Association of platelet-to-lymphocyte ratio levels with the risk of cardiac adverse events in people with type 2 diabetes undergoing percutaneous coronary intervention: A large-scale prospective cohort study.

BACKGROUND: The platelet-to-lymphocyte ratio (PLR), a promising inflammatory biomarker, contributes to the development of atherosclerosis and type 2 diabetes (T2D). Therefore, this study aimed to elucidate the importance of PLR in predicting adverse events in people undergoing percutaneous coronary intervention (PCI) with T2D. METHODS: We consecutively enrolled 8831 people who underwent PCI and divided them into four groups according to PLR and glycemic metabolic status (PLR-Low/High without T2D, PLR-Low/High with T2D). The endpoints were major adverse cardiovascular and cerebrovascular events (MACCE) and stent thrombosis. A multivariate Cox regression analysis was performed to determine this association. RESULTS: During the 2.4-year follow-up, 663 (7.5%) MACCE and 75 (0.85%) stent thromboses were recorded. The risk of MACCE (hazard ratio [HR]: 1.30, 95% confidence interval [CI]: 1.10-1.53, P = 0.002) and stent thrombosis (HR: 2.32, 95% CI: 1.38-3.90, P = 0.002) was significantly higher in people with high PLR levels than in those with low PLR. Among people with T2D, the PLR-High group showed a significantly higher risk of MACCE (HR: 1.59, 95% CI: 1.21-2.09, P = 0.001) and stent thrombosis (HR: 3.15, 95% CI: 1.32-7.52, P = 0.010). However, these associations were not significant in people without T2D. CONCLUSIONS: PLR has been originally documented as a significant predictor of poor prognosis and a high incidence of stent thrombosis in people undergoing PCI, especially in those with T2D.

Underlying mechanism of atrial fibrillation-associated Nppa-I137T mutation and cardiac effect of potential drug therapy.

BACKGROUND: More than a hundred genetic loci have been associated with atrial fibrillation (AF). But the exact mechanism remains unclear and the treatment needs to be improved. OBJECTIVE: This study aimed to investigate the mechanism and potential treatment of NPPA mutation-associated AF. METHODS: Nppa knock-in (KI, p.I137T) rats were generated, and cardiac function was evaluated. Blood pressure was recorded using a tail-cuff system. The expression levels were measured using real-time polymerase chain reaction, enzyme-linked immunosorbent assay or Western blot analysis, and RNA-sequence analysis. Programmed electrical stimulation, patch clamp, and multielectrode array were used to record the electrophysical characteristics. RESULTS: Mutant rats displayed downregulated expression of atrial natriuretic peptide but elevated blood pressure and enlarged left atrial end-diastolic diameter. Further, gene topology analysis suggested that the majority of differently expressed genes in Nppa KI rats were related to inflammation, electrical remodeling, and structural remodeling. The expression levels of C-C chemokine ligand 5 and galectin-3 involved in remodeling were higher, while there were declined levels of Nav1.5, Cav1.2, and connexin 40. AF was more easily induced in KI rats. Electrical remodeling included abbreviated action potentials, effective refractory period, increased late sodium current, and reduced calcium current, giving rise to conduction abnormalities. These electrophysiological changes could be reversed by the late sodium current blocker ranolazine and the Nav1.8 blocker A-803467. CONCLUSION: Our findings suggest that structural remodeling related to inflammation and fibrosis and electrical remodeling involved in late sodium current underly the major effects of the Nppa (p.I137T) variant to induce AF, which can be attenuated by the late sodium current blocker and Nav1.8 blocker.

Melatonin inhibits arrhythmias induced by increased late sodium currents in ventricular myocytes / 药学学报

