Discovery of MT-1207: A Novel, Potent Multitarget Inhibitor as a Promising Clinical Candidate for the Treatment of Hypertension.

Herein, a series of novel arylpiperazine (piperidine) derivatives were designed, synthesized, and evaluated for mechanisms of action through in vitro and in vivo studies. The most promising compound, II-13 (later named as MT-1207), is a potent α1 and 5-HT2A receptor antagonist with remarkable IC50 in the picomolar level. Importantly, in the in vivo assay, II-13 achieved an effective blood pressure (BP) reduction in the 2K2C rat model without damaging renal function. Compound II-13, with its significant advantages in terms of pharmacological effects, pharmacokinetic parameters, and a large safety window, was extensively investigated. Moreover, data also showed that compound II-13 had fewer side effects in a postural BP assay and could prevent the onset of postural hypotension. Together, these results suggested that compound II-13 is a highly potent antihypertensive drug candidate with multitarget mechanisms of action in preclinical models. Currently, MT-1207 is in phase II hypertensive clinical trials in China.

Impact of urban space on PM2.5 distribution: A multiscale and seasonal study in the Yangtze River Delta urban agglomeration.

Despite concerted efforts in emission control, air pollution control remains challenging. Urban planning has emerged as a crucial strategy for mitigating PM2.5 pollution. What remains unclear is the impact of urban form and their interactions with seasonal changes. In this study, base on the air quality monitoring stations in the Yangtze River Delta urban agglomeration, the relationship between urban spatial indicators (building morphology and land use) and PM2.5 concentrations was investigated using full subset regression and variance partitioning analysis, and seasonal differences were further analysed. Our findings reveal that PM2.5 pollution exhibits different sensitivities to spatial scales, with higher sensitivity to the local microclimate formed by the three-dimensional structure of buildings at the local scale, while land use exerts greater influence at larger scales. Specifically, land use indicators contributed sustantially more to the PM2.5 prediction model as buffer zone expand (from an average of 2.41% at 100 m range to 47.30% at 5000 m range), whereas building morphology indicators display an inverse trend (from an average of 13.84% at 100 m range to 1.88% at 5000 m range). These results enderscore the importance of considering building morphology in local-scale urban planning, where the increasing building height can significantly enhance the disperion of PM2.5 pollution. Conversely, large-scale urban planning should prioritize the mixed use of green spaces and construction lands to mitigate PM2.5 pollution. Moreover, the significant seasonal differences in the ralationship between urban spatical indicatiors and PM2.5 pollution were observed. Particularly moteworthy is the heightened association between forest, water indicators and PM2.5 concentrations in summer, indicating the urban forests may facilitate the formation of volatile compunds, exacerbating the PM2.5 pollution. Our study provides a theoretical basis for addressing scale-related challenges in urban spatial planning, thereby forstering the sustainable development of cities.

Discovery of novel ß-elemene hybrids with hydrogen sulfide-releasing moiety possessing cardiovascular protective activity for the treatment of atherosclerosis.

Herein, a series of novel ß-elemene hybrids with different types of hydrogen sulfide (H2S) donors was designed and synthesized for the first time. In addition, all compounds were tested for H2S release in phosphate buffer solution assay, among which the derivatives with 5-p-hydroxyphenyl-3H-1,2-dithiole-3-thione (ADT-OH) as the H2S donor released the best level. The results of the isolated vasodilation assay revealed that all the compounds exhibited a degree of vasodilatory effect, and the representative compound "ß-elemene-H2S gas donor" hybrid L13-2h produced more than 50% vasodilatory activity at a concentration of 20 µM. Furthermore, L13-2h possessed good concentration dependence and significantly better vasodilatory activity than the lead compound L13. In the RAW 264.7 cellular lipid inhibition against oxidized low-density lipoprotein (ox-LDL) stimulation assay, eight compounds, including L13-2g and L13-2h, produced significant cellular lipid-lowering activity. The results of the further antioxidant activity study showed that the representative compounds L13-2g and L13-2h improved H2O2-induced oxidative damage in HUVEC cells and compound L13-2h exhibited excellent antioxidant damage protection activity compared to the positive control. Moreover, none of the target compounds appeared to be significantly cytotoxic at the tested concentrations. These results suggest that the hybridization of hydrogen sulfide donors with ß-elemene provides a promising approach for the discovery of novel anti-atherosclerotic drugs from natural products.

