HCN channels in the lateral habenula regulate pain and comorbid depressive-like behaviors in mice.

AIMS: Comorbid anxiodepressive-like symptoms (CADS) in chronic pain are closely related to the overactivation of the lateral habenula (LHb). Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels have been implicated to play a key role in regulating neuronal excitability. However, the role of HCN channels in the LHb during CADS has not yet been characterized. This study aimed to investigate the effect of HCN channels in the LHb on CADS during chronic pain. METHODS: After chronic neuropathic pain induction by spared nerve injury (SNI), mice underwent a sucrose preference test, forced swimming test, tail suspension test, open-field test, and elevated plus maze test to evaluate their anxiodepressive-like behaviors. Electrophysiological recordings, immunohistochemistry, Western blotting, pharmacological experiments, and virus knockdown strategies were used to investigate the underlying mechanisms. RESULTS: Evident anxiodepressive-like behaviors were observed 6w after the SNI surgery, accompanied by increased neuronal excitability, enhanced HCN channel function, and increased expression of HCN2 isoforms in the LHb. Either pharmacological inhibition or virus knockdown of HCN2 channels significantly reduced LHb neuronal excitability and ameliorated both pain and depressive-like behaviors. CONCLUSION: Our results indicated that the LHb neurons were hyperactive under CADS in chronic pain, and this hyperactivation possibly resulted from the enhanced function of HCN channels and up-regulation of HCN2 isoforms.

Study on the mechanisms of acupuncture combined with paroxetine in the treatment of mild to moderate depression based on DNA methylation analysis. / 基于DNA甲基化探讨针刺联合帕罗西汀治疗轻中度抑郁症的疗效机制.

OBJECTIVES: To explore the therapeutic effect of acupuncture combined with paroxetine for mild to moderate depression and the regulatory role of brain derived neurotrophic factor (BDNF) in patients based on DNA methylation. METHODS: A total of 66 patients with mild to moderate depression who met the inclusion and exclusion criteria were randomly divided into an observation (acupuncture+medication) group and a control (medication) group, with 33 patients in each group, and other 25 healthy volunteers were taken as the healthy group. The patients of the control group were treated by oral administration of paroxetine 20 mg/d for 4 weeks. The patients of the observation group were treated by acupuncture stimulation of Zhongwan (CV12), Qihai (CV6), Zusanli (ST36), Sanyinjiao (SP6), Shangxing (GV23), Shuigou (GV26), Shaoshang (LU11), Yinbai (SP1) and Daling (PC7) (for 20 min, 3 times a week for 4 weeks) on the basis of medication treatment (the same as that of the control group). Before treatment, 2 and 4 weeks of treatment, and 2 weeks of follow-up, the therapeutic effect was assessed using Hamilton Depression Scale 17 (HAMD-17). The SPSS25.0 software was used to form a randomized grouping and to randomly select 25 patients from the observation group and 25 patients from the control group for blood collecting and data analysis. The blood samples were taken for assaying serum BDNF content and the methylation degree of BDNF gene promotor I with ELISA and MassARRAY techniques, respectively. RESULTS: 1) In comparison with those before treatment, the total score of HAMD-17, sleep disorder factor score, and anxiety somatization factor score of both the observation and control groups were significantly decreased after 2 and 4 weeks of treatment, and 2 weeks of follow-up (P<0.05), except sleep disorder factor score in the control group after 2 weeks of the treatment. Compared with the same time-points of the control group, the HAMD-17 total score and sleep disorder factor score of the observation group were decreased after 2 and 4 weeks of treatment, and 2 weeks of follow-up (P<0.05), while the anxiety somatization factor score was evidently decreased after 2 weeks of treatment (P<0.05). 2) Following 2 weeks of treatment, the total effective rate and markedly effective rate of the observation group were 80%(24/30)and 36.67% (11/30), respectively, being significantly higher than those ï¼»(26.67% and 0 %)ï¼½ of the control group. After 4 weeks of treatment, the markedly effective rate of the observation group was 70.00% (21/30), being significantly higher than that 40% (12/30) of the control group (P<0.05), while the total effective rates of the observation and control groups were the same (100%). 3) Before the treatment, comparison among the healthy, observation and control groups showed no statistical significance in the methylation degree of each site (CpG1.2, CpG5.6, CpG8.9, CpG26, CpG27, CpG31, and CpG33.34) of BDNF gene promotor I, while after 4 weeks of the treatment, the methylation degree of CpG31 was considerably lower in the observation group than in the control group (P<0.05). 4) Before the treatment, the contents of serum BDNF of both observation and control group had no significant difference, but were evidently lower than that of the healthy group (P<0.05). Compared with that before treatment, the serum BDNF contents in both observation and control groups were significantly increased after the treatment (P<0.05), and was significantly higher in the observation group than in the control group (P<0.05). 5) The correlation analysis showed a negative correlation between the BDNF protein content and HAMD-17 score (correlation coefficient ρ=-0.686, P<0.01). CONCLUSIONS: Acupuncture may have an antidepressant role by decreasing CpG31 methylation of BDNF and increasing the serum content of BDNF protein in patients with depression. In addition, acupuncture combined with paroxetine has more advantages in treating mild to moderate depression than oral paroxetine alone, and can improve sleep disorders and anxiety somatization symptoms more quickly.

