Effects of flunarizine combined with ginkgo leaf extract and dipyridamole injection on hemorheology in elderly patients with vertigo.

Objective: To investigate the effect of flunarizine combined with ginkgo leaf extract and dipyridamole injection (GDI) on hemorheology of elderly patients with vertigo. Methods: Clinical data of 105 elderly patients with vertigo who were treated in The First People's Hospital of Lin'an District from June 2019 to December 2022 were retrospectively selected. Of them, 54 patients received flunarizine combined with GDI (Study group) while 51 patients received flunarizine treatment alone (Control group). The treatment effect and adverse reactions of the two groups, functional rehabilitation before and after treatment, including the Simplified Vertigo Symptom Score Scale (VSS-SF), Berg Balance Scale (BBS), and Dizziness Handicap Inventory (DHI) were measured. Hemodynamics including blood flow velocity (Vm) of basilar artery (BA), left vertebral artery (LVA), and right vertebral artery (RVA) before and after treatment were also assessed. Results: The total efficacy of the treatment in the study group was higher than that in the control group (94.4 % vs. 75.9%; P<0.05). After the treatment, the Vm of the BA, LVA, and RVA was increased in both groups compared to before treatment, and the increase was greater in the study group than in the control group (P<0.05). In addition, the BBS scores of the two groups after the treatment were higher than before the treatment, while the DHI and VSS-SF scores were lower than before the treatment. BBS scores of the study group were higher than those of the control group, while the DHI and VSS-SF scores were lower than those of the control group (P<0.05). There was no statistically significant difference in the incidence of adverse reactions between the study group (5.6%) and the control group (2.0%; P>0.05). Conclusions: The combination of flunarizine and GDI in elderly patients with vertigo can effectively regulate hemodynamics of the patient, reduce the degree of vertigo, improve balance, and have a significant overall therapeutic effect without increasing the risk of adverse reactions.

[Research progress in raw and processed Raphani Semen and prediction of quality markers].

Raphani Semen, with both edible and medicinal values, is a typical Chinese herbal medicine with different effects before and after processing. The raw helps ascending and the cooked helps descending. This paper comprehensively summarizes the differences in chemical constituents and pharmacological effects between raw and processed Raphani Semen that are reported in recent years. Based on the principle of quality markers(Q-markers) of traditional Chinese medicines, the chemical constituent sources, chemical constituent detection techniques, and correlation between bidirectional regulatory efficacy and chemical constituents are compared between raw and processed Raphani Semen. The results suggest that sulforaphene and glucoraphanin could be used as candidate Q-markers of raw and processed Raphani Semen, respectively. This review is expected to provide a reference for further research on the processing, new drug development, and improvement of safety and effectiveness of Raphani Semen in clinical application.

Well-Ordered Au Nanoarray for Sensitive and Reproducible Detection of Hepatocellular Carcinoma-Associated miRNA via CHA-Assisted SERS/Fluorescence Dual-Mode Sensing.

Ultra-sensitive detection of cancer-related biomarkers in serum is of great significance for early diagnosis, treatment, prognosis, and staging of cancer. In this work, we proposed a surface-enhanced Raman scattering and fluorescence (SERS/FL) dual-mode biosensor for hepatocellular carcinoma (HCC)-related miRNA (miR-224) detection using the composition of well-arranged Au nanoarrays (Au NAs) substrate coupled with the target-catalyzed hairpin assembly (CHA) strategy. The hot spots densely and uniformly distributed on the Au array offers considerably enhanced and reproducible SERS signals, along with their wide and open surface to facilitate miR-224 adsorption. By this sensing strategy, the target miR-224 can be detected in a wide linear range (1 fM to 1 nM) with a limit of detection of 0.34 fM in the SERS mode and 0.39 fM in the FL mode. Meanwhile, this biosensor with exceptional specificity and anti-interference ability can discriminate target miR-224 from other interference miRNAs. Practical analysis of human blood samples also demonstrated considerable reliability and repeatability of our developed strategy. Furthermore, this biosensor can distinguish HCC cancer subjects from normal ones and monitor HCC patients before and after hepatectomy as well as guide the distinct Barcelona clinic liver cancer (BCLC) stages. Overall, benefiting from a well-arranged Au nanoarray, CHA amplification strategy, and SERS/metal enhanced fluorescence effect, this established biosensor opens new avenues for the early prediction, warning, monitoring, and staging of HCC.

