Synthesis and biological evaluation of multimodal monoaminergic arylpiperazine derivatives with potential antidepressant profile.

Depression is a common psychiatric disorder with an estimated global prevalence of 4.4 %. Here, we designed a series of new multimodal monoaminergic arylpiperazine derivatives using a pharmacophore hybrid approach and synthesized them for the treatment of depression. Molecular docking was employed to elucidate the differences in activity and selectivity of the corresponding compounds on SERT, NET, and DAT. In vitro experiments demonstrated that compound A3 has a relatively balanced multi-target activity profile with SERT reuptake inhibition (IC50 = 12 nM), NET reuptake inhibition (IC50 = 78 nM), DAT reuptake inhibition (IC50 = 135 nM), and 5-HT1AR agonism (EC50 = 34 nM). Pharmacokinetic experiments revealed that A3 exhibited excellent bioavailability and low clearance in mice. Subsequent behavioral experiments further confirmed its significant antidepressant effects. These results further highlight the rationality of our design strategy.

Equivalent analysis model of a GaN LED used as a receiver.

In general, visible light communication (VLC) uses LEDs as transmitters. However, LEDs can serve as receivers to construct a simple duplex VLC system that uses only two LEDs instead of one LED and one photo-diode (PD). There is a lack of effective equivalent analysis models for characterizing and evaluating the inherent behavioral characteristics of LEDs used as receivers. This paper presents an equivalent analysis model for GaN LEDs as receivers. First, based on the proposed receiving equivalent circuit model, a third-order signal transmission mathematical analysis model is established, revealing the transmission relationship between the photocurrent and output voltage. Further research is conducted on the impact of parameter changes on the bandwidth, and the model can be simplified into a first-order low-pass mathematical analysis model under specific conditions, providing theoretical support for improving the bandwidth of LED receiving applications. The experimental results also confirm the theoretical predictions. This research result holds significant importance for revealing the intrinsic mechanisms and the improved optical communication performance of LEDs for effective reception.

Enhancing skin lesion segmentation with a fusion of convolutional neural networks and transformer models.

Accurate segmentation is crucial in diagnosing and analyzing skin lesions. However, automatic segmentation of skin lesions is extremely challenging because of their variable sizes, uneven color distributions, irregular shapes, hair occlusions, and blurred boundaries. Owing to the limited range of convolutional networks receptive fields, shallow convolution cannot extract the global features of images and thus has limited segmentation performance. Because medical image datasets are small in scale, the use of excessively deep networks could cause overfitting and increase computational complexity. Although transformer networks can focus on extracting global information, they cannot extract sufficient local information and accurately segment detailed lesion features. In this study, we designed a dual-branch encoder that combines a convolution neural network (CNN) and a transformer. The CNN branch of the encoder comprises four layers, which learn the local features of images through layer-wise downsampling. The transformer branch also comprises four layers, enabling the learning of global image information through attention mechanisms. The feature fusion module in the network integrates local features and global information, emphasizes important channel features through the channel attention mechanism, and filters irrelevant feature expressions. The information exchange between the decoder and encoder is finally achieved through skip connections to supplement the information lost during the sampling process, thereby enhancing segmentation accuracy. The data used in this paper are from four public datasets, including images of melanoma, basal cell tumor, fibroma, and benign nevus. Because of the limited size of the image data, we enhanced them using methods such as random horizontal flipping, random vertical flipping, random brightness enhancement, random contrast enhancement, and rotation. The segmentation accuracy is evaluated through intersection over union and duration, integrity, commitment, and effort indicators, reaching 87.7 % and 93.21 %, 82.05 % and 89.19 %, 86.81 % and 92.72 %, and 92.79 % and 96.21 %, respectively, on the ISIC 2016, ISIC 2017, ISIC 2018, and PH2 datasets, respectively (code: https://github.com/hyjane/CCT-Net).

Design, synthesis and structure-activity relationship of 1,8-naphthalimide derivatives as highly potent hCYP1B1 inhibitors.