Melatonin (Mel) has been shown to have cardioprotective effects, but its action on ion channels is unclear. In this experiment, we investigated the inhibitory effect of Mel on late sodium currents (INa.L) in mouse ventricular myocytes and the anti-arrhythmic effect at the organ level as well as its mechanism. The whole-cell patch clamp technique was applied to record the ionic currents and action potential (AP) in mouse ventricular myocytes while the electrocardiogram (ECG) and monophasic action potential (MAP) were recorded simultaneously in mouse hearts using a multichannel acquisition and analysis system. The results demonstrated that the half maximal inhibitory concentration (IC50) values of Mel on transient sodium current (INa.T) and specific INa.L opener 2 nmol·L-1 sea anemone toxins II (ATX II) increased INa.L were 686.615 and 7.37 μmol·L-1, respectively. Mel did not affect L-type calcium current (ICa.L), transient outward current (Ito), and AP. In addition, 16 μmol·L-1 Mel shortened ATX II-prolonged action potential duration (APD), suppressed ATX II-induced early afterdepolarizations (EADs), and significantly reduced the incidence of ventricular tachycardia (VT) and ventricular fibrillation (VF) in Langendorff-perfused mouse hearts. In conclusion, Mel exerted its antiarrhythmic effects principally by blocking INa.L, thus providing a significant theoretical basis for new clinical applications of Mel. Animal welfare and experimental process are in accordance with the regulations of the Experimental Animal Ethics Committee of Wuhan University of Science and Technology (2023130).

Traditional Chinese Medicine Compound (Tongxinluo) and Clinical Outcomes of Patients With Acute Myocardial Infarction: The CTS-AMI Randomized Clinical Trial.

Importance: Tongxinluo, a traditional Chinese medicine compound, has shown promise in in vitro, animal, and small human studies for myocardial infarction, but has not been rigorously evaluated in large randomized clinical trials. Objective: To investigate whether Tongxinluo could improve clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI). Design, Setting, and Participants: Randomized, double-blind, placebo-controlled clinical trial was conducted among patients with STEMI within 24 hours of symptom onset from 124 hospitals in China. Patients were enrolled from May 2019 to December 2020; the last date of follow-up was December 15, 2021. Interventions: Patients were randomized 1:1 to receive either Tongxinluo or placebo orally for 12 months (a loading dose of 2.08 g after randomization, followed by the maintenance dose of 1.04 g, 3 times a day), in addition to STEMI guideline-directed treatments. Main Outcomes and Measures: The primary end point was 30-day major adverse cardiac and cerebrovascular events (MACCEs), a composite of cardiac death, myocardial reinfarction, emergent coronary revascularization, and stroke. Follow-up for MACCEs occurred every 3 months to 1 year. Results: Among 3797 patients who were randomized, 3777 (Tongxinluo: 1889 and placebo: 1888; mean age, 61 years; 76.9% male) were included in the primary analysis. Thirty-day MACCEs occurred in 64 patients (3.4%) in the Tongxinluo group vs 99 patients (5.2%) in the control group (relative risk [RR], 0.64 [95% CI, 0.47 to 0.88]; risk difference [RD], -1.8% [95% CI, -3.2% to -0.6%]). Individual components of 30-day MACCEs, including cardiac death (56 [3.0%] vs 80 [4.2%]; RR, 0.70 [95% CI, 0.50 to 0.99]; RD, -1.2% [95% CI, -2.5% to -0.1%]), were also significantly lower in the Tongxinluo group than the placebo group. By 1 year, the Tongxinluo group continued to have lower rates of MACCEs (100 [5.3%] vs 157 [8.3%]; HR, 0.64 [95% CI, 0.49 to 0.82]; RD, -3.0% [95% CI, -4.6% to -1.4%]) and cardiac death (85 [4.5%] vs 116 [6.1%]; HR, 0.73 [95% CI, 0.55 to 0.97]; RD, -1.6% [95% CI, -3.1% to -0.2%]). There were no significant differences in other secondary end points including 30-day stroke; major bleeding at 30 days and 1 year; 1-year all-cause mortality; and in-stent thrombosis (<24 hours; 1-30 days; 1-12 months). More adverse drug reactions occurred in the Tongxinluo group than the placebo group (40 [2.1%] vs 21 [1.1%]; P = .02), mainly driven by gastrointestinal symptoms. Conclusions and Relevance: In patients with STEMI, the Chinese patent medicine Tongxinluo, as an adjunctive therapy in addition to STEMI guideline-directed treatments, significantly improved both 30-day and 1-year clinical outcomes. Further research is needed to determine the mechanism of action of Tongxinluo in STEMI. Trial Registration: ClinicalTrials.gov Identifier: NCT03792035.

Precessing jet nozzle connecting to a spinning black hole in M87.