Two new meroterpenoids from the bark of Cinnamomum cassia and their antioxidant activity.

Two new (1 and 2) meroterpenoids were isolated from the bark of Cinnamomum cassia. Their structures were determined by spectroscopic analyses and chemical methods. Antioxidant activities of 1 and 2 were evaluated by the ORAC and DPPH radical scavenging assays, and the results revealed that compound 2 displayed oxygen radical absorbance capacity. The discovery of compounds 1 and 2 added new members of this kind of natural product.

Exploring the chemical composition, medicinal benefits, and antioxidant activity of Plumula nelumbinis essential oil from different habitats in China.

Plumula nelumbinis, a widely used traditional Chinese medicine known for its calming and nerve-soothing properties, contains essential oil as a primary component. However, research on P. nelumbinis essential oil (PNEO) is limited. This study aimed to investigate PNEO components, network target analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and antioxidant activity of P. nelumbinis from ten different habitats. GC-MS analysis identified 14 compounds in the essential oil, with CP12 (ß-Sitosterol) having the highest concentration. Five compounds were identified for the first time in P. nelumbinis, with three of them reported for the first time in the Nelumbo. Network target analysis revealed 185 potential targets for 11 compounds and GO and KEGG enrichment analyses showed that PNEO was mainly located in the plasma membrane and could regulate a variety of molecular functions. KEGG pathway enrichment analysis revealed that the essential oil was primarily enriched in pathways related to cancer and the nervous system. PNEO demonstrated strong antioxidant activity, with N8 (Fujiannanping) showing the highest ABTS scavenging capacity and N7 (Hunanxiangtan) showing the highest DPPH radical scavenging capacity. Cell experiments showed that CP4, CP5 and CP10 had protective effects against H2O2-induced oxidative damage. The study suggests that P. nelumbinis from different regions may have slightly different pharmacological effects due to the presence of unique compounds, and further research is necessary to explore the potential therapeutic benefits of PNEO.

Novel Ag-bridged dual Z-scheme g-C3N4/BiOI/AgI plasmonic heterojunction: Exceptional photocatalytic activity towards tetracycline and the mechanism insight.

Rational design and synthesis of highly efficient and robust photocatalysts with positive exciton splitting and interfacial charge transfer for environmental applications is critical. Herein, aiming at overcoming the common shortcomings of traditional photocatalysts such as weak photoresponsivity, rapid combination of photo-generated carriers and unstable structure, a novel Ag-bridged dual Z-scheme g-C3N4/BiOI/AgI plasmonic heterojunction was successfully synthesized using a facile method. Results showed that Ag-AgI nanoparticles and three-dimensional (3D) BiOI microspheres were decorated highly uniformly on the 3D porous g-C3N4 nanosheet, resulting in a higher specific surface area and abundant active sites. The optimized 3D porous dual Z-scheme g-C3N4/BiOI/Ag-AgI manifested exceptional photocatalytic degradation efficiency of tetracycline (TC) in water with approximately 91.8% degradation efficiency within 165 min, outperforming majority of the reported g-C3N4-based photocatalysts. Moreover, g-C3N4/BiOI/Ag-AgI exhibited good stability in terms of activity and structure. In-depth radical scavenging and electron paramagnetic resonance (EPR) analyses confirmed the relative contributions of various scavengers. Mechanism analysis indicated that the improved photocatalytic performance and stability were ascribed to the highly ordered 3D porous framework, fast electron transfer of dual Z-scheme heterojunction, desirable photocatalytic performance of BiOI/AgI and synergistic effect of Ag plasmas. Therefore, the 3D porous Z-scheme g-C3N4/BiOI/Ag-AgI heterojunction had a good prospect for applications in water remediation. The current work provides new insight and useful guidance for designing novel structural photocatalysts for environment-related applications.