Clinical effect of acupuncture at ghost points combined with fluoxetine hydrochloride on mild-to-moderate depression.

BACKGROUND: Depression is a common, chronic, and recurrent mood disorder that has become a worldwide health hazard. Fluoxetine hydrochloride, a common treatment method, can inhibit 5-hydroxytryptamine (5-HT) recycling in the presynaptic membrane; however, the efficacy of a single drug is inadequate. At present, mild-to-moderate depression can be treated with acupuncture of ghost caves, but the clinical curative effect of combined therapy with fluoxetine hydrochloride has not been sufficiently reported. AIM: To evaluate the clinical effect of acupuncture at ghost points combined with fluoxetine hydrochloride in the treatment of mild-to-moderate depression. METHODS: This retrospective study included 160 patients with mild-to-moderate depression who were admitted to Shanghai Hospital of Integrated Traditional Chinese and Western Medicine, Affiliated to Shanghai University of Traditional Chinese Medicine, between January 2022 and June 2023. Patients were separated into a single-agent group (fluoxetine hydrochloride treatment, n = 80) and a coalition group (fluoxetine hydrochloride treatment combined with acupuncture at ghost points, n = 80). Pre-treatment symptoms were recorded, and the clinical curative effect and adverse reactions [Asberg Antidepressant Side Effects Scale (SERS)] were assessed. Depression before and after treatment [Hamilton Depression Scale (HAMD)-24], neurotransmitter levels [5-HT, norepinephrine (NE), dopamine (DA)], oxidative stress indicators [superoxide dismutase (SOD), malondialdehyde (MDA)], and sleep quality [Pittsburgh Sleep Quality Index (PSQI)] were compared. RESULTS: The total efficacy rate was 97.50% in the coalition group and 86.25% in the single-agent group (P < 0.05). After 2, 4, 6, and 8 wk of treatment, the HAMD, self-rating depression scale, and SERS scores of the coalition and single-agent groups decreased compared with pre-treatment, and the decrease was more significant in the coalition group (P < 0.05). After 8 wk of treatment, the levels of NE, DA, 5-HT, and SOD in the coalition and single-agent groups increased, while the levels of MDA decreased; the increases and decrease in the coalition group were more significant (P < 0.05). The PSQI scores of the coalition and single-agent groups decreased, and the decrease was more significant in the coalition group (P < 0.05). CONCLUSION: Acupuncture at ghost points combined with paroxetine tablets can safely improve depressive symptoms and sleep disorders, regulate neurotransmitter levels, and reduce stress responses in patients with mild-to-moderate depression.

APG-1252 combined with Cabozantinib inhibits hepatocellular carcinoma by suppressing MEK/ERK and CREB/Bcl-xl pathways.