Human cytochrome P450 1B1 enzyme (hCYP1B1), a member of hCYP1 subfamily, plays a crucial role in multiple diseases by participating in many metabolic pathways. Although a suite of potent hCYP1B1 inhibitors have been previously reported, most of them also act as aryl hydrocarbon receptor (AhR) agonists that can up-regulate the expression of hCYP1B1 and then counteract their inhibitory potential in living systems. This study aimed to develop novel efficacious hCYP1B1 inhibitors that worked well in living cells but without AhR agonist effects. For these purposes, a series of 1,8-naphthalimide derivatives were designed and synthesized, and their structure-activity relationships (SAR) as hCYP1B1 inhibitors were analyzed. Following three rounds SAR studies, several potent hCYP1B1 inhibitors were discovered, among which compound 3n was selected for further investigations owing to its extremely potent anti-hCYP1B1 activity (IC50 = 0.040 nM) and its blocking AhR transcription activity in living cells. Inhibition kinetic analyses showed that 3n potently inhibited hCYP1B1 via a mix inhibition manner, showing a Ki value of 21.71 pM. Docking simulations suggested that introducing a pyrimidine moiety to the hit compound (1d) facilitated 3n to form two strong interactions with hCYP1B1/heme, viz., the C-Br⋯π halogen bond and the N-Fe coordination bond. Further investigations demonstrated that 3n (5 µM) could significantly reverse the paclitaxel (PTX) resistance in H460/PTX cells, evidenced by the dramatically reduced IC50 values, from 632.6 nM (PTX alone) to 100.8 nM (PTX plus 3n). Collectively, this study devised a highly potent hCYP1B1 inhibitor (3n) without AhR agonist effect, which offered a promising drug candidate for overcoming hCYP1B1-associated drug resistance.

D3EGFR: a webserver for deep learning-guided drug sensitivity prediction and drug response information retrieval for EGFR mutation-driven lung cancer.

As key oncogenic drivers in non-small-cell lung cancer (NSCLC), various mutations in the epidermal growth factor receptor (EGFR) with variable drug sensitivities have been a major obstacle for precision medicine. To achieve clinical-level drug recommendations, a platform for clinical patient case retrieval and reliable drug sensitivity prediction is highly expected. Therefore, we built a database, D3EGFRdb, with the clinicopathologic characteristics and drug responses of 1339 patients with EGFR mutations via literature mining. On the basis of D3EGFRdb, we developed a deep learning-based prediction model, D3EGFRAI, for drug sensitivity prediction of new EGFR mutation-driven NSCLC. Model validations of D3EGFRAI showed a prediction accuracy of 0.81 and 0.85 for patients from D3EGFRdb and our hospitals, respectively. Furthermore, mutation scanning of the crucial residues inside drug-binding pockets, which may occur in the future, was performed to explore their drug sensitivity changes. D3EGFR is the first platform to achieve clinical-level drug response prediction of all approved small molecule drugs for EGFR mutation-driven lung cancer and is freely accessible at https://www.d3pharma.com/D3EGFR/index.php.

Impact of Halogen Bonds on Protein-Peptide Binding and Protein Structural Stability Revealed by Computational Approaches.

Halogen bonds (XBs) are essential noncovalent interactions in molecular recognition and drug design. Current studies on XBs in drug design mainly focus on the interactions between halogenated ligands and target proteins, lacking a systematic study of naturally existing and artificially prepared halogenated residue XBs (hr_XBs) and their characteristics. Here, we conducted a computational study on the potential hr_XBs in proteins/peptides using database searching, quantum mechanics calculations, and molecular dynamics simulations. XBs at the protein-peptide interaction interfaces are found to enhance their binding affinity. Additionally, the formation of intramolecular XBs (intra_XBs) within proteins may significantly contribute to the structural stability of structurally flexible proteins while having a minor impact on proteins with inherently high structural rigidity. Impressively, introducing halogens without the formation of intra_XBs may lead to a decrease in the protein structural stability. This study enriches our understanding of the roles and effects of halogenated residue XBs in biological systems.

Unexpected effect of halogenation on the water solubility of small organic compounds.

