Caveolin-3 negatively regulates endocytic recycling of cardiac KATP channels.

Sarcolemmal ATP-sensitive potassium (KATP) channels play a vital role in cardioprotection. Cardiac KATP channels are enriched in caveolae and physically interact with the caveolae structural protein caveolin-3 (Cav3). Disrupting caveolae impairs the regulation of KATP channels through several signaling pathways. However, the direct functional effect of Cav3 on KATP channels is still poorly understood. Here, we used the cardiac KATP channel subtype, Kir6.2/SUR2A, and showed that Cav3 greatly reduced KATP channel surface density and current amplitude in a caveolae-independent manner. A screen of Cav3 functional domains revealed that a 25 amino acid region in the membrane attachment domain of Cav3 is the minimal effective segment (MAD1). The peptide corresponding to the MAD1 segment decreased KATP channel current in a concentration-dependent manner with an IC50 of ∼5 µM. The MAD1 segment prevented KATP channel recycling, thus decreasing KATP channel surface density and abolishing the cardioprotective effect of ischemic preconditioning. Our research identified the Cav3 MAD1 segment as a novel negative regulator of KATP channel recycling, providing pharmacological potential in the treatment of diseases with KATP channel trafficking defects.NEW & NOTEWORTHY Cardiac KATP channels physically interact with caveolin-3 in caveolae. In this study, we investigated the functional effect of caveolin-3 on KATP channel activity and identified a novel segment (MAD1) in the C-terminus domain of Caveolin-3 that negatively regulates KATP channel surface density and current amplitude by impairing KATP channel recycling. The peptide corresponding to the MAD1 segment abolished the cardioprotective effect of ischemic preconditioning.

The Arabidopsis thaliana onset of leaf death 12 mutation in the lectin receptor kinase P2K2 results in an autoimmune phenotype.

BACKGROUND: Plant immunity relies on the perception of immunogenic signals by cell-surface and intracellular receptors and subsequent activation of defense responses like programmed cell death. Under certain circumstances, the fine-tuned innate immune system of plants results in the activation of autoimmune responses that cause constitutive defense responses and spontaneous cell death in the absence of pathogens. RESULTS: Here, we characterized the onset of leaf death 12 (old12) mutant that was identified in the Arabidopsis accession Landsberg erecta. The old12 mutant is characterized by a growth defect, spontaneous cell death, plant-defense gene activation, and early senescence. In addition, the old12 phenotype is temperature reversible, thereby exhibiting all characteristics of an autoimmune mutant. Mapping the mutated locus revealed that the old12 phenotype is caused by a mutation in the Lectin Receptor Kinase P2-TYPE PURINERGIC RECEPTOR 2 (P2K2) gene. Interestingly, the P2K2 allele from Landsberg erecta is conserved among Brassicaceae. P2K2 has been implicated in pathogen tolerance and sensing extracellular ATP. The constitutive activation of defense responses in old12 results in improved resistance against Pseudomonas syringae pv. tomato DC3000. CONCLUSION: We demonstrate that old12 is an auto-immune mutant and that allelic variation of P2K2 contributes to diversity in Arabidopsis immune responses.

Treatment with a flow diverter-assisted coil embolization for ruptured blood blister-like aneurysms of the internal carotid artery: a technical note and analysis of single-center experience with pooled data.