BACKGROUND AND PURPOSE: Liver cancer is the fourth leading cause of cancer-related death worldwide, with hepatocellular carcinoma (HCC) being the most common type of primary liver cancer. APG-1252 is a small molecule inhibitor targeting Bcl-2 and Bcl-xl. However, its anti-tumor effects in HCC, alone or in combination with Cabozantinib, have not been extensively studied. EXPERIMENTAL: Approach: TCGA database analysis was used to analysis the gene expression levels of Bcl-2 and Bcl-xl in HCC tissues. Western blot was employed to detect the protein expression levels. And the inhibitory effects of APG-1252 and Cabozantinib on the proliferation of HCC cell lines was detected by CCK-8. The effect on the migration and invasion of HCC cells was verified by transwell assay. Huh7 xenograft model in nude mice was used to investigate the combination antitumor effect in vivo. KEY RESULTS: Our study demonstrated that APG-1252 monotherapy inhibited the proliferation and migration ability of HCC cells, and induced HCC cells apoptosis. The combination of APG-1252 and Cabozantinib showed significant synergistic antitumor effects. Furthermore, the in vivo experiment demonstrated that the combination therapy exerted a synergistic effect in delaying tumor growth, notably downregulating MEK/ERK phosphorylation levels. In terms of mechanism, Cabozantinib treatment caused an increase in the phosphorylation levels of CREB and Bcl-xl proteins, while the combination with APG-1252 mitigated this effect, thereby enhanced the antitumor effect of Cabozantinib. CONCLUSION AND IMPLICATIONS: Our findings suggest that APG-1252 in combination with Cabozantinib offers a more effective treatment strategy for HCC patients, warranting further clinical investigation.

Adaptive Signal Modulation Evolved by the Inherent Nonlinearity of Phase-Change Quantum-Dot String.

To simulate a topological neural network handling weak signals via stochastic resonance (SR), it is necessary to introduce an inherent nonlinearity into nanoscale devices. We use the self-assembly method to successfully fabricate a phase-change quantum-dot string (PCQDS) crossing Pd/Nb:AlNO/AlNO/Nb:AlNO/Pd multilayer. The inherent nonlinearity of phase change couples with electron tunneling so that PCQDS responds to a long signal sequence in a modulated output style, in which the pulse pattern evolves to that enveloped by two sets of periodic wave characterized by neural action potential. We establish an SR mode consisting of several two-state systems in which dissipative tunneling is coupled to environment. Size oscillations owing to NbO QDs adaptively adjust barriers and wells, such that tunneling can be periodically modulated by either asymmetric energy or local temperature. When the external periodic signals are applied, the system first follows the forcing frequency. Subsequently, certain PCQDs oscillate independently and consecutively to produce complicated frequency and amplitude modulations.

Host-Guest Cocrystallization of Phenanthrene[2]arene Macrocycles Facilitating Structure Determination of Liquid Organic Molecules.

Single-crystal X-ray diffraction analysis has emerged as the most reliable method for determining the structures of organic molecules. However, numerous analytes, such as liquid organic molecules, pose challenges in crystallization, making their structures directly elusive via X-ray crystallography methods. Herein, we introduced the rapid cocrystallization of a macrocycle named phenanthrene[2]arene (PTA, host) with 15 liquid organic molecules (guests). The guest liquid organic molecules were successively cocrystallized with the aid of the PTA host. Moreover, the chemical structures of the liquid organic molecules could be determined through single-crystal X-ray diffraction analysis. PTA exhibited high adaptivity and was capable of encapsulating liquid organic molecules without forming covalent bonds or strong directional interactions. The results revealed that the adaptive crystals of PTA exhibited excellent cocrystallization capacity. Weak noncovalent interactions between the host and guest molecules were crucial for organizing the guests in an ordered pattern.

Prognostic factors in lung transplantation after extracorporeal membrane oxygenation bridging therapy: a systematic review and meta-analysis.