The nearby radio galaxy M87 offers a unique opportunity to explore the connections between the central supermassive black hole and relativistic jets. Previous studies of the inner region of M87 revealed a wide opening angle for the jet originating near the black hole1-4. The Event Horizon Telescope resolved the central radio source and found an asymmetric ring structure consistent with expectations from general relativity5. With a baseline of 17 years of observations, there was a shift in the jet's transverse position, possibly arising from an 8- to 10-year quasi-periodicity3. However, the origin of this sideways shift remains unclear. Here we report an analysis of radio observations over 22 years that suggests a period of about 11 years for the variation in the position angle of the jet. We infer that we are seeing a spinning black hole that induces the Lense-Thirring precession of a misaligned accretion disk. Similar jet precession may commonly occur in other active galactic nuclei but has been challenging to detect owing to the small magnitude and long period of the variation.

Cardio-oncology: Shared Genetic, Metabolic, and Pharmacologic Mechanism.

PURPOSE OF REVIEW: The article aims to investigate the complex relationship between cancer and cardiovascular disease (CVD), with a focus on the effects of cancer treatment on cardiac health. RECENT FINDINGS: Advances in cancer treatment have improved long-term survival rates, but CVD has emerged as a leading cause of morbidity and mortality in cancer patients. The interplay between cancer itself, treatment methods, homeostatic changes, and lifestyle modifications contributes to this comorbidity. Recent research in the field of cardio-oncology has revealed common genetic mutations, risk factors, and metabolic features associated with the co-occurrence of cancer and CVD. This article provides a comprehensive review of the latest research in cardio-oncology, including common genetic mutations, risk factors, and metabolic features, and explores the interactions between cancer treatment and CVD drugs, proposing novel approaches for the management of cancer and CVD.

Novel PORCN inhibitor WHN-88 targets Wnt/ß-catenin pathway and prevents the growth of Wnt-driven cancers.

Wnt/ß-catenin signaling pathway is a classical and crucial oncogenic pathway in many carcinomas, and Porcupine (PORCN) is an O-acyltransferase, which is indispensable and highly specific for catalyzing palmitoylation of Wnt ligands and facilitating their secretion and biofunction. Targeting PORCN provides a promising approach to specifically cure Wnt-driven cancers from the root. In this study, we designed series of pyridonyl acetamide compounds, and discovered a novel PORCN inhibitor WHN-88 with a unique di-iodinated pyridone structural fragment, which is significantly different from the reported inhibitors. We demonstrated that WHN-88 effectively abolished palmitoylation of Wnt ligands and prevented their secretion and the subsequent Wnt/ß-catenin signaling transduction. Further experiments showed that, at well-tolerated doses, WHN-88 remarkably suppressed the spontaneous occurrence and growth of MMTV-Wnt1 murine breast tumors. Consistently, WHN-88 also notably restrained the progress of xenografted Wnt-driven human tumors, including PA-1 teratocarcinoma with high autocrine Wnt signaling and Aspc-1 pancreatic carcinoma with Wnt-sensitizing RNF43 mutation. Additionally, we disclosed that WHN-88 inhibited cancer cell stemness obviously. Together, we verified WHN-88 is a novel PORCN inhibitor with potent efficacy against the Wnt-driven cancers. Our findings enriched the structural types of PORCN inhibitors, and facilitated the development and application of PORCN inhibiting therapy in clinic.

Inflammatory biomarkers in assessing severity and prognosis of immune checkpoint inhibitor-associated cardiotoxicity.

AIMS: Inflammatory biomarkers, including CRP, the neutrophil-to-lymphocyte ratio (NLR), and the neutrophil-to-eosinophil ratio (NER), may predict outcomes in cancer. However, their value in immune checkpoint inhibitor (ICI) therapy-associated cardiotoxicity remains elusive. We aimed to characterize the relationship of inflammatory markers with severity of ICI-related cardiotoxicities (iRCs) and prognosis among patients with iRCs. METHODS: Patients who were diagnosed with iRCs between January 2019 and December 2021 were retrospectively enrolled and were dichotomized based on iRC severity into low-grade (grade 1-2) vs. high-grade (grade 3-4) groups. RESULTS: Forty-seven patients were included. The median time-to-event from first ICI infusion to onset of iRCs was 35 days (IQR: 19.0-65.5 days). When compared with respective baseline values, cardiac biomarkers and inflammatory markers were significantly elevated at onset of iRCs. Compared with low-grade iRCs, NER at iRC onset was significantly increased among patients with high-grade iRCs (Group × Time, P < 0.01). When grouped by the median NER (184.33) at iRC onset, NER ≥ 184.33 was associated with high-grade iRCs (OR: 10.77, P < 0.05) and had a 36.3% increased mortality compared to the lower NER group (HR: 2.67, P < 0.05). CONCLUSIONS: In patients who develop iRCs, NER is significantly elevated at iRC onset, and higher NER correlates with greater iRC severity and higher mortality. Larger datasets are needed to validate these findings.

