin increases DNA damage sensitivity through the Sae2CtIP-dependent pathway. • The combination of corylin and Doxorubicin significantly suppressed tumor growth. [ABSTRACT FROM AUTHOR]

[Display omitted] • 37 β -carboline derivatives were synthesized, with monomer M3 and dimer D4 possessing the selective activity and higher cytotoxicity in tumor cells than in normal cells. • The antitumor mechanism of M3 and D4 was explored, identifying CDK2 and DNA as potential key targets. • M3 and D4 interacts with DNA and CDK2 at sub-micromolar concentrations in endothermic interactions caused by entropy-driven adsorption processes. • M3 , as a dual-pocket inhibitor of CDK2, is a promising framework for the rational design of next-generation CDK2 inhibitors. β -Carboline alkaloids are natural and synthetic products with outstanding antitumor activity. C3 substituted and dimerized β -carbolines exert excellent antitumor activity. In the present research, 37 β -carboline derivatives were synthesized and characterized. Their cytotoxicity, cell cycle, apoptosis, and CDK2- and DNA-binding affinity were evaluated. β -Carboline monomer M3 and dimer D4 showed selective activity and higher cytotoxicity in tumor cells than in normal cells. Structure-activity relationships (SAR) indicated that the amide group at C3 enhanced the antitumor activity. M3 blocked the A549 (IC 50 = 1.44 ± 1.10 μM) cell cycle in the S phase and inhibited A549 cell migration, while D4 blocked the HepG2 (IC 50 = 2.84 ± 0.73 μM) cell cycle in the G0/G1 phase, both of which ultimately induced apoptosis. Furthermore, associations of M3 and D4 with CDK2 and DNA were proven by network pharmacology analysis, molecular docking, and western blotting. The expression level of CDK2 was downregulated in M3 -treated A549 cells and D4 -treated HepG2 cells. Moreover, M3 and D4 interact with DNA and CDK2 at sub-micromolar concentrations in endothermic interactions caused by entropy-driven adsorption processes, which means that the favorable entropy change (ΔS > 0) overcomes the unfavorable enthalpy change (ΔH > 0) and drives the spontaneous reaction (ΔG < 0). Overall, these results clarified the antitumor mechanisms of M3 and D4 through disrupting the cell cycle by binding DNA and CDK2, which demonstrated the potential of M3 and D4 as novel antiproliferative drugs targeting mitosis. [ABSTRACT FROM AUTHOR]

The cover image is based on the Original Article Ginseng in white and red processed forms: Ginsenosides and cardiac side effects by Jiexin Zhou et al., https://doi.org/10.1002/fsn3.3879.By Jiexin Zhou; Jiarui Zhang; Pu Jing; Yu Lan; Xiaonian Cao; Huafang Feng; Xiaogang Liu and Qingqing LiuReported by Author; Author; Author; Author; Author; Author; Author; Author [Extracted from the article]