Novel quinoline-based derivatives as the PqsR inhibitor against Pseudomonas aeruginosa PAO1.

AIMS: The emerging of drug resistant Pseudomonas aeruginosa is a critical challenge and renders an urgent action to discover innovative antimicrobial interventions. One of these interventions is to disrupt the pseudomonas quinolone signal (pqs) quorum sensing (QS) system, which governs multiple virulence traits and biofilm formation. This study aimed to investigate the QS inhibitory activity of a series of new PqsR inhibitors bearing a quinoline scaffold against Ps. aeruginosa. METHODS AND RESULTS: The results showed that compound 1 suppressed the expression of QS-related genes and showed the best inhibitory activity to the pqs system of wild-type Ps. aeruginosa PAO1 with an IC50 of 20.22 µmol L-1 . The virulence factors including pyocyanin, total protease, elastase and rhamnolipid were significantly suppressed in a concentration-dependent manner with the compound. In addition, compound 1 in combination with tetracycline inhibited synergistically the bacterial growth and suppressed the biofilm formation of PAO1. The molecular docking studies also suggested that compound 1 could potentially interact with the ligand-binding domain of the Lys-R type transcriptional regulator PqsR as a competitive antagonist. CONCLUSIONS: The quinoline-based derivatives were found to interrupt the quorum sensing system via the pqs pathway and thus the production of virulence factors was inhibited and the antimicrobial susceptibility of Ps. aeruginosa was enhanced. SIGNIFICANCE AND IMPACT OF STUDY: The study showed that the quinoline-based derivatives could be used as an anti-virulence agent for treating Ps. aeruginosa infections.

Inhibitory Effects of Compounds from Plumula nelumbinis on Biofilm and Quorum Sensing Against P. aeruginosa.

Quorum sensing (QS), which controls the survival and virulence of Pseudomonas aeruginosa, including the formation of biofilm, is considered to be a new target to overcome pathogens. The aim of this study was to identify new QS inhibitors against P. aeruginosa and provide potential treatments for clinical infections. In this study, 25 compounds were isolated from Plumula nelumbini. Among these compounds, C25 showed the most significant biofilm inhibition activity, reaching 44.63% at 100 µM without inhibiting bacterial growth. Furthermore, C25 showed significant inhibition activity of rhamnolipid, pyocyanin, and elastase. Further mechanistic studies have confirmed that C25 could downregulate key genes in the QS system, including lasI, lasR, lasA, lasB, and pqsR, and Molecular docking studies have shown that C25 can bind to the active sites of the LasR and PqsR receptors. The present study suggests that C25 is a promising QS inhibitor for treating P. aeruginosa infections.

Choice of intravenous thrombolysis therapy in patients with mild stroke complaining of acute dizziness.

BACKGROUND: Quick identification of patients with mild ischemic stroke complaining of dizziness from other patients with benign peripheral vestibular disorders who also experience dizziness in the emergency department (ED) may be difficult. Decision-making on intravenous thrombolysis therapy (IVT) in patients whose chief symptoms include acute dizziness or vertigo remains a severe challenge for ED physicians. This study evaluated the diagnosis, treatment processes and the short-term outcomes in patients with mild vestibular stroke in the ED. METHODS: A total of 89 consecutive patients with mild ischemic stroke primarily presenting with vestibular symptoms, who arrived at ED within 4.5 after onset, and were admitted at the stroke center of Zhejiang Provincial People's Hospital between January 2015 and March 2021 were retrospectively enrolled. Patients treated with IVT (n = 47) were compared to patients without IVT (n = 42) in terms of demographics, onset-to-door time (ODT), baseline clinical characteristics, risk factors of stroke, imaging findings, and short-term outcomes. The correlation between these parameters and IVT decision-making was analyzed. RESULTS: Patients in IVT group more frequently presented with shorter ODT, focal neurological deficits (dysarthria, facial palsy, hemiglossoplegia, hemiparesis, hemisensory loss), disabling deficits, higher baseline National Institute of Health Stroke Scale (NIHSS) scores, and underwent multi-mode imaging before a decision. A higher proportion of isolated vestibular symptoms, acute transient vestibular syndrome, and vestibulo-vagal symptoms were found in the no-IVT group. There were no differences in demographics between the two groups. ODT was negatively correlated with the decision-making on IVT, and baseline NIHSS scores were positively correlated with the decision-making on IVT. CONCLUSION: ODT and baseline NIHSS scores were correlated with the IVT decision in mild stroke patients primarily presenting with vestibular symptoms. Severe vestibular symptoms and disabling deficits were weakly associated with IVT decision, while the vestibulo-oculomotor signs and multi-mode imaging did not result as the influencing factors promoting the IVT decision-making for mild vestibular stroke.