Background: Extracorporeal membrane oxygenation (ECMO) has recently emerged as a critical support system for lung function in patients awaiting lung transplantation. This meta-analysis investigates the prognostic factors of lung transplantation following ECMO bridging therapy. Methods: A comprehensive search was conducted in PubMed, Cochrane Library, Embase, CINAHL, Web of Science, Scopus, and ProQuest databases from inception to August 11, 2023. Included were cohort or case-control studies focusing on prognostic factors of lung transplantation with ECMO bridging therapy. Data extraction was performed independently, and study quality was assessed. A meta-analysis was carried out using RevMan 5.4 and Stata17.0 software to aggregate mortality rates and pertinent prognostic factors of ECMO as a bridge to lung transplantation. Results: The search identified eight trials encompassing 1,086 participants. The prognosis of patients undergoing lung transplantation with ECMO bridging was significantly associated with several factors: prolonged ECMO support [odds ratio 1.07, 95% confidence interval (CI): 1.02-1.12, I2=77%], deterioration in liver and kidney function (odds ratio 3.62, 95% CI: 2.37-5.54, I2=0%), and complications during ECMO (odds ratio 2.24, 95% CI: 1.45-3.44, I2=5%). Conclusions: Prolonged ECMO support, declining liver and kidney functions, and complications during ECMO are vital prognostic factors in lung transplantation following ECMO bridging therapy.

Rapid and Visual Detection of Volatile Amines Based on Their Gas-Solid Reaction with Tetrachloro-p-Benzoquinone.

The detection of volatile amines is necessary due to the serious toxicity hazards they pose to human skin, respiratory systems, and nervous systems. However, traditional amines detection methods require bulky equipment, high costs, and complex measurements. Herein, we report a new simple, rapid, convenient, and visual method for the detection of volatile amines based on the gas-solid reactions of tetrachloro-p-benzoquinone (TCBQ) and volatile amines. The gas-solid reactions of TCBQ with a variety of volatile amines showed a visually distinct color in a time-dependent manner. Moreover, TCBQ can be easily fabricated into simple and flexible rapid test strips for detecting and distinguishing n-propylamine from other volatile amines, including ethylamine, n-butyamine, n-pentamine, n-butyamine and dimethylamine, in less than 3 s without any equipment assistance.

Construction of ß-Oximino Phosphorodithioates via (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl-Promoted Difunctionalization of Alkenes with tert-Butyl Nitrite, P4S10, and Alcohols.

A (2,2,6,6-tetramethylpiperidin-1-yl)oxyl-mediated difunctionalization of alkenes with tert-butyl nitrite, P4S10, and alcohols has been developed for the synthesis of ß-oximino phosphorodithioates. The reaction goes through a radical pathway with the successive installation of phosphorodithioate and an oxime group. This four-component protocol offers a practical approach to constructing a variety of ß-oximino phosphorodithioates in moderate to good yields with favorable functional group tolerance.

Novel Diagnostic Biomarker BST2 Identified by Integrated Transcriptomics Promotes the Development of Endometriosis via the TNF-α/NF-κB Signaling Pathway.

Endometriosis (EMS) is a common gynecological condition with apparent heterogeneity, lack of diagnostic markers, and unclear pathogenesis. A series of bioinformatics methods were employed to explore EMS's pathological mechanisms and potential biomarkers by analyzing the combined datasets of EMS (GSE7305, GSE7307, GSE58198, E-MTAB-694), which included 34 normal, 127 eutopic, and 46 ectopic endometrium samples. Then, wet-laboratory experiments (including Western blot, qRT-PCR, and Immunohistochemistry, Immunofluorescence, CCK-8, EdU, Wound healing, Transwell, and Adhesion assays) were applied to examine the biomarkers' expression and function in primary endometrial stromal cells. Bioinformatic analysis indicated that the core pathogenesis of EMS was dysregulated immune-inflammation and tissue remolding processes. Among the upregulated DEGs, BST2 was screened as a potential diagnostic biomarker in EMS, which associated with the revised American Fertility Society (r-AFS) stage and immune-inflammation processes of EMS. Moreover, BST2's overexpression was affirmed in the RNA and protein levels in EMS tissues. In vitro experiments demonstrated that TNF-α promoted the expression of BST2 in ESCs. And BST2 knockdown inhibited migration, invasion, adhesion, and inflammation except for the proliferation of ESCs, probably via the TNF-α/NF-κB pathway. Through a combination of wet and dry studies, we concluded that the core pathogenesis of endometriosis was dysregulated immune-inflammation and tissue remolding, and BST2 might be a potential diagnostic and therapeutic target in endometriosis.