Treatment of blood blister-like aneurysms (BBAs) of the supraclinoid internal carotid artery (ICA) with flow diverters (FDs) has become widespread in recent years. However, ruptured blood blister-like aneurysm (BBA) of ICA treatment with flow diverter-assisted coil embolization (FDAC) remains controversial. Moreover, limited direct comparative studies have been conducted between the two treatment modalities, FDs and FDAC, for BBAs. The purpose of this study was to document our experience and evaluate the effectiveness and safety of FDAC. We conducted a retrospective analysis of clinical and radiological information from ten patients who experienced ruptured BBAs of the supraclinoid ICA at our center from January 2021 to February 2023. The technical details of FDAC for ruptured BBAs were described, and the technical steps were named "pipeline embolization device (PED)-Individualized shaping(microcatheter)-Semi deploying-Rivet(coils)-Massage(microwire)" as the PEISSERM technique. Clinical outcomes were assessed using the modified Rankin Scale (mRS), whereas radiological results were determined through angiography. A pooled analysis was implemented, incorporating data from literature sources that reported perioperative and long-term clinical and angiographic outcomes of ruptured BBAs treated with FD and FDAC strategies, along with our data. Data in our analysis pool were categorized into FD and FDAC strategy groups to explore the preferred treatment modalities for BBAs. The PEISSERM technique was utilized to treat ten patients, seven males, and three females, with an average age of 41.7 years. A single PED was deployed in conjunction with coils in all ten patients. All PEDs were documented to have good wall apposition. The immediate postoperative angiograms demonstrated Raymond grade I in ten aneurysms. Angiographic follow-up of nine patients at 4-25 months showed total occlusion of the aneurysms. At the most recent follow-up, the mRS scores of nine patients hinted at a good prognosis. Pooled analysis of 233 ICA-BBA cases of FD revealed a technical success rate of 91% [95% confidence interval (CI), 0.88 to 0.95], a rate of complete occlusion of 79% (95% CI, 0.73 to 0.84), a recurrence rate of 2% (95% CI, 0.00 to 0.04), a rebleed rate of 2% (95% CI, 0.00 to 0.04), and the perioperative stroke rate was 8% (95% CI, 0.04 to 0.11). The perioperative mortality was 4% (95% CI, 0.01 to 0.07). The long-term good clinical outcome rate was 85% (95% CI, 0.80 to 0.90). The mortality rate was 6% (95% CI, 0.03 to 0.09). Results from the subgroup analysis illustrated that the FDAC strategy for BBAs had a significantly higher immediate postoperative complete occlusion rate (P < 0.001), total occlusion rate (P = 0.016), and a good outcome rate (P = 0.041) compared with the FD strategy. The FDAC strategy can yield a higher rate of good outcomes than the FD strategy. The PEISSERM technique employed by the FDAC is a reliable and effective treatment approach as it can minimize the hemodynamic burden of BBA's fragile dome, thereby achieving an excellent occlusion rate. The PEISSERM technique in the FDAC strategy contributes to understanding the BBA's treatment and offers a potentially optimal treatment for BBA.

Five new biflavonoids with acetylcholinesterase inhibitory activity from Diphylleia sinensis.

Five new biflavonoids, diphybiflavonoids A - E (1-5), were isolated from the roots and rhizomes of Diphylleia sinensis. Their structures were elucidated by extensive spectroscopic data, including UV, IR, HR-ESI-MS and 2D NMR. Their absolute configurations were determined by ECD spectra. All isolated compounds were evaluated for acetylcholinesterase (AChE) inhibitory activity. Compounds 1-4 exhibited the potent AChE inhibitory activities with IC50 values of 1.62, 2.10, 2.08, and 5.15 µM, respectively. The preliminary structure-activity relationship study indicated that the connection mode (C2-O-C4'''/C3-O-C3''' or C2-O-C3'''/C3-O-C4''') of biflavonoid subunits, and 3-hydroxy group of flavonol subunit were important structural factors for AChE inhibitory activity. Biflavonoids, containing a C2-O-C4'''/C3-O-C3''' or C2-O-C3'''/C3-O-C4''' linkage, can be a potentially useful platform for development of cholinesterase inhibitors.

The role of small RNAs in resistant melon cultivar against Phelipanche aegyptiaca parasitization.

Bidirectional trans-kingdom RNA silencing, a pivotal factor in plant-pathogen interactions, remains less explored in plant host-parasite dynamics. Here, using small RNA sequencing in melon root systems, we investigated microRNA (miRNA) expression variation in resistant and susceptible cultivars pre-and post-infection by the parasitic plant, broomrape. This approach revealed 979 known miRNAs and 110 novel miRNAs across 110 families. When comparing susceptible (F0) and resistant (R0) melon lines with broomrape infection (F25 and R25), 39 significantly differentially expressed miRNAs were observed in F25 vs. F0, 35 in R25 vs. R0, and 5 in R25 vs. F25. Notably, two miRNAs consistently exhibited differential expression across all comparisons, targeting genes linked to plant disease resistance. This suggests their pivotal role in melon's defense against broomrape. The target genes of these miRNAs were confirmed via degradome sequencing and validated by qRT-PCR, ensuring reliable sequencing outcomes. GO and KEGG analyses shed light on the molecular functions and pathways of these differential miRNAs. Furthermore, our study unveiled four trans-kingdom miRNAs, forming a foundation for exploring melon's resistance to broomrape.