Click-Reaction-Triggered SERS Signals for Specific Detection of Monoamine Oxidase B Activity.

Human monoamine oxidases (MAOs) play important roles in maintaining the homeostasis of biogenic amines. One of its isoforms, monoamine oxidase B (MAOB), is thought to be involved in several neurodegenerative diseases, which make the selective detection of MAOB activity essential. In this work, a novel surface-enhanced Raman scattering (SERS) sensor was fabricated and the MAOB activity was specifically determined by detecting the SERS signals of an enzyme-catalyzed reaction product via an amine-aldehyde click reaction. This process was simply achieved by coating core-shell gold-silver nanoparticles (Au@Ag NPs) on 3-aminopropyl aminopropyl triethoxysilane (APTES)-modified glass, and then, a monolayer of cysteamine (CA) was attached to the nanoparticle surface as a linker through Ag-S bonds. Using phenethylamine (PA) as a specific substrate of MAOB, the enzyme product phenylacetaldehyde (PAA) will produce significant Raman signals via the amine-aldehyde click reaction with CA, while other molecules, such as MAOB and PA, have no signal output because they cannot form close interaction with nanoparticles due to the existence of a CA layer. This sensor was further used for the specific determination of MAOB activity in clinical blood samples and the MAOB inhibitor assessment successfully. Meanwhile, by changing the click reaction types and taking advantage of the SERS fingerprint peaks for the specific click reaction products, this strategy offers huge potential to detect multiple enzyme activities simultaneously and can be used for new click reaction screening, enzyme-related disease diagnosis, drug screening, and clinical diagnosis.

Cycloartane-type triterpenoids from the root of Astragalus membranaceus var. mongholicus.

Three new (1-3) and 11 known (4-14) cycloartane-type triterpenoids were isolated from the root of Astragalus membranaceus var. mongholicus. Their structures were determined by spectroscopic analyses and chemical methods. Cycloartane-type triterpenoids are a class of major bioactive constituents in the root of A. membranaceus var. mongholicus, and the discovery of compounds 1-3 added new members of this kind of natural product. [Formula: see text].

Novel 2, 8-bit derivatives of quinolines attenuate Pseudomonas aeruginosa virulence and biofilm formation.

Signal molecules are stimulators of multiple quroum-sensing virulence and biofilm formation. Small molecule analogues have been suspected as a potent inhibitor in therapeutic strategy. Herein, we synthesized a series of small molecule compounds from the 2, 8-bit derivatives of quinoline by Suzuki coupling reaction. We found that these compounds have the biofilm inhibitory effect in normal condition instead of phosphate limitation state. Furthermore, lacZ reporter strain assay and rhamnolipids as well as pyocyanin experiments showed that these compounds did not affect las and pqs system but reduced the expression of rhl. All these results suggest that quinoline derivatives can be treated as potent inhibitors against biofilm and reduce virulence through the rhl system. This research will be useful in designing new quorum sensing inhibitors to attenuate the infection of bacteria.

Redox/NIR dual-responsive MoS2 for synergetic chemo-photothermal therapy of cancer.