Halogenation is an indispensable method in the structural modification of lead compounds. It is known to increase lipophilicity and is hence used to improve membrane permeability and thus bioavailability. In this study, we compare the water solubility (logS) of organohalogen compounds and their non-halogenated parent compounds using the molecular matched pair (MMP) analysis method. Unexpectedly, 19.9% of the compounds increased their water solubility upon halogenation. Iodination was observed to have the greatest effect on solubility, followed by chlorination, bromination, and fluorination. Introducing amino, hydroxyl and carboxyl groups into organohalogens improves their aqueous solubilities, whereas introducing a trifluoromethyl group has the opposite effect. According to our quantum chemical calculations, the increased water solubility upon halogenation is, at least partially, attributed to an increased polarity and polarizability. These results improve our understanding of the influence of halogenation on bioactivity.

Dihydrocelastrol induces cell death and suppresses angiogenesis through BCR/AP-1/junb signalling in diffuse large B cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Although treatment options have improved, a large proportion of patients show low survival rates, highlighting an urgent need for novel therapeutic strategies. The aim of this study was to investigate the efficacy of the new small-molecule compound dihydrocelastrol (DHCE), acquired through the structural modification of celastrol (CE), in the treatment of DLBCL. DHCE showed potent anti-lymphoma efficacy and synergistic effects with doxorubicin. DHCE triggered DLBCL cell apoptosis and G0/G1-phase blockade, thereby hindering angiogenesis. DHCE inhibited B-cell receptor cascade signalling and Jun B and p65 nuclear translocation, thereby suppressing pro-tumourigenic signalling. Finally, DHCE exerted lower toxicity than CE, which showed severe hepatic, renal, and reproductive toxicity in vivo. Our findings support further investigation of the clinical efficacy of DHCE against DLBCL.

A Bioengineered Nanovesicle Vaccine Boosts T-B cell Interaction for Immunotherapy of Echinococcus multilocularis.

Alveolar echinococcosis (AE) is a zoonotic parasitic disease, resulting from being infected with the metacestode larvae of the tapeworm Echinococcus multilocularis (E. multilocularis). Novel prophylactic and therapeutic interventions are urgently needed since the current chemotherapy displays limited efficiency in AE treatment. Bioengineered nano cellular membrane vesicles are widely used for displaying the native conformational epitope peptides because of their unique structure and biocompatibility. In this study, four T-cells and four B-cells dominant epitope peptides of E. multilocularis with high immunogenicity were engineered into the Vero cell surface to construct a membrane vesicle nanovaccine for the treatment of AE. The results showed that the nanovesicle vaccine can efficiently activate dendritic cells, induce specific T/B cells to form a mutually activated circuit, and inhibit E. multilocularis infection. This study presents for the first time a nanovaccine strategy that can completely eliminate the burden of E. multilocularis.

Opportunistic lung cancer screening with low-dose computed tomography in National Cancer Center of China: The first 14 years' experience.

BACKGROUND: In China, over 50% of lung cancer cases occur in nonsmokers. Thus, identifying high-risk individuals for targeted lung cancer screening is crucial. Beyond age and smoking, determining other risk factors for lung cancer in the Asian population has become a focal point of research. Using 30,000 participants in the prospectively enrolled cohort at China's National Cancer Center (NCC) over the past 14 years, we categorized participants by risk, with an emphasis on nonsmoking females. MATERIALS AND METHODS: Between November 2005 and December 2019, 31,431 individuals voluntarily underwent low-dose computed tomography (LDCT) scans for lung cancer screening at the NCC. We recorded details like smoking history, exposure to hazards, and family history of malignant tumors. Using the 2019 NCCN criteria, participants were categorized into high-, moderate-, and low-risk groups. Additionally, we separated non-high-risk groups into female never smokers (aged over 40) exposed to second-hand smoke (SHS) and others. Any positive results from initial scans were monitored per the I-ELCAP protocol (2006), and suspected malignancies were addressed through collaborative decisions between patients and physicians. We analyzed and compared the detection rates of positive results, confirmed lung cancers, and cancer stages across risk, age, and gender groups. RESULTS: Out of 31,431 participants (55.9% male, 44.1% female), 3695 (11.8%) showed positive baseline LDCT scans with 197 (0.6%; 106 females, 91 males) confirmed as lung cancer cases pathologically. Malignancy rate by age was 0.1% among those aged under 40 years, 0.4% among those aged 40-49 years, 0.8% among those aged 50-59 years, and 1.2% among those aged 60 years and older. From the 25,763 participants (56.9% male, 43.1% female) who completed questionnaires, 1877 (7.3%) were categorized as high risk, 6500 (25.2%) as moderate risk, and 17,386 (67.5%) as low risk. Of the 23,886 in the non-high-risk category, 8041 (33.7%) were females over 40 years old exposed to SHS. The high-risk group showed the highest lung cancer detection rate at 1.4%. However, females exposed to SHS had a notably higher detection rate than the rest of the non-high-risk group (1.1% vs. 0.5%; p < 0.0001). In this cohort, 84.8% of the detected lung cancers were at an early stage. CONCLUSIONS: In our study, using LDCT for lung cancer screening proved significant for high-risk individuals. For non-high-risk populations, LDCT screening could be considered for nonsmoking women with exposure to SHS.