Self-Metallized Whole Cell Vaccines Prepared by Microfluidics for Bioorthogonally Catalyzed Antitumor Immunotherapy.

Tumor whole cell, carrying a complete set of tumor-associated antigens and tumor-specific antigens, has shown great potential in the construction of tumor vaccines but is hindered by the complex engineering means and limited efficacy to cause immunity. Herein, we provided a strategy for the self-mineralization of autologous tumor cells with palladium ions in microfluidic droplets, which endowed the engineered cells with both immune and catalytic functions, to establish a bioorthogonally catalytic tumor whole-cell vaccine. This vaccine showed strong inhibition both in the occurrence and recurrence of tumor by invoking the immediate antitumor immunity and building a long-term immunity.

Microfluidic Synthesis of CuH Nanoparticles for Antitumor Therapy through Hydrogen-Enhanced Apoptosis and Cuproptosis.

Cuproptosis has drawn enormous attention in antitumor material fields; however, the responsive activation of cuproptosis against tumors using nanomaterials with high atom utilization is still challenging. Herein, a copper-based nanoplatform consisting of acid-degradable copper hydride (CuH) nanoparticles was developed via a microfluidic synthesis. After coating with tumor-targeting hyaluronic acid (HA), the nanoplatform denoted as HA-CuH-PVP (HCP) shows conspicuous damage toward tumor cells by generating Cu+ and hydrogen (H2) simultaneously. Cu+ can induce apoptosis by relying on Fenton-like reactions and lead to cuproptosis by causing mitochondrial protein aggregation. Besides, the existence of H2 can enhance both cell death types by causing mitochondrial dysfunction and intracellular redox homeostatic disorders. In vivo experimental results further exhibit the desirable potential of HCP for killing tumor cells and inhibiting lung metastases, which will broaden the horizons of designing copper-based materials triggering apoptosis and cuproptosis for better antitumor efficacy.

Self-Generating Gold Nanocatalysts in Autologous Tumor Cells for Targeted Catalytic Immunotherapy.

Employing tumor whole cells for tumor immunotherapy is a promising tumor therapy proposed in the early stage, but its therapeutic efficacy is weakened by the methods of eliminating pathogenicity and the mass ratio of the effective antigen carried by itself. Here, by adding gold ion to live cancer cells in the microfluidic droplets, this work obtains dead tumor whole cells with NIR-controlled catalytic ability whose pathogenicity is removed while plenary tumor antigens, major structure, and homing ability are reserved. The engineered tumor cell (Cell-Au) with the addition of prodrug provides 1O2 in an O2-free Russell mechanism, which serves better in a hypoxic tumor microenvironment. This tumor whole-cell catalytic vaccine (TWCV) promotes the activation of dendritic cells and the transformation of macrophages into tumor suppressor phenotype. In 4T1 tumor-bearing mice, the Cell-Au-based vaccine supports the polarization of cytotoxicity T cells, resulting in tumor eradication and long-term animal survival. Compared with antigen vaccines or adoptive cell therapy which takes months to obtain, this TWCV can be prepared in just a few days with satisfactory immune activation and tumor therapeutic efficacy, which provides an alternative way for the preparation of personalized tumor vaccines across tumor types and gives immunotherapy a new path.

Keto-Adamantane-Based Macrocycle Crystalline Supramolecular Assemblies Showing Selective Vapochromism to Tetrahydrofuran.

Here, we report the synthesis of adamantane-based macrocycle 2 by combining adamantane building blocks with π-donor 1,3-dimethoxy-benzene units. An unpredictable keto-adamantane-based macrocycle 3 was obtained by the oxidation of 2 using DDQ as an oxidant. Moreover, a new type of macrocyclic molecule-based CT cocrystal was prepared through exo-wall CT interactions between 3 and DDQ. The cocrystal material showed selective vapochromism behavior towards THF, specifically, among nine volatile organic solvents commonly used in the laboratory. Powder X-ray diffraction; UV-Vis diffuse reflectance spectroscopy; 1H NMR; and single crystal X-ray diffraction analyses revealed that color changes are attributed to the vapor-triggered decomplexation of cocrystals.