Double C-Arm Digital Subtraction Angiography Guidance During Transjugular Intrahepatic Portosystemic Shunt Placement.

BACKGROUND This study aimed to evaluate the safety and efficacy of portal vein puncture with a new guidance system using double C-arm digital subtraction angiography (DSA) during transjugular intrahepatic portosystemic shunt (TIPS) placement. MATERIAL AND METHODS The procedure details of TIPS placements performed on 39 patients in our center between January and December 2021 were retrospectively analyzed. The procedure was performed under double C-arm DSA guidance (study group) and C-arm DSA (control group) in 18 and 21 patients, respectively. We analyzed the procedure's technical success, duration of the overall procedure, portal vein puncture, fluoroscopy, radiation exposure, complications, and mortality and morbidity rates 30 days after the procedure. RESULTS TIPS placement was performed successfully in all patients. The mean portal vein puncture time in the study group (9±5.7 min) was significantly shorter than in the control group (33±14.9 min, p=0.02). The complete mean dose area product of the procedure showed no significant differences (study group, 126±53 Gy/cm²; control group. 142±66 Gy/cm²; p=0.42). The intraprocedural complication rates were 0% and 19% in the study and control groups, respectively (p=0.04). The 30-day post-procedural mortality rate in the control group was 4.8% (1/21), with no deaths from technical complications. CONCLUSIONS Double C-arm DSA guidance is a safe and effective method to assist TIPS placement. This approach may result in shorter portal vein puncture time and lower intraprocedural complication rates.

An immune-related prognostic signature associated with immune landscape and therapeutic responses in gastric cancer.

Immune-related genes (IRGs) have attracted attention in recent years as therapeutic targets in various tumors. However, the role of IRGs in gastric cancer (GC) has not been clearly elucidated. This study presents a comprehensive analysis exploring the clinical, molecular, immune, and drug response features characterizing the IRGs in GC. Data were acquired from the TCGA and GEO databases. The Cox regression analyses were performed to develop a prognostic risk signature. The genetic variants, immune infiltration, and drug responses associated with the risk signature were explored using bioinformatics methods. Lastly, the expression of the IRS was verified by qRT-PCR in cell lines. In this manner, an immune-related signature (IRS) was established based on 8 IRGs. According to the IRS, patients were divided into the low-risk group (LRG) and high-risk group (HRG). Compared with the HRG, the LRG was characterized by a better prognosis, high genomic instability, more CD8+ T cell infiltration, greater sensitivity to chemotherapeutic drugs, and greater likelihood of benefiting from the immunotherapy. Moreover, the expression result showed good consistency between the qRT-PCR and TCGA cohort. Our findings provide insights into the specific clinical and immune features underlying the IRS, which may be important for patient treatment.

Molecular recognition of two endogenous hormones by the human parathyroid hormone receptor-1.

Parathyroid hormone (PTH) and PTH-related peptide (PTHrP) are two endogenous hormones recognized by PTH receptor-1 (PTH1R), a member of class B G protein- coupled receptors (GPCRs). Both PTH and PTHrP analogs including teriparatide and abaloparatide are approved drugs for osteoporosis, but they exhibit distinct pharmacology. Here we report two cryo-EM structures of human PTH1R bound to PTH and PTHrP in the G protein-bound state at resolutions of 2.62 Å and 3.25 Å, respectively. Detailed analysis of these structures uncovers both common and unique features for the agonism of PTH and PTHrP. Molecular dynamics (MD) simulation together with site-directed mutagenesis studies reveal the molecular basis of endogenous hormones recognition specificity and selectivity to PTH1R. These results provide a rational template for the clinical use of PTH and PTHrP analogs as an anabolic therapy for osteoporosis and other disorders.