BACKGROUND: The construction of a multifunctional drug delivery system with a variety of advantageous features, including targeted delivery, controlled release and combined therapy, is highly attractive but remains a challenge. RESULTS: In this study, we developed a MoS2-based hyaluronic acid (HA)-functionalized nanoplatform capable of achieving targeted delivery of camptothecin (CPT) and dual-stimuli-responsive drug release. HA was connected to MoS2 via a disulfide linkage, forming a sheddable HA shell on the surface of MoS2. This unique design not only effectively prevented the encapsulated CPT from randomly leaking during blood circulation but also significantly accelerated the drug release in response to tumor-associated glutathione (GSH). Moreover, the MoS2-based generated heat upon near-infrared (NIR) irradiation could further increase the drug release rate as well as induce photothermal ablation of cancer cells. The results of in vitro and in vivo experiments revealed that MoS2-SS-HA-CPT effectively suppressed cell proliferation and inhibited tumor growth in lung cancer cell-bearing mice under NIR irradiation via synergetic chemo-photothermal therapy. CONCLUSIONS: The as-prepared MoS2-SS-HA-CPT with high targeting ability, dual-stimuli-responsive drug release, and synergistic chemo-photothermal therapy may provide a new strategy for cancer therapy.

Functionalized MoS2-erlotinib produces hyperthermia under NIR.

BACKGROUND: Molybdenum disulfide (MoS2) has been widely explored for biomedical applications due to its brilliant photothermal conversion ability. In this paper, we report a novel multifunctional MoS2-based drug delivery system (MoS2-SS-HA). By decorating MoS2 nanosheets with hyaluronic acid (HA), these functionalized MoS2 nanosheets have been developed as a tumor-targeting chemotherapeutic nanocarrier for near-infrared (NIR) photothermal-triggered drug delivery, facilitating the combination of chemotherapy and photothermal therapy into one system for cancer therapy. RESULTS: The nanocomposites (MoS2-SS-HA) generated a uniform diameter (ca. 125 nm), exhibited great biocompatibility as well as high stability in physiological solutions, and could be loaded with the insoluble anti-cancer drug erlotinib (Er). The release of Er was greatly accelerated under near infrared laser (NIR) irradiation, showing that the composites can be used as responsive systems, with Er release controllable through NIR irradiation. MTT assays and confocal imaging results showed that the MoS2-based nanoplatform could selectively target and kill CD44-positive lung cancer cells, especially drug resistant cells (A549 and H1975). In vivo tumor ablation studies prove a better synergistic therapeutic effect of the joint treatment, compared with either chemotherapy or photothermal therapy alone. CONCLUSION: The functionalized MoS2 nanoplatform developed in this work could be a potent system for targeted drug delivery and synergistic chemo-photothermal cancer therapy.

Lycorine induces apoptosis of bladder cancer T24 cells by inhibiting phospho-Akt and activating the intrinsic apoptotic cascade.

Lycorine, an alkaloid extracted from Amaryllidaceae genera, exhibits antitumor activities against several human solid-tumor and leukemia cells with extensive influence on various cell signaling molecules. However, the effect of lycorine on bladder cancer has not yet been investigated. In this study, we demonstrated that lycorine induced apoptosis in human bladder cancer T24 cells, an effect that is mediated via inhibition of phospho-Akt expression and the consequent activation of caspase-3 and Bax in vitro. In an in vivo experiment, T24 cells were subcutaneously implanted in the right rear flank of nu/nu mice. Lycorine treatment for 14 days significantly inhibited tumor growth compared with that in controls. Collectively, our findings suggest that lycorine suppressed the Akt pathway and activated the intrinsic apoptotic cascade, leading to the apoptosis of bladder cancer cells. We suggest that lycorine can be a viable therapeutic option for bladder cancer patients.

Bioactive Phenylpropanoid Glycosides, Dimers, and Heterodimers from the Bark of Cinnamomum cassia (L.) J.Presl.