D3Rings: A Fast and Accurate Method for Ring System Identification and Deep Generation of Drug-Like Cyclic Compounds.

Continuous exploration of the chemical space of molecules to find ligands with high affinity and specificity for specific targets is an important topic in drug discovery. A focus on cyclic compounds, particularly natural compounds with diverse scaffolds, provides important insights into novel molecular structures for drug design. However, the complexity of their ring structures has hindered the applicability of widely accepted methods and software for the systematic identification and classification of cyclic compounds. Herein, we successfully developed a new method, D3Rings, to identify acyclic, monocyclic, spiro ring, fused and bridged ring, and cage ring compounds, as well as macrocyclic compounds. By using D3Rings, we completed the statistics of cyclic compounds in three different databases, e.g., ChEMBL, DrugBank, and COCONUT. The results demonstrated the richness of ring structures in natural products, especially spiro, macrocycles, and fused and bridged rings. Based on this, three deep generative models, namely, VAE, AAE, and CharRNN, were trained and used to construct two data sets similar to DrugBank and COCONUT but 10 times larger than them. The enlarged data sets were then used to explore the molecular chemical space, focusing on complex ring structures, for novel drug discovery and development. Docking experiments with the newly generated COCONUT-like data set against three SARS-CoV-2 target proteins revealed that an expanded compound database improves molecular docking results. Cyclic structures exhibited the best docking scores among the top-ranked docking molecules. These results suggest the importance of exploring the chemical space of structurally novel cyclic compounds and continuous expansion of the library of drug-like compounds to facilitate the discovery of potent ligands with high binding affinity to specific targets. D3Rings is now freely available at http://www.d3pharma.com/D3Rings/.

Design and synthesis of cantharidin derivative DCZ5418 as a TRIP13 inhibitor with anti-multiple myeloma activity in vitro and in vivo.

Natural product cantharidin can inhibit multiple myeloma cell growth in vitro, while serious adverse effects limited its clinical application. Therefore, the structural modification of cantharidin is needed. Herein, inspired by the structural similarity of the aliphatic endocyclic moiety in cantharidin and TRIP13 inhibitor DCZ0415, we designed and synthesized DCZ5418 and its nineteen derivatives. The molecular docking study indicated that DCZ5418 had a similar binding mode to TRIP13 protein as DCZ0415 while with a stronger docking score. Moreover, the bioassay studies of the MM-cells viability inhibition, TRIP13 protein binding affinity and enzyme inhibiting activity showed that DCZ5418 had good anti-MM activity in vitro and definite interaction with TRIP13 protein. The acute toxicity test of DCZ5418 showed less toxicity in vivo than cantharidin. Furthermore, DCZ5418 showed good anti-MM effects in vivo with a lower dose administration than DCZ0415 (15 mg/kg vs 25 mg/kg) on the tumor xenograft models. Thus, we obtained a new TRIP13 inhibitor DCZ5418 with improved safety and good activity in vivo, which provides a new example of lead optimization by using the structural fragments of natural products.

Loss of RACK1 promotes glutamine addiction via activating AKT/mTOR/ASCT2 axis to facilitate tumor growth in gastric cancer.