The role of Ginkgo Folium on antitumor: Bioactive constituents and the potential mechanism.

ETHNOPHARMACOLOGICAL RELEVANCE: Ginkgo biloba L. is a well-known and highly regarded resource in Chinese traditional medicine due to its effectiveness and safety. Ginkgo Folium, the leaf of Ginkgo biloba L., contains biologically active constituents with diverse pharmacological activities. Recent studies have shown promising antitumor effects of the bioactive constituents found in Ginkgo Folium against various types of cancer cells, highlighting its potential as a natural source of antitumor agents. Further research is needed to elucidate the underlying mechanisms and optimize its therapeutic potential. AIM OF THE REVIEW: To provide a detailed understanding of the pharmacological activities of Ginkgo Folium and its potential therapeutic benefits for cancer patients. MATERIALS AND METHODS: In this study, we conducted a thorough and systematic search of multiple online databases, including PubMed, Web of Science, Medline, using relevant keywords such as "Ginkgo Folium," "flavonoids," "terpenoids," "Ginkgo Folium extracts," and "antitumor" to cover a broad range of studies that could inform our review. Additionally, we followed a rigorous selection process to ensure that the studies included in our review met the predetermined inclusion criteria. RESULTS: The active constituents of Ginkgo Folium primarily consist of flavonoids and terpenoids, with quercetin, kaempferol, isorhamnetin, ginkgolides, and bilobalide being the major compounds. These active constituents exert their antitumor effects through crucial biological events such as apoptosis, cell cycle arrest, autophagy, and inhibition of invasion and metastasis via modulating diverse signaling pathways. During the process of apoptosis, active constituents primarily exert their effects by modulating the caspase-8 mediated death receptor pathway and caspase-9 mediated mitochondrial pathway via regulating specific signaling pathways. Furthermore, by modulating multiple signaling pathways, active constituents effectively induce G1, G0/G1, G2, and G2/M phase arrest. Among these, the pathways associated with G2/M phase arrest are particularly extensive, with the cyclin-dependent kinases (CDKs) being most involved. Moreover, active constituents primarily mediate autophagy by modulating certain inflammatory factors and stressors, facilitating the fusion stage between autophagosomes and lysosomes. Additionally, through the modulation of specific chemokines and matrix metalloproteinases, active constituents effectively inhibit the processes of epithelial-mesenchymal transition (EMT) and angiogenesis, exerting a significant impact on cellular invasion and migration. Synergistic effects are observed among the active constituents, particularly quercetin and kaempferol. CONCLUSION: Active components derived from Ginkgo Folium demonstrate a comprehensive antitumor effect across various levels and pathways, presenting compelling evidence for their potential in new drug development. However, in order to facilitate their broad and adaptable clinical application, further extensive experimental investigations are required to thoroughly explore their efficacy, safety, and underlying mechanisms of action.

Roles of Fascin in Dendritic Cells.

Dendritic cells (DCs) are professional antigen-presenting cells that play a crucial role in activating naive T cells through presenting antigen information, thereby influencing immunity and anti-cancer responses. Fascin, a 55-kDa actin-bundling protein, is highly expressed in mature DCs and serves as a marker protein for their identification. However, the precise role of fascin in intratumoral DCs remains poorly understood. In this review, we aim to summarize the role of fascin in both normal and intratumoral DCs. In normal DCs, fascin promotes immune effects through facilitating DC maturation and migration. Through targeting intratumoral DCs, fascin inhibitors enhance anti-tumor immune activity. These roles of fascin in different DC populations offer valuable insights for future research in immunotherapy and strategies aimed at improving cancer treatments.

ß-Elemene induced ferroptosis via TFEB-mediated GPX4 degradation in EGFR wide-type non-small cell lung cancer.