Long­term survival of a patient with advanced lung cancer treated with targeted therapy and anti­PD­1 immunotherapy as multi­line therapy: A case report.

Lung cancer is the most common type of cancer worldwide. Lung adenocarcinoma, a type of non-small cell lung cancer (NSCLC), is a common type of lung cancer. In recent years, immunotherapy has become the primary method of treatment for several solid cancers, including NSCLC. In the present study, the case of a patient with NSCLC following left superior lobectomy is reported. Different systemic therapies failed, such as a pemetrexed + carboplatin regimen, paclitaxel liposome + cisplatin and pembrolizumab, and albumin-bound paclitaxel + toripalimab, but long-term survival was achieved following targeted therapy and anti-programmed cell death protein-1 (PD-1) immunotherapy. The patient survived for >4 years following lung cancer progression, which is notably longer than expected for patients with advanced lung cancer. In conclusion, the present case demonstrated the efficacy of targeted therapy and anti-PD-1 immunotherapy for the treatment of advanced lung cancer following the occurrence of drug resistance and progressive disease.

Research progress on the biological basis of Traditional Chinese Medicine syndromes of gastrointestinal cancers.

Gastrointestinal cancers account for 11.6 % of all cancers, and are the second most frequently diagnosed type of cancer worldwide. Traditional Chinese medicine (TCM), together with Western medicine or alone, has unique advantages for the prevention and treatment of cancers, including gastrointestinal cancers. Syndrome differentiation and treatment are basic characteristics of the theoretical system of TCM. TCM syndromes are the result of the differentiation of the syndrome and the basis of treatment. Genomics, transcriptomics, proteomics, metabolomics, intestinal microbiota, and serology, generated around the central law, are used to study the biological basis of TCM syndromes in gastrointestinal cancers. This review summarizes current research on the biological basis of TCM syndrome in gastrointestinal cancers and provides useful references for future research on TCM syndrome in gastrointestinal cancers.

Design, synthesis and biological evaluation of novel dihydroquinolin-4(1H)-one derivatives as novel tubulin polymerization inhibitors.

A series of novel dihydroquinolin-4(1H)-one derivatives targeting colchicine binding site on tubulin were designed, synthesized and evaluated as anticancer agents. The most potent compound 6t showed remarkable antiproliferative activities against four cancer cell lines with IC50 values among 0.003-0.024 µM and tubulin polymerization inhibitory activity (IC50 = 3.06 µM). Further mechanism studies revealed that compound 6t could induce K562 cells apoptosis and arrest at the G2/M phase. Meanwhile, 6t significantly inhibited migration and invasion of MDA-MB-231 cells, and disrupted the angiogenesis in human umbilical vein endothelial cells (HUVECs) in vitro. In addition, compound 6t inhibited tumor growth in H22 allograft tumor model with a tumor growth inhibition (TGI) rate of 63.3 % (i.v., 20 mg/kg per day) without obvious toxicity. Collectively, these results indicated that compound 6t was a novel tubulin polymerization inhibitor with potent anticancer properties in vitro and in vivo.

Synthesis and bioevaluation of novel stilbene-based derivatives as tubulin/HDAC dual-target inhibitors with potent antitumor activities in vitro and in vivo.

A series of novel stilbene-based derivatives were designed and synthesized as tubulin/HDAC dual-target inhibitors. Among forty-three target compounds, compound II-19k not only exhibited considerable antiproliferative activity in the hematological cell line K562 with IC50 value of 0.003 µM, but also effectively inhibited the growth of various solid tumor cell lines with IC50 values ranging from 0.005 to 0.036 µM. The mechanism studies demonstrated that II-19k could inhibit microtubules and HDACs at the cellular level, block cell cycle arrest at G2 phase, induce cell apoptosis, and reduce solid tumor cells metastasis. What's more, the vascular disrupting effects of compound II-19k were more pronounced than the combined administration of parent compound 8 and HDAC inhibitor SAHA. The in vivo antitumor assay of II-19k also showed the superiority of dual-target inhibition of tubulin and HDAC. II-19k significantly suppressed the tumor volume and effectively reduced tumor weight by 73.12% without apparent toxicity. Overall, the promising bioactivities of II-19k make it valuable for further development as an antitumor agent.