Jigsaw training-based background reverse attention transformer network for guidewire segmentation.

PURPOSE: Guidewire segmentation plays a crucial role in percutaneous coronary intervention. However, it is a challenging task due to the low signal-to-noise ratio of X-ray sequences and the great imbalance between the number of foreground and background pixels. Besides, most existing guidewire segmentation methods are designed for single guidewire segmentation. This paper aims to solve the task of single and dual guidewire segmentation in X-ray fluoroscopy sequences. METHODS: A jigsaw training-based background reverse attention (BRA) transformer network is proposed. A jigsaw training strategy is used to train the guidewire segmentation network. A BRA module is also designed to reduce the influence of background information. First, robust principal component is conducted to generate background maps for guidewire sequences. Then, BRA is computed on the basis of the background features. RESULTS: The experimental results on the dataset collected from three hospitals show that the proposed method can achieve single and dual guidewire segmentation in X-ray fluoroscopy sequences. Higher F1 score and precision than state-of-the-art guidewire segmentation methods can be obtained in most cases. CONCLUSION: The jigsaw training strategy helps reduce the need for dual guidewire data and improve the performance of the network. Our BRA module helps reduce the influence of background information and distinguish the guidewire. The proposed methods can obtain higher performance than state-of-the-art guidewire segmentation methods.

Effects of site-directed mutagenesis of GLP-1 and glucagon receptors on signal transduction activated by dual and triple agonists.

The paradigm of one drug against multiple targets, known as unimolecular polypharmacology, offers the potential to improve efficacy while overcoming some adverse events associated with the treatment. This approach is best exemplified by targeting two or three class B1 G protein-coupled receptors, namely, glucagon-like peptide-1 receptor (GLP-1R), glucagon receptor (GCGR) and glucose-dependent insulinotropic polypeptide receptor for treatment of type 2 diabetes and obesity. Some of the dual and triple agonists have already shown initial successes in clinical trials, although the molecular mechanisms underlying their multiplexed pharmacology remain elusive. In this study we employed structure-based site-directed mutagenesis together with pharmacological assays to compare agonist efficacy across two key signaling pathways, cAMP accumulation and ERK1/2 phosphorylation (pERK1/2). Three dual agonists (peptide 15, MEDI0382 and SAR425899) and one triple agonist (peptide 20) were evaluated at GLP-1R and GCGR, relative to the native peptidic ligands (GLP-1 and glucagon). Our results reveal the existence of residue networks crucial for unimolecular agonist-mediated receptor activation and their distinct signaling patterns, which might be useful to the rational design of biased drug leads.

Research Progress for Targeting Deubiquitinases in Gastric Cancers.

Gastric cancers (GCs) are malignant tumors with a high incidence that threaten global public health. Despite advances in GC diagnosis and treatment, the prognosis remains poor. Therefore, the mechanisms underlying GC progression need to be identified to develop prognostic biomarkers and therapeutic targets. Ubiquitination, a post-translational modification that regulates the stability, activity, localization, and interactions of target proteins, can be reversed by deubiquitinases (DUBs), which can remove ubiquitin monomers or polymers from modified proteins. The dysfunction of DUBs has been closely linked to tumorigenesis in various cancer types, and targeting certain DUBs may provide a potential option for cancer therapy. Multiple DUBs have been demonstrated to function as oncogenes or tumor suppressors in GC. In this review, we summarize the DUBs involved in GC and their associated upstream regulation and downstream mechanisms and present the benefits of targeting DUBs for GC treatment, which could provide new insights for GC diagnosis and therapy.

Fisetin Ameliorates Alcohol-Induced Liver Injury through Regulating SIRT1 and SphK1 Pathway.