Six new phenylpropanoid glycosides (1-6), two new phenylethanol glycosides (7 and 8), one new phenylmethanol glycoside (9), three new phenylpropanoid dimers (10-12), two new phenylpropanoid-flavan-3-ol heterodimers (13 and 14), and six known relevant compounds (15-20) were isolated and identified from the well-liked edible and medicinal substance (the bark of Cinnamomum cassia (L.) J.Presl). The structures of these isolates were determined by using spectroscopic analyses, chemical methods, and quantum chemical calculations. Notably, compounds 4-9 were rare apiuronyl-containing glycosides, and compounds 13 and 14 were heterodimers of phenylpropanoids and flavan-3-ols linked through C-9″-C-8 bonds. The antioxidant and α-glucosidase inhibitory activities of all isolates were evaluated. Compounds 10 and 12 exhibited DPPH radical scavenging capacities with IC50 values of 20.1 and 13.0 µM, respectively (vitamin C IC50 value of 14.3 µM). In the ORAC experiment, all these compounds exhibited different levels of capacity for scavenging free radicals, and compound 10 displayed extraordinary free radical scavenging capacity with the ORAC value of 6.42 ± 0.01 µM TE/µM (EGCG ORAC value of 1.54 ± 0.02 µM TE/µM). Compound 12 also showed significant α-glucosidase inhibitory activity with an IC50 of 56.3 µM (acarbose IC50 of 519.4 µM).

Single-cell and bulk transcriptomics reveals M2d macrophages as a potential therapeutic strategy for mucosal healing in ulcerative colitis.

Mucosal healing is essential for treating ulcerative colitis (UC), which results from imbalanced macrophage polarization and dysregulated inflammatory responses. However, the mechanisms of cellular communication and signal transduction that regulate mucosal healing among macrophage subtypes require further investigation. We use bulk and single-cell RNA sequencing analysis to reveal that macrophage subtypes vary in different UC states. At the same time, chemokine and angiogenesis signaling is strongly associated with M2 macrophage's infiltrated proportion. To get more insight into subtypes of macrophages in mucosal healing, we divided macrophages into M1, M2b, and M2d macrophages. Based on the differentially expressed genes (DEGs) between M2d and M1 macrophages, KEGG and GO analysis highlights M2d macrophages' ability to alleviate inflammation and promote epithelial healing. Trajectory analysis revealed opposite differentiation of macrophage subsets between UC and healthy groups, with M1 and M2d macrophages coexisting in the same differentiation branch under UC conditions. Along the pseudotime axis, CCL3 and VEGFA expression increased in UC, while IL10RA remained stable in UC but increased in healthy controls. CellChat identified CCL3-CCR1 has strong communication between M1 and M2d macrophages, while the IL10 signaling pathway is activated explicitly in M2d macrophages to mitigate inflammation and promote epithelial healing. We also speculate that high levels of VEGFA activate endothelial cells expressing VEGFR and worsen inflammation. To conclude, we suggested IL10 and VEGF signaling in M2d macrophages as potential therapeutic targets for mucosal healing. However, it is necessary to establish reliable methods for isolating and purifying M2d macrophages before these targets can be effectively utilized.

Antiviral activities of Artemisia vulgaris L. extract against herpes simplex virus.