INTRODUCTION: ß-Elemene (ß-ELE), derived from Curcuma wenyujin, has anticancer effect on non-small cell lung cancer (NSCLC). However, the potential target and detail mechanism were still not clear. TFEB is the master regulator of lysosome biogenesis. Ferroptosis, a promising strategy for cancer therapy could be triggered via suppression on glutathione peroxidase 4 (GPX4). Weather TFEB-mediated lysosome degradation contributes to GPX4 decline and how ß-ELE modulates on this process are not clear. OBJECTIVES: To observe the action of ß-ELE on TFEB, and the role of TFEB-mediated GPX4 degradation in ß-ELE induced ferroptosis. METHODS: Surface plasmon resonance (SPR) and molecular docking were applied to observe the binding affinity of ß-ELE on TFEB. Activation of TFEB and lysosome were observed by immunofluorescence, western blot, flow cytometry and qPCR. Ferroptosis induced by ß-ELE was observed via lipid ROS, a labile iron pool (LIP) assay and western blot. A549TFEB KO cells were established via CRISPR/Cas9. The regulation of TFEB on GPX4 and ferroptosis was observed in ß-ELE treated A549WT and A549TFEB KO cells, which was further studied in orthotopic NOD/SCID mouse model. RESULTS: ß-ELE can bind to TFEB, notably activate TFEB, lysosome and transcriptional increase on downstream gene GLA, MCOLN1, SLC26A11 involved in lysosome activity in EGFR wild-type NSCLC cells. ß-ELE increased GPX4 ubiquitination and lysosomal localization, with the increase on lysosome degradation of GPX4. Furthermore, ß-ELE induced ferroptosis, which could be promoted by TFEB overexpression or compromised by TFEB knockout. Genetic knockout or inactivation of TFEB compromised ß-ELE induced lysosome degradation of GPX4, which was further demonstrated in orthotopic NSCLC NOD/SCID mice model. CONCLUSION: This study firstly demonstrated that TFEB promoted GPX4 lysosome degradation contributes to ß-ELE induced ferroptosis in EGFR wild-type NSCLC, which gives a clue that TFEB mediated GPX4 degradation would be a novel strategy for ferroptosis induction and NSCLC therapy.

TFEB: a double-edged sword for tumor metastasis.

Transcription factor EB, a member of the microphthalmia-associated transcription factor (MiTF/TFE) family, is a master regulator of autophagy, lysosome biogenesis, and TAMs. Metastasis is one of the main reasons for the failure of tumor therapy. Studies on the relationship between TFEB and tumor metastasis are contradictory. On the positive side, TFEB mainly affects tumor cell metastasis via five aspects, including autophagy, epithelial-mesenchymal transition (EMT), lysosomal biogenesis, lipid metabolism, and oncogenic signaling pathways; on the negative side, TFEB mainly affects tumor cell metastasis in two aspects, including tumor-associated macrophages (TAMs) and EMT. In this review, we described the detailed mechanism of TFEB-mediated regulation of metastasis. In addition, we also described the activation and inactivation of TFEB in several aspects, including the mTORC1 and Rag GTPase systems, ERK2, and AKT. However, the exact process by which TFEB regulates tumor metastasis remains unclear in some pathways, which requires further studies.

Hyperprogression, a challenge of PD-1/PD-L1 inhibitors treatments: potential mechanisms and coping strategies.

Immunotherapy is now a mainstay in cancer treatments. Programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) immune checkpoint inhibitor (ICI) therapies have opened up a new venue of advanced cancer immunotherapy. However, hyperprogressive disease (HPD) induced by PD-1/PD-L1 inhibitors caused a significant decrease in the overall survival (OS) of the patients, which compromise the efficacy of PD-1/PD-L1 inhibitors. Therefore, HPD has become an urgent issue to be addressed in the clinical uses of PD-1/PD-L1 inhibitors. The mechanisms of HPD remain unclear, and possible predictive factors of HPD are not well understood. In this review, we summarized the potential mechanisms of HPD and coping strategies that can effectively reduce the occurrence and development of HPD.

Mechanical Thrombectomy with Tandem Double Stent Retriever in Combination with Intermediate Catheter Aspiration for Refractory Severe Hemorrhagic Cerebral Venous Sinus Thrombosis.

OBJECTIVE: We aimed to describe the initial experience of mechanical thrombectomy using tandem double stent retrievers combined with intermediate catheter aspiration to treat refractory severe hemorrhagic (SH)-cerebral venous sinus thrombosis (CVST). METHODS: All refractory SH-CVST patients treated with mechanical thrombectomy using tandem double stent retriever (SR) combined with intermediate catheter aspiration (MT-TDSA) in our institution were retrospectively reviewed. MT-TDSA is a technique that fully engages the clot with double SRs and retrieves the clot using a double SR in combination with aspiration from an intermediate catheter. Demographics, clinical manifestation, medical history, the location of the occluded venous sinus, intraoperative details, procedure-related complications, and modified Rankin Scale (1, 6, 12 months postoperatively) were collected and analyzed. RESULTS: Fourteen patients (median age, 43 years) with refractory SH-CVST were treated with MT-TDSA between January 2016 and January 2020. Ten of 14 (71.4%) had a successful intraoperative recanalization rate (>90%) using MT-TDSA. No procedure-related complications occurred. Eleven patients had good clinical outcomes (modified Rankin Scale score 0-2 at 12 months postoperatively). CONCLUSIONS: MT-TDSA for refractory SH-CVST might improve clot-capturing ability and remove blood clots from cerebral venous sinuses effectively and safely, achieving good clinical outcomes.