Alcoholic liver disease (ALD) often leads to hepatitis, hepatic cirrhosis, and even hepatocellular carcinoma. Fisetin has been shown to confer protection against liver injury. Herein, we investigated whether fisetin could prevent ethanol-induced hepatotoxicity. Mice were fed on 5% (v/v) Lieber-DeCarli ethanol diet. Human primary hepatic stellate cells (HSCs) co-cultured with ethanol were used to verify the therapeutic effect of fisetin. The results of alanine/aspartate aminotransferase (ALT/AST), Triglyceride (TG), total cholesterol (TC) in serum, Oil O Red and Masson staining revealed that fisetin (80[Formula: see text]mg/kg) ameliorated ethanol-induced mice liver injury and fibrosis. Besides, immunofluorescence results of [Formula: see text]-SMA revealed that fisetin suppressed HSCs activation. The suppression was dose-dependent. Furthermore, fisetin promoted SIRT1-mediated autophagy and inhibited Sphk1-mediated endoplasmic reticulum stress (ER stress) both in vitro and in vivo. Molecular docking results indicated potential interaction of fisetin with SIRT1 and SphK1. The inhibitory effect of fisetin on HSCs activation was reversed on co-culturing with EX-527, a specific inhibitor against STIR1 overexpression. Thus, fisetin has the potential to ameliorate alcohol-induced liver injury through suppression of HSCs activation, SIRT1-mediated autophagy and Sphk1-mediated ER stress.

Insights Into the Properties, Biological Functions, and Regulation of USP21.

Deubiquitylating enzymes (DUBs) antagonize ubiquitination by removing ubiquitin from their substrates. The role of DUBs in controlling various physiological and pathological processes has been extensively studied, and some members of DUBs have been identified as potential therapeutic targets in diseases ranging from tumors to neurodegeneration. Ubiquitin-specific protease 21 (USP21) is a member of the ubiquitin-specific protease family, the largest subfamily of DUBs. Although USP21 was discovered late and early research progress was slow, numerous studies in the last decade have gradually revealed the importance of USP21 in a wide variety of biological processes. In particular, the pro-carcinogenic effect of USP21 has been well elucidated in the last 2 years. In the present review, we provide a comprehensive overview of the current knowledge on USP21, including its properties, biological functions, pathophysiological roles, and cellular regulation. Limited pharmacological interventions for USP21 have also been introduced, highlighting the importance of developing novel and specific inhibitors targeting USP21.

Genetic parameters for dairy calf and replacement heifer wellness traits and their association with cow longevity and health indicators in Holstein cattle.

High mortality and involuntary culling rates cause great economic losses to the worldwide dairy cattle industry. However, there is low emphasis on wellness traits in replacement animals (dairy calves and replacement heifers) during their development stages in modern dairy cattle breeding programs. Therefore, the main objectives of this study were to estimate genetic parameters of wellness traits in replacement cattle (replacement wellness traits) and obtain their genetic correlations with 12 cow health and longevity traits in the Chinese Holstein population. Seven replacement wellness traits were analyzed, including birth weight, survival from 3 to 60 d (Sur1), survival from 61 to 365 d (Sur2), survival from 366 d to the first calving (Sur3), calf diarrhea, calf pneumonia, and calf serum total protein (STP). Single and bivariate animal models were employed to estimate (co)variance components using the data from 189,980 Holstein cattle. The genetic correlations between replacement wellness traits and cow longevity, health traits were calculated by employing bivariate models, including 6 longevity traits and 6 health traits (clinical mastitis, metritis, ketosis, displaced abomasum, milk fever, and hoof health or hoof disease). The estimated heritabilities (± SE) were 0.335 (± 0.008), 0.088 (± 0.005), 0.166 (± 0.006), 0.102 (±0 .006), 0.048 (± 0.003), 0.063 (± 0.004), and 0.170 (± 0.019) for birth weight, Sur1, Sur2, Sur3, pneumonia, diarrhea, and STP, respectively. The majority of the genetic correlations among the 7 replacement wellness traits were negligible. The genetic correlations among Sur1, Sur2, and Sur3 ranged from 0.112 (Sur1 and Sur3) to 0.445 (Sur1 and Sur2) when fitting a linear model (estimates in the observed scale), and from 0.560 (Sur1 and Sur3) to 0.773 (Sur1 and Sur2) when fitting a threshold model (estimates in the liability scale). The genetic correlations between replacement wellness and cow longevity were low (absolute value lower than 0.30), but some of them were significantly different from zero. Compared with other replacement wellness traits, Sur3 and STP had relatively high genetic correlations with cow longevity. Replacement wellness traits are heritable and can be improved through direct genetic and genomic selection. The results from the current study will contribute for better balancing dairy cattle breeding goals to genetically improve dairy cattle wellness in the period from birth to first calving.