Bicyclic Amidine-Triggered Cyclization of o-Alkynylisocyanobenzenes: Synthesis of Lactam-Derived Quinolines.

Efficient access to the synthesis of lactam-derived quinoline through a bicyclic amidine-triggered cyclization reaction from readily prepared o-alkynylisocyanobenzenes has been developed. The reaction was initiated by nucleophilic attack of the bicyclic amidines to o-alkynylisocyanobenzenes, subsequently with intramolecular cyclization to produce a DBU-quinoline-based amidinium salt, followed by hydrolysis to afford the lactam-derived quinoline in moderate to good yields.

Case report: Double filtration plasmapheresis (DFPP) for severe rhesus-D alloimmunization in two pregnant patients.

Maternal erythrocyte alloimmunization is one of the most important causes of fetal anemia. The standard treatment for anemic fetuses is intrauterine blood transfusion (IUT). However, IUT may have adverse effects, particularly before 20 weeks of gestation. In this report, two women who had previously had severely affected alloimmunized pregnancy developed high titers of anti-D antibodies before 20 weeks of gestation. Ultrasound Doppler showed severe fetal anemia, and intrauterine transfusion was expected to be unavoidable. To prolong pregnancy to a gestation in which intravascular IUT was possible, we used repeated double filtration plasmapheresis (DFPP) as a rescue therapy. The titers of IgG-D, IgG-A, and IgG-B decreased after DFPP treatment. One woman successfully prolonged pregnancy until 20 weeks of gestation. Subsequently, she underwent four cycles of IUTs and delivered at 30 weeks of gestation by emergency cesarean section due to fetal bradycardia during the fifth intrauterine transfusion. The other woman successfully delayed intrauterine transfusion until 26 weeks of gestation. The favorable results of the two patients indicate that DFPP may be an effective and safe treatment modality for RhD immunity in pregnant women. Moreover, DFPP is potentially helpful for reducing the occurrence of ABO hemolytic disease in neonates due to the clearance of IgG-A and IgG-B antibodies (e.g., O pregnant women harbored A/B/AB neonates). However, more clinical trials are needed to verify the results.

Discovery of a Novel Vascular Disrupting Agent Inhibiting Tubulin Polymerization and HDACs with Potent Antitumor Effects.

Most vascular disrupting agents (VDAs) fail to prevent the regrowth of blood vessels at the edge of tumors, causing tumor rebound and relapse. Herein, a series of novel multifunctional vascular disrupting agents (VDAs) capable of inhibiting microtubule polymerization and histone deacetylases (HDACs) were designed and synthesized using the tubulin polymerization inhibitor TH-0 as the lead compound. Among them, compound TH-6 exhibited the most potent antiproliferative activity (IC50 = 18-30 nM) against a panel of cancer cell lines. As expected, TH-6 inhibited tubulin assembly and increased the acetylation level of HDAC substrate proteins in HepG2 cells. Further in vivo antitumor assay displayed that TH-6 effectively inhibited tumor growth with no apparent toxicity. More importantly, TH-6 disrupted both the internal and peripheral tumor vasculatures, which contributed to the persistent tumor inhibitory effects after drug withdrawal. Altogether, TH-6 deserves to be further investigated for the new approach to clinical cancer therapy.

Design and synthesis of NAD(P)H: Quinone oxidoreductase (NQO1)-activated prodrugs of 23-hydroxybetulinic acid with enhanced antitumor properties.

A series of NQO1 selectively activated prodrugs were designed and synthesized by introducing indolequinone moiety to the C-3, C-23 or C-28 position of 23-hydroxybetulinic acid (23-HBA) and its analogues. Among them, the representative compound 32j exhibited significant antiproliferative activities against NQO1-overexpressing HT-29 cells and A549 cells, with IC50 values of 1.87 and 2.36 µM, respectively, which were 20-30-fold more potent than those of parent compound 23-HBA. More importantly, it was demonstrated in the in vivo antitumor experiment that 32j effectively suppressed the tumor volume and largely reduced tumor weight by 72.69% with no apparent toxicity, which was more potent than the positive control 5-fluorouracil. This is the first breakthrough in the improvement of in vivo antitumor activities of 23-HBA derivatives. The further molecular mechanism study revealed that 32j blocked cell cycle arrest at G2/M phase, induced cell apoptosis, depolarized mitochondria and elevated the intracellular ROS levels in a dose-dependent manner. Western blot analysis indicated that 32j induced cell apoptosis by interfering with the expression of apoptosis-related proteins. These findings suggest that compound 32j could be considered as a potent antitumor prodrug candidate which deserves to be further investigated for personalized cancer therapy.