Correction: Zhang et al. Admission Serum Iron as an Independent Risk Factor for Postoperative Delayed Cerebral Ischemia Following Aneurysmal Subarachnoid Hemorrhage: A Propensity-Matched Analysis. Brain Sci. 2022, 12, 1183.

We would like to submit the following corrections to our recently published paper [...].

Structurally diverse biflavonoids from Dysosma versipellis and their bioactivity.

Five pairs of new biflavonoid enantiomers, (±)-dysosmabiflavonoids A-E (1-5), two new biflavonoids, dysosmabiflavonoids F-G (6-7), and four biosynthetically related precursors (8-11) were isolated from the roots and rhizomes of Dysosma versipellis. Their structures were elucidated by extensive spectroscopic analysis, including HR-ESI-MS and 2D NMR. Their absolute configurations were determined by comparison of the calculated and experimental ECD spectra. All isolated compounds were evaluated for AChE inhibitory activity. Compounds 6 and 7 exhibited more potent inhibitory activities with IC50 values of 1.42 and 0.73 µM, respectively, than their biosynthetically related precursors kaempferol (8, 17.90 µM) and quercetin (9, 3.96 µM). The preliminary structure-activity relationship study indicated that the connection mode of biflavonoid subunits, oxidation degree of the C ring, and 3,4-dihydroxy group of the B ring were important structural factors for AChE inhibitory activity. Racemates 1-5 and their corresponding levorotatory and dextrorotatory enantiomers were tested for their potential to impede the generation of NO in lipopolysaccharide-stimulated RAW264.7 cells, and their mushroom tyrosinase inhibitory effect. Racemate 1 displayed more potent mushroom tyrosinase inhibitory activity (IC50, 28.27 µM) than the positive control kojic acid (IC50, 32.59 µM). D. versipellis may have therapeutic potential for melanogenesis disorders and neurodegenerative diseases.

Admission Serum Iron as an Independent Risk Factor for Postoperative Delayed Cerebral Ischemia Following Aneurysmal Subarachnoid Hemorrhage: A Propensity-Matched Analysis.

This study aimed to investigate the association between serum iron (SI) and postoperative delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH). We retrospectively analyzed 985 consecutive adult patients diagnosed with aSAH. Demographic, clinical, and laboratory data were recorded. Univariate and multivariate analyses were employed to assess the association between SI and DCI. Propensity-score matching (PSM) analysis was implemented to reduce confounding. Postoperative DCI developed in 14.38% of patients. Lower SI upon admission was detected in aSAH patients with severe clinical conditions and severe aSAH. SI was negatively correlated with WFNS grade (r = −0.3744, p < 0.001) and modified Fisher (mFisher) grade (r = −0.2520, p < 0.001). Multivariable analysis revealed lower SI was independently associated with DCI [odds ratios (OR) 0.281, 95% confidence interval (CI) 0.177−0.448, p < 0.001], while WFNS grade and mFisher grade were not. The receiver-operating characteristics (ROC) curve analysis of SI for DCI gave an area under the curve (AUC) of 0.7 and an optimal cut-off of 7.5 µmol/L (95% CI 0.665 to 0.733, p < 0.0001). PSM demonstrated the DCI group had a significantly lower SI than the non-DCI group (10.91 ± 6.86 vs. 20.34 ± 8.01 µmol/L, p < 0.001). Lower SI remained a significant independent predictor for DCI and an independent poor prognostic factor of aSAH in multivariate analysis (OR 0.363, 95% CI 0.209−0.630, p < 0.001). The predictive performance of SI for poor outcome had a corresponding AUC of 0.718 after PSM. Lower SI upon admission is significantly associated with WFNS grade, mFisher grade, and predicts postoperative DCI and poor outcome at 90 days following aSAH.

Microcatheter-guided compartment packing of acutely ruptured complex intracerebral aneurysms (ARCIAs): Preliminary experience and technical note.