BACKGROUND: Metabolic reprogramming is closely related to the development of gastric cancer (GC), which remains as the fourth leading cause of cancer-related death worldwide. As a tumor suppressor for GC, whether receptor for activated C-kinase 1 (RACK1) play a modulatory role in metabolic reprogramming remains largely unclear. METHODS: GC cell lines and cell-derived xenograft mouse model were used to identify the biological function of RACK1. Flow cytometry and Seahorse assays were applied to examine cell cycle and oxygen consumption rate (OCR), respectively. Western blot, real-time PCR and autophagy double fluorescent assays were utilized to explore the signaling. Immunohistochemistry was performed to detect the expression of RACK1 and other indicators in tissue sections. RESULTS: Loss of RACK1 facilitated the viability, colony formation, cell cycle progression and OCR of GC cells in a glutamine-dependent manner. Further investigation revealed that RACK1 knockdown inhibited the lysosomal degradation of Alanine-serine-cysteine amino acid transporter 2 (ASCT2). Mechanistically, depletion of RACK1 remarkably decreased PTEN expression through up-regulating miR-146b-5p, leading to the activation of AKT/mTOR signaling pathway which dampened autophagy flux subsequently. Moreover, knockdown of ASCT2 could reverse the promotive effect of RACK1 depletion on GC tumor growth both in vitro and in vivo. Tissue microarray confirmed that RACK1 was negatively correlated with the expression of ASCT2 and p62, as well as the phosphorylation of mTOR. CONCLUSION: Together, our results demonstrate that the suppressive function of RACK1 in GC is associated with ASCT2-mediated glutamine metabolism, and imply that targeting RACK1/ASCT2 axis provides potential strategies for GC treatment.

Ribosomal protein S3 mediates drug resistance of proteasome inhibitor: potential therapeutic application in multiple myeloma.

Multiple myeloma (MM) remains incurable due to drug resistance. Ribosomal protein S3 (RPS3) has been identified as a non-Rel subunit of NF-κB. However, the detailed biological roles of RPS3 remain unclear. Here, we report for the first time that RPS3 is necessary for MM survival and drug resistance. RPS3 was highly expressed in MM, and knockout of RPS3 in MM inhibited cell growth and induced cell apoptosis both in vitro and in vivo. Overexpression of RPS3 mediated the proteasome inhibitor resistance of MM and shortened the survival of MM tumor-bearing animals. Moreover, our present study found an interaction between RPS3 and the thyroid hormone receptor interactor 13 (TRIP13), an oncogene related to MM tumorigenesis and drug resistance. We demonstrated that the phosphorylation of RPS3 was mediated by TRIP13 via PKCδ, which played an important role in activating the canonical NF-κB signaling and inducing cell survival and drug resistance in MM. Notably, the inhibition of NF-κB signaling by the small-molecule inhibitor targeting TRIP13, DCZ0415, was capable of triggering synergistic cytotoxicity when combined with bortezomib in drug-resistant MM. This study identifies RPS3 as a novel biomarker and therapeutic target in MM.

A novel pterostilbene compound DCZ0825 induces macrophage M1 differentiation and Th1 polarization to exert anti-myeloma and immunomodulatory.

Multiple myeloma (MM) is an incurable and recurrent malignancy characterized by abnormal plasma cell proliferation. There is an urgent need to develop effective drugs in MM. DCZ0825 is a small molecule compound derived from pterostilbene with direct anti-myeloma activity and indirect immune-killing effects though reversal of the immunosuppression. DCZ0825 inhibits the activity and proliferation of MM cells causing no significant toxicity to normal cells. Using flow cytometry, this study found that DCZ0825 induced caspase-dependent apoptosis in MM cells and arrested the cell cycle in the G2/M phase by down-regulating CyclinB1, CDK1 and CDC25. Moreover, DCZ0825 up-regulated IRF3 and IRF7 to increase IFN-γ, promoting M2 macrophages to transform into M1 macrophages, releasing the immunosuppression of CD4T cells and stimulated M1 macrophages and Th1 cells to secrete more INF-γ to form immune killing effect on MM cells. Treatment with DCZ0825 resulted in an increased proportion of positive regulatory cells such as CD4T, memory T cells, CD8T, and NK cells, with downregulation of the proportion of negative regulatory cells such as Treg cells and MDSCs. In conclusion, DCZ0825 is a novel compound with both antitumor and immunomodulatory activity.

The novel norcantharidin derivative DCZ5417 suppresses multiple myeloma progression by targeting the TRIP13-MAPK-YWHAE signaling pathway.