The Emerging Potential of Parthenolide Nanoformulations in Tumor Therapy.

Plant-derived sesquiterpene lactones are promising natural sources for the discovery of anti-cancer drugs. As an extensively studied sesquiterpene lactone, the tumor suppression effect of parthenolide (PTL) has been clarified by targeting a number of prominent signaling pathways and key protein regulators in carcinogenesis. Notably, PTL was also the first small molecule reported to eradicate cancer stem cells. Nevertheless, the clinical application of PTL as an antitumor agent remains limited, owing to some disadvantages such as low water solubility and poor bioavailability. Thus, nanomedicine has attracted much interest because of its great potential for transporting poorly soluble drugs to desired body sites. In view of the significant advantages over their free small-molecule counterparts, nanoparticle delivery systems appear to be a potential solution for addressing the delivery of hydrophobic drugs, including PTL. In this review, we summarized the key anticancer mechanisms underlined by PTL as well as engineered PTL nanoparticles synthesized to date. Therefore, PTL nanoformulations could be an alternative strategy to maximize the therapeutic value of PTL.

[Application of RUNX2 gene over expression vector modified exosomes from BMSC combined with calcium carbonate scaffold system in bone defect].

OBJECTIVE: To investigate the effect of RUNX2 gene overexpression vector modified exosomes derived from bone marrow mesenchymal stem cells (BMSCs) combined with calcium carbonate scaffold system in bone defect. METHODS: Rabbit BMSCs were used as the research object, and BMSCs were identified by flow cytometry. Construct RUNX2 gene overexpression vector, transfect BMSCs with lentivirus, and collect exosomes by ultracentrifugation. The morphology of exosomes was observed by transmission electron microscope, the expression of exosome marker CD63 was detected by Western blot, and the calcium carbonate scaffold was constructed by three chamber parallel automatic temperature control reaction system. According to whether the RUNX2 gene overexpression vector was transfected or not, the complex of BMSCs and calcium carbonate scaffold was divided into three groups, namely BMSCs group, RUNX2 overexpression group and exosome group. The osteogenic differentiation of BMSCs was detected by oil red O staining and RT-PCR. There were 9 clean adult healthy male New Zealand white rabbits, aged (12.97±1.21) months, with a body weight of (19.3±3.6) kg, with 3 rabbits in each group. The animal model of skull defect was constructed by surgical method, and the repair of bone defect was evaluated by imaging, he staining and Masson staining. RESULTS: The results of flow cytometry showed that the expression of CD29 protein, CD44 protein, CD11b protein and CD45 protein on the surface of BMSCs were 99.5%, 100%, 0.1% and 0.1%, respectively. Transmission electron microscopy showed that the exosomes were bilayer vesicles with a diameter of 50 to 150 nm. Western blot showed that the molecular marker CD63 of exosomes was positive. Oil red O staining showed that the osteogenic differentiation of BMSCs in exosome group was significantly higher than that in RUNX2 overexpression group and BMSCs group. The results of RT-PCR showed that the relative expressions of RUNX2, BMP-2 and ALP mRNA in BMSCs in exosome group were significantly higher than those in RUNX2 overexpression group and BMSCs group (P<0.05). The imaging results showed that the repair effect of skull defect in exosome group was better than that in RUNX2 overexpression group. HE staining and Masson staining showed that the repair effect of skull defect in exosome group was better than that in RUNX2 overexpression group (P<0.05). MSCs in exosome group was significantly higher than that in RUNX2 overexpression group and BMSCs group. The results of RT-PCR showed that the relative expressions of RUNX2, BMP-2 and ALP mRNA in BMSCs in exosome group were significantly higher than those in RUNX2 overexpression group and BMSCs group(P<0.05). The imaging results showed that the repair effect of skull defect in exosome group was better than that in RUNX2 overexpression group. HE staining and Masson staining showed that the repair effect of skull defect in exosome group was better than that in RUNX2 overexpression group(P<0.05). CONCLUSION: Compared with RUNX2 gene overexpression vector transfection, extraction of exosomes directly can promote the differentiation of BMSCs into osteoblasts more efficiently, and the combination with calcium carbonate scaffold can better promote the healing of bone defects. So as to provide new ideas and methods for the clinical treatment of bone defects.