Objective: We present our initial experience using the microcatheter-guided compartment packing (MCP) technique for endovascular embolization of acutely ruptured complex intracerebral aneurysms (ARCIAs) and evaluate the safety, feasibility, and efficiency of this technique. Methods: This retrospective, single-center study included 28 patients who underwent coil embolization using the MCP technique for ARCIAs at our institution between January 2021 and January 2022. The MCP technique was the placement of microcatheters in different compartments within the aneurysm to deploy the coils simultaneously or sequentially. Patient demographics, aneurysm characteristics, procedural parameters, grade of occlusion, complications, and clinical results were analyzed. The clinical outcomes were evaluated with modified Rankin Scale (mRS) scores. Results: Of the 28 patients successfully treated with the MCP technique, 24 (85.7%) aneurysms were considered as complete occlusions (Raymond I) based on the immediate postembolization angiogram results. Complications occurred in 2/28 treatments, including guidewire perforation with subarachnoid hemorrhage and cerebral vasospasm-related cerebral infarction. An angiography follow-up demonstrated complete occlusion in 25/28 aneurysms. Twenty-six (92.9%) patients had favorable 90-day outcomes (mRS 0-2) after the endovascular coil embolization. Conclusion: The MCP technique is simple, safe, and effective, achieving good packing density and initial occlusion rate when used to treat ARCIAs.

Catalyst-free Synthesis of Aminomethylphenol Derivatives in Cyclopentyl Methyl Ether via Petasis Borono-Mannich Reaction.

OBJECTIVE: Aminomethylphenol molecules have wider applications in pharmaceuticals, agrochemicals, plant protection and promising functional materials. The development of an efficient and practical method to prepare this class of compound is highly desirable from both environmental and economical points of view. MATERIALS AND METHODS: In order to establish an effective synthetic method for preparing aminomethylphenol derivatives, the Petasis borono-Mannich reaction of salicylaldehyde, phenylboronic acid and 1,2,3,4- tetrahydroisoquinoline was selected as a model reaction. A variety of reaction conditions are investigated, including solvent and temperature. The generality and limitation of the established method were also evaluated. RESULTS AND DISCUSSION: It was found that model reaction can be carried out in cyclopentyl methyl ether at 80 oC under catalyst-free conditions. This protocol, with broad substrate applicability, the reaction of various arylboronic acid, secondary amine and salicylaldehyde proceeded smoothly under optimal reaction conditions to afford various aminomethylphenol derivatives in high yields. A practical, scalable, and high-yielding synthesis of aminomethylphenol derivatives was successfully accomplished. CONCLUSION: A catalyst-free practical method for the synthesis of minomethylphenol derivatives based on Petasis borono-Mannich (PBM) reaction of various arylboronic acid, secondary amine and salicylaldehyde in cyclopentyl methyl ether has been developed. The salient features of this protocol are avoidance of any additive/catalyst and toxic organic solvents, use of cyclopentyl methyl ether as the reaction medium, clean reaction profiles, easy operation, and high to excellent yield.

Advanced glycosylation end products inhibit the proliferation of bone-marrow stromal cells through activating MAPK pathway.

BACKGROUND: The purpose of present study was to explore the mechanism of nuclear factor-kappa B (NF-κB), phosphatidylinositol 3-kinase (PI3K)/protein kinase B(PKB/Akt) and mitogen-activated protein kinase (MAPK) signaling pathways after intervention of advanced glycosylation end products (AGEs) on rat bone-marrow stromal cells (BMSCs). METHODS: Prepare and identify AGEs. BMSCs were isolated from 16 SD rats and cultured with different concentration of AGEs. Cell viability was detected by cell counting kit-8 (CCK-8). BMSCs were cultured with AGEs (0.25 mg/ml) for 30 min, 12 h, 24 h, 72 h and 120 h. In addition, BMSCs were cultured with AGEs, AGEs + JNK inhibitor and AGEs + P38 inhibitor for 24 h and 48 h, respectively. Western blotting and RT-PCR were used to determine the protein and mRNA expression levels, respectively. RESULTS: Cell viability of BMSCs was significantly correlated with concentration and effect time of AGEs (P < 0.05), and the most appropriate concentration was 0.25 mg/ml. AGEs stimulation significantly increased the protein expression levels of NF-κB p65, JNK, p38 (P < 0.05), decreased IκB (P < 0.05), but had no effect on the protein expression of Akt in BMSCs (P > 0.05). At the mRNA level, JNK and p38 inhibitors significantly reduced the levels of NF-κB p65, p38 and JNK, increased IκB (P > 0.05), but had no effect on Akt in BMSCs (P > 0.05). At the protein level, JNK and p38 inhibitors notably decreased the expression of NF-κB p65, p38, p-JNK, P-IκB and JNK (P < 0.001), and increased IκB (P < 0.05). CONCLUSION: Advanced glycosylation end products can inhibit the proliferation of bone-marrow stromal cells through activating MAPK pathway.