BACKGROUND: Artemisia vulgaris L. is often used as a traditional Chinese medicine with the same origin of medicine and food. Its active ingredient in leaves have multiple biological functions such as anti-inflammatory, antibacterial and insecticidal, anti-tumor, antioxidant and immune regulation, etc. It is confirmed that folium Artemisiae argyi has obvious anti-HBV activity, however, its antiviral activity and mechanism against herpesvirus or other viruses are not clear. Hence, we aimed to screen the crude extracts (Fr.8.3) isolated and extracted from folium A. argyi to explore the anti-herpesvirus activity and mechanism. METHODS: The antiherpes virus activity of Fr.8.3 was mainly characterized by cytopathic effects, real-time PCR detection of viral gene replication and expression levels, western blotting, viral titer determination and plaque reduction experiments. The main components of Fr.8.3 were identified by using LC-MS, and selected protein targets of these components were investigated through molecular docking. RESULTS: We collected and isolated a variety of A. vulgaris L. samples from Tangyin County, Henan Province and then screened the A. vulgaris L. leaf extracts for anti-HSV-1 activity. The results of the plaque reduction test showed that the crude extract of A. vulgaris L.-Fr.8.3 had anti-HSV-1 activity, and we further verified the anti-HSV-1 activity of Fr.8.3 at the DNA, RNA and protein levels. Moreover, we found that Fr.8.3 also had a broad spectrum of antiviral activity. Finally, we explored its anti-HSV-1 mechanism, and the results showed that Fr.8.3 exerted an anti-HSV-1 effect by acting directly on the virus itself. Then, the extracts were screened on HSV-1 surface glycoproteins and host cell surface receptors for potential binding ability by molecular docking, which further verified the phenotypic results. LC-MS analysis showed that 1 and 2 were the two main components of the extracts. Docking analysis suggested that compounds from extract 1 might similarly cover the binding domain between the virus and the host cells, thus interfering with virus adhesion to cell receptors, which provides new ideas and insights for clinical drug development for herpes simplex virus type 1. CONCLUSION: We found that Fr.8.3 has anti-herpesvirus and anti-rotavirus effects. The main 12 components in Fr.8.3 were analyzed by LC-MS, and the protein targets were finally predicted through molecular docking, which showed that alkaloids may play a major role in antiviral activity.

Phosphorylation of USP29 by CDK1 Governs TWIST1 Stability and Oncogenic Functions.

Triple-negative breast cancer (TNBC) is a highly lethal malignancy with limited therapy options. TWIST1, a key transcriptional factor of epithelial-mesenchymal transition (EMT), contributes to self-renewal of cancer stem-like cells (CSCs), chemo-resistance, metastasis, and TNBC-related death. However, the mechanism by which TWIST1 is deregulated in TNBC remains elusive. Here, USP29 is identified as a bona fide deubiquitinase of TWIST1. The deubiquitination of TWIST1 catalyzed by USP29 is required for its stabilization and subsequent EMT and CSC functions in TNBC, thereby conferring chemotherapeutic resistance and metastasis. Furthermore, the results unexpectedly reveal that CDK1 functions as the direct USP29 activator. Mechanistically, CDK1-mediated phosphorylation of USP29 is essential for its deubiquitinase activity toward TWIST1 and TWIST1 driven-malignant phenotypes in TNBC, which could be markedly mitigated by the genetic ablation or pharmacological inhibition of CDK1. Moreover, the histological analyses show that CDK1 and USP29 are highly upregulated in TNBC samples, which positively correlate with the expression of TWIST1. Taken together, the findings reveal a previously unrecognized tumor-promoting function and clinical significance of the CDK1-USP29 axis through stabilizing TWIST1 and provide the preclinical evidence that targeting this axis is an appealing therapeutic strategy to conquer chemo-resistance and metastasis in TNBC.

Novel Coumarin Derivatives Inhibit the Quorum Sensing System and Iron Homeostasis as Antibacterial Synergists against Pseudomonas aeruginosa.

Pseudomonas aeruginosa (P. aeruginosa) is well-known to cause biofilm-associated drug resistance and infections that often lead to treatment failure. Herein, we reported a dual-acting antibiofilm strategy by inhibiting both the bacterial quorum sensing system and the iron uptake system. A series of coumarin derivatives were synthesized and evaluated, and compound 4t was identified as the most effective biofilm inhibitor (IC50 = 3.6 µM). Further mechanistic studies have confirmed that 4t not only inhibits the QS systems but also competes strongly with pyoverdine as an iron chelator, causing an iron deficiency in P. aeruginosa. Additionally, 4t significantly improved the synergistic antibacterial effects of ciprofloxacin and tobramycin by more than 200-1000-fold compared to the single-dose antibiotic treatments. Therefore, our study has shown that 4t is a potentially novel antibacterial synergist candidate to treat bacterial infections.