Logic-gated tumor-microenvironment nanoamplifier enables targeted delivery of CRISPR/Cas9 for multimodal cancer therapy.

Recent innovations in nanomaterials inspire abundant novel tumor-targeting CRISPR-based gene therapies. However, the therapeutic efficiency of traditional targeted nanotherapeutic strategies is limited by that the biomarkers vary in a spatiotemporal-dependent manner with tumor progression. Here, we propose a self-amplifying logic-gated gene editing strategy for gene/H2O2-mediated/starvation multimodal cancer therapy. In this approach, a hypoxia-degradable covalent-organic framework (COF) is synthesized to coat a-ZIF-8 in which glucose oxidase (GOx) and CRISPR system are packaged. To intensify intracellular redox dyshomeostasis, DNAzymes which can cleave catalase mRNA are loaded as well. When the nanosystem gets into the tumor, the weakly acidic and hypoxic microenvironment degrades the ZIF-8@COF to activate GOx, which amplifies intracellular H+ and hypoxia, accelerating the nanocarrier degradation to guarantee available CRISPR plasmid and GOx release in target cells. These tandem reactions deplete glucose and oxygen, leading to logic-gated-triggered gene editing as well as synergistic gene/H2O2-mediated/starvation therapy. Overall, this approach highlights the biocomputing-based CRISPR delivery and underscores the great potential of precise cancer therapy.

Developing and validating a prediction model of live birth in patients with moderate-to-severe intrauterine adhesions: a new approach with endometrial morphology measurement by 3D transvaginal ultrasound.

Background: There is no reliable method to predict the live birth rate among patients with moderate-to-severe intrauterine adhesions (IUA) after second-look hysteroscopy. Therefore, we aimed to construct a practical prediction model mainly based on the features of 3D transvaginal ultrasound (3D-TVUS). and other clinical characteristics. Methods: From January 2018 to February 2020, a total of 870 IUA patients with fertility requirements were retrospectively enrolled based on the same method. First, the predictors were screened by logistic regression analysis. A nomogram was constructed based on the screened predictive factors in the derivation cohort. Next, receiver operating characteristic (ROC), calibration curve, and decision curve analysis (DCA) were used to assess the predictive accuracy and discriminability of the model. Finally, correlation analysis was performed to analyze the correlation between the results of 3D-TVUS and second-look hysteroscopy. Results: A total of 558 (64.14%) participants had live births. Age, endometrial thickness, assisted reproductive technology, a homogeneous endometrial echo, a lower segment of scar contraction, and upper segmentation of the endometrial absence were included in the model. The predictive model showed good predictive performance in the derivation cohort (area under the curve, 0.837) and validation cohort (0.857). DCA demonstrated its clinical utility. A homogeneous endometrial echo was related to no segmentation of scar contraction (r=0.219; P<0.001) or no segmentation of the endometrial absence (r=0.226; P<0.001). Thicker endometrium was associated with no segmentation of the endometrial absence (r=-0.145; P=0.007). Conclusions: The proposed method can effectively predict live birth. 3D-TVUS should be an important means for evaluating the endometrium of moderate-to-severe patients with IUA preparing for pregnancy after operation.

Pulmonary rehabilitation protocols in urgent lung transplantation patients.

BACKGROUND: Prolonged invasive respiratory support and extracorporeal membrane oxygenation (ECMO) in patients requiring urgent lung transplantation (ULTx) present significant challenges to clinical practice due to severe underlying diseases and complex conditions. The aim of the study was to report the clinical outcomes of patients who received ULTx and followed the perioperative rehabilitation protocol implemented in a lung transplant center. METHODS: A retrospective analysis was conducted in ULTx patients who required preoperative invasive mechanical ventilation (IMV) and ECMO between January 2018 and January 2023. Data were retrieved from electronic medical records at our lung transplant center. RESULTS: Fourteen patients (mean age 57.43±10.97 years; 12 males, 2 females) underwent ULTx with bridging ECMO and IMV. The mean body mass index was 23.94±3.33 kg/m², and the mean Acute Physiology and Chronic Health Evaluation (APACHE) II score was 21.50±3.96. The Nutritional Risk Screening 2002 (NRS 2002) scores were ≥3. ULTx was performed after an 8.5-day waiting period (interquartile interval [IQR] 5.0-26.5 d). Following the surgeries, the average lengths of ECMO and IMV were 1.0 (IQR 1.0-2.0) d and 5.0 (IQR 3.0-7.3) d, respectively. The total length of hospital stay was 60.1±30.8 d, with an average intensive care unit stay of 38.3±22.9 d and post-operative hospitalization stay of 45.8±26.1 d. Two patients died within 30 d after ULTx, with a 30-day survival rate of 85.71%. CONCLUSION: Patients receiving ULTx showed an acceptable short-term survival rate, validating the practicality and safety of the treatment protocols implemented in our center.