Lipid Perfluorohexane Nanoemulsion Hybrid for MRI-Guided High-Intensity Focused Ultrasound Therapy of Tumors.

Magnetic resonance imaging-guided high-intensity focused ultrasound (MRI-guided HIFU) is a non-invasive strategy of diagnosis and treatment that is applicable in tumor ablation. Here, we prepared a multifunctional nanotheranostic agent (SSPN) by loading perfluorohexane (PFH) and superparamagnetic iron oxides (SPIOs) in silica lipid for MRI-guided HIFU ablation of tumors. PFH was introduced to improve the ablation effect of HIFU and the ultrasound (US) contrast performance. Due to its liquid-to-gas transition characteristic, it is sensitive to temperature. SPIOs were used as an MRI contrast agent. Silica lipid was selected because it is a more stable carrier material compared with normal lipid. Previous studies have shown that SSPNs have good biocompatibility, stability, imaging, and therapeutic effects. Therefore, this system is expected to develop an important therapeutic agent for MRI-guided HIFU therapy against tumors.

Sex-differences in the management and clinical outcome among patients with acute coronary syndrome.

BACKGROUND: The current study was to compare the management and clinical outcome between women and men with acute coronary syndrome (ACS). METHOD: This was a retrospective study. Patients with ACS presented to the emergency department were enrolled. Management and clinical outcomes (including mortality and acute decompensated heart failure [ADHF]) were compared between women and men. RESULTS: A total of 686 patients were included and women accounted for 38.5% (n = 264). Women were less likely to receive ticagrelor at the emergency department (18.2% vs 25.1%). Duration from arrival at the emergency department to undergo electrocardiogram was longer in women (7.5 min vs 5.3 min). The duration from symptom onset to undergo percutaneous coronary intervention was longer in women (14.4 h vs 7.2 h). After adjusting for covariates, odds ratio (OR) for cardiovascular mortality was 0.42 (95% confidence interval [CI] 0.37-1.02) and ADHF was 0.63 (95% CI 0.55-1.01) for women vs men. Socioeconomic status, duration from symptom onset to arrive at the emergency department, and management at the emergency department were the important factors contributing to the sex-differences in clinical outcome. CONCLUSION: Among ACS patients undergoing PCI, there was no sex-difference in in-hospital clinical outcome after adjusting for covariates. Future studies are needed to evaluate whether improving management at the emergency department can improve clinical outcomes in women and men with ACS.

Polymer-assisted synthesis and applications of hydroxyapatite (HAp) anchored nitrogen-doped 3D graphene foam-based nanostructured ceramic framework.

In the present work, a hydroxyapatite anchored nitrogen-doped three-dimensional graphene (HAp-N3DG) skeletal network (foam) based nanostructured ceramic framework (CF) was developed through a polymer-assisted solvothermal route. Field emission scanning electron microscopy (FESEM) and transmission electron microscopy (TEM) studies reveal that the nano sized 0D HAp particles are anchored on the N3DG skeletal network with an average size of less than 50 nm. EDX and X-ray photoelectron spectroscopy (XPS) analysis confirmed the presence of Ca, P, O, N, and C. In addition, XPS analysis reveals the existence of N-C bonds in the prepared sample. The X-ray diffraction (XRD) patterns indicate the presence of hexagonal phase hydroxyapatite and the calculated average crystallite size was found to be 12 nm. The developed HAp-N3DG foam based nanostructured CF was found to have a mesoporous structure and the measured specific surface area (SSA) and the mean pore diameter were found to be 64.73 m2 g-1 and 23.6 nm, respectively. Electrochemical analysis shows that HAp anchored on nitrogen-doped 3D graphene foam based nanostructured CF has moderate electrochemical activity towards lithium ion charge/discharge. In addition, the prepared material showed adsorption activity values of 204.89 mg g-1 and 243.89 mg g-1 for the volatile organic compounds (VOCs) benzene and toluene, respectively. The present findings suggest that the newly developed HAp anchored nitrogen-doped 3DG (HAp-N3DG) skeletal network (foam) based nanostructured CF material can be used in energy devices and in the removal of volatile organic compounds. Moreover, the present study initiates a new kind of approach in energy device (lithium ion battery-LIB) research and in the removal of VOCs.