BACKGROUND: Multiple myeloma (MM), an incurable disease owing to drug resistance, requires safe and effective therapies. Norcantharidin (NCTD), an active ingredient in traditional Chinese medicines, possesses activity against different cancers. However, its toxicity and narrow treatment window limit its clinical application. In this study, we synthesized a series of derivatives of NCTD to address this. Among these compounds, DCZ5417 demonstrated the greatest anti-MM effect and fewest side effects. Its anti-myeloma effects and  the mechanism were further tested. METHODS: Molecular docking, pull-down, surface plasmon resonance-binding, cellular thermal shift, and ATPase assays were used to study the targets of DCZ5417. Bioinformatic, genetic, and pharmacological approaches were used to elucidate the mechanisms associated with DCZ5417 activity. RESULTS: We confirmed a highly potent interaction between DCZ5417 and TRIP13. DCZ5417 inhibited the ATPase activity of TRIP13, and its anti-MM activity was found to depend on TRIP13. A mechanistic study verified that DCZ5417 suppressed cell proliferation by targeting TRIP13, disturbing the TRIP13/YWHAE complex and inhibiting the ERK/MAPK signaling axis. DCZ5417 also showed a combined lethal effect with traditional anti-MM drugs. Furthermore, the tumor growth-inhibitory effect of DCZ5417 was demonstrated using in vivo tumor xenograft models. CONCLUSIONS: DCZ5417 suppresses MM progression in vitro, in vivo, and in primary cells from drug-resistant patients, affecting cell proliferation by targeting TRIP13, destroying the TRIP13/YWHAE complex, and inhibiting ERK/MAPK signaling. These results imply a new and effective therapeutic strategy for MM treatment.

TI17, a novel compound, exerts anti-MM activity by impairing Trip13 function of DSBs repair and enhancing DNA damage.

BACKGROUND: Thyroid hormone receptor interacting protein 13 (Trip13) is an AAA-ATPase that regulates the assembly or disassembly protein complexes and mediates Double-strand breaks (DSBs) repair. Overexpression of Trip13 has been detected in many cancers and is associated with myeloma progression, disease relapse and poor prognosis inmultiple myeloma (MM). METHODS: We have identified a small molecular, TI17, through a parallel compound-centric approach, which specifically targets Trip13. To identify whether TI17 targeted Trip13, pull-down and nuclear magnetic resonance spectroscopy (NMR) assays were performed. Cell counting kit-8, clone formation, apoptosis and cell cycle assays were applied to investigate the effects of TI17. We also utilized a mouse model to investigate the effects of TI17 in vivo. RESULTS: TI17 effectively inhibited the proliferation of MM cells, and induced the cycle arrest and apoptosis of MM cells. Furthermore, treatment with TI17 abrogates tumor growth and has no apparent side effects in mouse xenograft models. TI17 specifically impaired Trip13 function of DSBs repair and enhanced DNA damage responses in MM. Combining with melphalan or HDAC inhibitor panobinostat triggers synergistic anti-MM effect. CONCLUSIONS: Our study suggests that TI17 could be acted as a specific inhibitor of Trip13 and supports a preclinical proof of concept for therapeutic targeting of Trip13 in MM.

Dihydrocelastrol induces antitumor activity and enhances the sensitivity of bortezomib in resistant multiple myeloma by inhibiting STAT3-dependent PSMB5 regulation.

Multiple myeloma (MM) is characterized by excessive aggregation of B-cell-derived malignant plasma cells in the hematopoietic system of bone marrow. Previously, we synthesized an innovative molecule named dihydrocelastrol (DHCE) from celastrol, a triterpene purified from medicinal plant Tripterygium wilfordii. Herein, we explore the therapeutic properties and latent signal transduction mechanism of DHCE action in bortezomib (BTZ)-resistant (BTZ-R) MM cells. In this study, we first report that DHCE shows antitumor activities in vitro and in vivo and exerts stronger inhibitory effects than celastrol on BTZ-R cells. We find that DHCE inhibits BTZ-R cell viability by promoting apoptosis via extrinsic and intrinsic pathways and suppresses BTZ-R MM cell proliferation by inducing G0/G1 phase cell cycle arrest. In addition, inactivation of JAK2/STAT3 and PI3K/Akt pathways are involved in the DHCE-mediated antitumor effect. Simultaneously, DHCE acts synergistically with BTZ on BTZ-R cells. PSMB5, a molecular target of BTZ, is overexpressed in BTZ-R MM cells compared with BTZ-S MM cells and is demonstrated to be a target of STAT3. Moreover, DHCE downregulates PSMB5 overexpression in BTZ-R MM cells, which illustrates that DHCE overcomes BTZ resistance through increasing the sensitivity of BTZ in resistant MM via inhibiting STAT3-dependent PSMB5 regulation. Overall, our findings imply that DHCE may become a potential therapeutic option that warrants clinical evaluation for BTZ-R MM.