Methionine restriction attenuates the migration and invasion of gastric cancer cells by inhibiting nuclear p65 translocation through TRIM47.

The prevention and treatment of gastric cancer has been the focus and difficulty of medical research. We aimed to explore the mechanism of inhibiting migration and invasion of gastric cancer cells by methionine restriction (MR). The human gastric cancer cell lines AGS and MKN45 cultured with complete medium (CM) or medium without methionine were used for in vitro experiments. MKN45 cells were injected tail vein into BALB/c nude mice and then fed with normal diet or methionine diet for in vivo experiments. MR treatment decreased cell migration and invasion, increased E-cadherin expression, decreased N-cadherin and p-p65 expressions, and inhibited nuclear p65 translocation of AGS and MKN45 cells when compared with CM group. MR treatment increased IκBα protein expression and protein stability, and decreased IκBα protein ubiquitination level and TRIM47 expression. TRIM47 interacted with IκBα protein, and overexpression of TRIM47 reversed the regulatory effects of MR. TRIM47 promoted lung metastasis formation and partially attenuated the effect of MR on metastasis formation in vivo compared to normal diet group mice. MR reduces TRIM47 expression, leads to the degradation of IκBα, and then inhibits the translocation of nuclear p65 and the migration and invasion of gastric cancer cells.

Antimicrobial activities of lavandulylated flavonoids in Sophora flavences against methicillin-resistant Staphylococcus aureus via membrane disruption.

INTRODUCTION: The continuous emergence and rapid spread of multidrug-resistant bacteria have accelerated the demand for the discovery of alternative antibiotics. Natural plants contain a variety of antibacterial components, which is an important source for the discovery of antimicrobial agents. OBJECTIVE: To explore the antimicrobial activities and related mechanisms of two lavandulylated flavonoids, sophoraflavanone G and kurarinone in Sophora flavescens against methicillin-resistant Staphylococcus aureus. METHODS: The effects of sophoraflavanone G and kurarinone on methicillin-resistant Staphylococcus aureus were comprehensively investigated by a combination of proteomics and metabolomics studies. Bacterial morphology was observed by scanning electron microscopy. Membrane fluidity, membrane potential, and membrane integrity were determined using the fluorescent probes Laurdan, DiSC3(5), and propidium iodide, respectively. Adenosine triphosphate and reactive oxygen species levels were determined using the adenosine triphosphate kit and reactive oxygen species kit, respectively. The affinity activity of sophoraflavanone G to the cell membrane was determined by isothermal titration calorimetry assays. RESULTS: Sophoraflavanone G and kurarinone showed significant antibacterial activity and anti-multidrug resistance properties. Mechanistic studies mainly showed that they could target the bacterial membrane and cause the destruction of the membrane integrity and biosynthesis. They could inhibit cell wall synthesis, induce hydrolysis and prevent bacteria from synthesizing biofilms. In addition, they can interfere with the energy metabolism of methicillin-resistant Staphylococcus aureus and disrupt the normal physiological activities of the bacteria. In vivo studies have shown that they can significantly improve wound infection and promote wound healing. CONCLUSION: Kurarinone and sophoraflavanone G showed promising antimicrobial properties against methicillin-resistant Staphylococcus aureus, suggesting that they may be potential candidates for the development of new antibiotic agents against multidrug-resistant bacteria.