Porous carbon derived from metal-organic framework@graphene quantum dots as electrode materials for supercapacitors and lithium-ion batteries.

The C@GQD composite was prepared by the combination of metal-organic framework (ZIF-8)-derived porous carbon and graphene quantum dots (GQDs) by a simple method. The resulting composite has a high specific surface area of 668 m2 g-1 and involves numerous micro- and mesopores. As a supercapacitor electrode, the material showed an excellent double-layer capacitance and a high capacity retention of 130 F g-1 at 2 A g-1. The excellent long-term stability was observed even after ∼10 000 charge-discharge cycles. Moreover, the composite as an anode material for a lithium-ion battery exhibited a good reversible capacity and outstanding cycle stability (493 mA h g-1 at 100 mA g-1 after 200 cycles). The synergistic effect of a MOF-derived porous carbon and GQDs was responsible for the improvement of electrochemical properties.

Cloud-Assisted UAV Data Collection for Multiple Emerging Events in Distributed WSNs.

In recent years, UAVs (Unmanned Aerial Vehicles) have been widely applied for data collection and image capture. Specifically, UAVs have been integrated with wireless sensor networks (WSNs) to create data collection platforms with high flexibility. However, most studies in this domain focus on system architecture and UAVs' flight trajectory planning while event-related factors and other important issues are neglected. To address these challenges, we propose a cloud-assisted data gathering strategy for UAV-based WSN in the light of emerging events. We also provide a cloud-assisted approach for deriving UAV's optimal flying and data acquisition sequence of a WSN cluster. We validate our approach through simulations and experiments. It has been proved that our methodology outperforms conventional approaches in terms of flying time, energy consumption, and integrity of data acquisition. We also conducted a real-world experiment using a UAV to collect data wirelessly from multiple clusters of sensor nodes for monitoring an emerging event, which are deployed in a farm. Compared against the traditional method, this proposed approach requires less than half the flying time and achieves almost perfect data integrity.

Stable cerasomes for simultaneous drug delivery and magnetic resonance imaging.

Magnetic liposomes have been frequently used as nanocarriers for targeted drug delivery and magnetic resonance imaging in recent years. Despite great potentials, their morphological/structural instability in the physiological environment still remains an intractable challenge for clinical applications. In this study, stable hybrid liposomal cerasomes (ie, liposomes partially coated with silica) which can co-encapsulate Fe3O4 nanoparticles and the anticancer drug paclitaxel were developed using thin film hydration method. Compared with the drug loaded liposomes, the paclitaxel-loaded magnetic cerasomes (PLMCs) exhibited much higher storage stability and better sustained release behavior. Cellular uptake study showed that the utilization of an external magnetic field significantly facilitated the internalization of PLMCs into cancer cells, resulting in potentiated drug efficacy of killing tumor cells. The T2 relaxivity (r2) of our PLMCs was much higher than that of free Fe3O4 nanoparticles, suggesting increased sensitivity in T2-weighted imaging. Given its excellent biocompatibility also shown in the study, such dual functional PLMC is potentially a promising nanosystem for effective cancer diagnosis and therapy.

Highly uniform and stable cerasomal microcapsule with good biocompatibility for drug delivery.

Efforts to improve the stability of liposomes have recently led to the development of organic-inorganic liposomal cerasomes. However, the uncontrollable size of cerasomes has greatly limited their biomedical applications. In this study, a novel strategy was introduced to fabricate hybrid liposomal cerasomes with high stability and uniform size. The hybrid lipids were first deposited onto CaCO3 microspheres through electrostatic interactions and self-assembly, and then the CaCO3 core was removed to obtain hollow microcapsules, i.e. the cerasomes. The species of the lipid oligomers was detected by MALDI-TOF-MS, which demonstrates the existence of siloxane network on microcapsules' surface. Anticancer drug doxorubicin hydrochloride (DOX) loaded cerasomal microcapsule (DLCM) exhibited an initial burst release behavior followed by the sustained release and remarkably high stability towards surfactant solubilization and long term storage. The DLCM displayed a pH-dependent and sustained DOX release profile in vitro, which can be well explained using a well established mathematical model. Our results indicate that these novel cerasomal microcapsules have great potential to be applied as drug delivery system in cancer therapy.