Berberine derivative DCZ0358 induce oxidative damage by ROS-mediated JNK signaling in DLBCL cells.

The most common neoplasm among adult lymphomas is diffuse large B-cell lymphoma (DLBCL), typically characterized by pain-free and progressive lymph node enlargement. Due to high heterogeneity of DLBCL, 30-40 % of patients are resistant to R-CHOP standard chemoimmunotherapy. DCZ0358 is a new compound designed and synthesized from berberine by our group and the molecular mechanism by which it inhibited DLBCL growth has attracted our widespread attention. In this study, we employed the CCK8 assay to reveal that DCZ0358 inhibited proliferation in a dependent manner of time and dosage of DLBCL cells. Moreover, flowcytometry and western blot results showed that DCZ0358 downregulated the expression of CDK4, CDK6 and CyclinD1 to block cell cycle progression in G0/G1 phase. Furthermore, DCZ0358 enhanced mitochondrial membrane potential depolarization, promoted mitochondrial permeability transport pore openness, increased cytoplastic Ca2+ levels and decreased intracellular adenosine triphosphate production, which led to mitochondrial dysfunction. In particular, DCZ0358 treatment triggered cell apoptosis and elevated intracellular reactive oxygen species (ROS) levels, which subsequently mediated JNK pathway activation. Further research indicated the pre-treatment with ROS scavenger N-acetylcysteine (NAC) and JNK inhibitor SP600125 could partially attenuate apoptosis and DNA damage triggered by DCZ0358. Most importantly, DCZ0358 exhibited synergistic anti-tumor effects when combined with etoposide, a common clinical anti-DLBCL drug, both in vitro and certainly in vivo. Above results demonstrated anti-tumor molecular mechanism of DCZ0358 in DLBCL cells and highlighted the ROS/JNK/DNA damage pathway as a potential target in therapies, which have implications for the development of more effective clinical treatments for DLBCL.

Discovery of zolinium TSG1180 as a novel agonist of transgelin-2 for treating asthma.

Asthma is a complex and heterogeneous respiratory disease that causes serious social and economic burdens. Current drugs such as ß2-agonists cannot fully control asthma. Our previous study found that Transgelin-2 is a potential target for treating asthmatic pulmonary resistance. Herein, we discovered a zolinium compound, TSG1180, that showed a strong interaction with Transgelin-2. The equilibrium dissociation constants (KD) of TSG1180 to Transgelin-2 were determined to be 5.363 × 10-6 and 9.81 × 10-6 M by surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC). Cellular thermal shift assay (CETSA) results showed that the thermal stability of Transgelin-2 increased after coincubation of TSG1180 with lysates of airway smooth muscle cells (ASMCs). Molecular docking showed that Arg39 may be the key residue for the binding. Then, the SPR result showed that the binding affinity of TSG1180 to Transgelin-2 mutant (R39E) was decreased by 1.69-fold. Real time cell analysis (RTCA) showed that TSG1180 treatment could relax ASMCs by 19 % (P < 0.05). Once Transgelin-2 was inhibited, TSG1180 cannot induce a relaxation effect, suggesting that the relaxation effect was specifically mediated by Transgelin-2. In vivo study showed TSG1180 effectively reduced pulmonary resistance by 64 % in methacholine-induced mice model (P < 0.05). Furthermore, the phosphorylation of Ezrin at T567 was increased by 8.06-fold, the phosphorylation of ROCK at Y722 was reduced by 38 % and the phosphorylation of RhoA at S188 was increased by 52 % after TSG1180 treatment. These results suggested that TSG1180 could be a Transgelin-2 agonist for further optimization and development as an anti-asthma drug.