Effects of regular breakfast habits on metabolic and cardiovascular diseases: A protocol for systematic review and meta-analysis.

BACKGROUND: Breakfast, which is considered as an important meal of the day, is being ignored by an increasing number of people as the pace of modern life accelerates. Although a large number of previous studies have reported the relationship between skipping breakfast and type 2 diabetes mellitus, most of them were cross-sectional studies. It remains unclear how skipping breakfast affects such specific cardio-metabolic diseases as hypertension, strokes and hypercholesterolemia. METHODS: The protocols and reports of this meta-analysis are based on a meta-analysis of observational studies in epidemiological guidelines (MOOSE). Relevant studies were systematically retrieved from PubMed, Embase, Web of Science and the Cochrane Library, and were restricted to English from the inception to May 10, 2019. All the results were obtained by RRs, and outcomes of interests should include the occurrence of cardiovascular and metabolic diseases. RESULTS: Fourteen cohort studies in total were eventually included. Compared with people having breakfast frequency≦3times/week, those with a frequency>3 times/week have reduced the risk of type 2 diabetes mellitus, obesity, Metabolic Syndrome, Low high-density lipoprotein cholesterolemia, Cardiovascular Diseases, cardiovascular Mortality, hypertension and strokes, with (RR = 0.8 [95% CI: 0.7-0.91], P = .142, I2 = 37.6%), (RR = 0.74 [95% CI: 0.59-0.94], P < .001, I2 = 89%), (RR = 0.86 [95% CI:0.75-0.99], P = .512, I2 = 0%), (RR = 0.75 [95% CI:0.61-0.93], P = .643, I2 = 0%), (RR = 0.87 [95% CI:0.81-0.93], P = .479, I2 = 0%), (RR = 0.63 [95% CI:0.51-0.78], P = .396, I2 = 0%), (RR = 0.92 [95% CI:0.86-0.98], P = .419, I2 = 0.7%), and (RR = 0.89 [95% CI:0.79-0.99], P = .238, I2 = 29%), respectively. CONCLUSIONS: A regular daily breakfast habit benefits the cardio-metabolism to a great extent, reducing the risk of Cardiovascular Diseases, type 2 diabetes mellitus, obesity, hypertension, strokes, Metabolic Syndrome, cardiovascular Mortality, Low high-density lipoprotein cholesterolemia, and Abdominal obesity, while it is not significantly related to hypercholesterolemia and coronary heart disease regardless of gender. Nevertheless, skipping breakfast once a week may greatly reduce the benefits of cardio-metabolism. Therefore, public institutions should promote and encourage citizens to cultivate regular daily breakfast habits.

Thiosemicarbazone-based lead optimization to discover high-efficiency and low-toxicity anti-gastric cancer agents.

In this paper, a series of thiosemicarbazone derivatives containing different aromatic heterocyclic groups were synthesized and the tridentate donor system of the lead compound was optimized. Most of the target compounds showed improved antiproliferative activity against MGC803 cells. SAR studies revealed that compound 5d displayed significant advantages in inhibition effect with an IC50 value of 0.031 µM, and better selectivity between cancer and normal cells than 3-AP and DpC (about 15- and 5-fold improved respectively). Besides, compound 5d showed selective antiproliferative activity in not only other cancer cells but also different gastric cancer cell lines. In-depth mechanism studies showed that compound 5d could induce mitochondria-related apoptosis which might be related to the elevation of intracellular ROS level, and cause cell cycle arrest at S phase. Moreover, 5d could evidently suppress the cell migration and invasion by blocking the EMT (epithelial-mesenchymal transition) process. Consequently, our studies provided a lead optimization strategy of thiosemicarbazone derivatives which would contribute to discover high-efficiency and low-toxicity agents for the treatment of gastric cancer.