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1.
Anal Chem ; 96(22): 9069-9077, 2024 Jun 04.
Article in English | MEDLINE | ID: mdl-38749062

ABSTRACT

Solid contact (SC) calcium ion-selective electrodes (Ca2+-ISEs) have been widely applied in the analysis of water quality and body fluids by virtue of the unique advantages of easy operation and rapid response. However, the potential drift during the long-term stability test hinders their further practical applications. Designing novel redox SC layers with large capacitance and high hydrophobicity is a promising approach to stabilize the potential stability, meanwhile, exploring the transduction mechanism is also of great guiding significance for the precise design of SC layer materials. Herein, flower-like copper sulfide (CunS-50) composed of nanosheets is meticulously designed as the redox SC layer by modification with the surfactant (CTAB). The CunS-50-based Ca2+-ISE (CunS-50/Ca2+-ISE) demonstrates a near-Nernstian slope of 28.23 mV/dec for Ca2+ in a wide activity linear range of 10-7 to 10-1 M, with a low detection limit of 3.16 × 10-8 M. CunS-50/Ca2+-ISE possesses an extremely low potential drift of only 1.23 ± 0.13 µV/h in the long-term potential stability test. Notably, X-ray absorption fine-structure (XAFS) spectra and electrochemical experiments are adopted to elucidate the transduction mechanism that the lipophilic anion (TFPB-) participates in the redox reaction of CunS-50 at the solid-solid interface of ion-selective membrane (ISM) and redox inorganic SC layer (CunS-50), thereby promoting the generation of free electrons to accelerate ion-electron transduction. This work provides an in-depth comprehension of the transduction mechanism of the potentiometric response and an effective strategy for designing redox materials of ion-electron transduction triggered by lipophilic anions.

2.
Sensors (Basel) ; 24(10)2024 May 19.
Article in English | MEDLINE | ID: mdl-38794077

ABSTRACT

Sensors are a key component in industrial automation systems. A fault or malfunction in sensors may degrade control system performance. An engineering system model is usually disturbed by input uncertainties, which brings a challenge for monitoring, diagnosis, and control. In this study, a novel estimation technique, called adaptive unknown-input observer, is proposed to simultaneously reconstruct sensor faults as well as system states. Specifically, the unknown input observer is used to decouple partial disturbances, the un-decoupled disturbances are attenuated by the optimization using linear matrix inequalities, and the adaptive technique is explored to track sensor faults. As a result, a robust reconstruction of the sensor fault as well as system states is then achieved. Furthermore, the proposed robustly adaptive fault reconstruction technique is extended to Lipschitz nonlinear systems subjected to sensor faults and unknown input uncertainties. Finally, the effectiveness of the algorithms is demonstrated using an aircraft system model and robotic arm and comparison studies.

3.
Anal Chim Acta ; 1306: 342612, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38692793

ABSTRACT

Despite the widespread utilization of variable valence metals in electrochemistry, it is still a formidable challenge to enhance the valence conversion efficiency to achieve excellent catalytic activity without introducing heterophase elements. Herein, the in-situ precipitation of Co particles on Co2VO4 not only enhanced the concentration of oxygen vacancies (Ov) but also generated a greater number of low-valence metals, thereby enabling efficient reduction towards Hg(II). The electroanalysis results demonstrate that the sensitivity of Co/Co2VO4 towards Hg(II) was measured at an impressive value of 1987.74 µA µM-1 cm-2, significantly surpassing previously reported results. Further research reveals that Ov acted as the main adsorption site to capture Hg(II). The redox reactions of Co2+/Co3+ and V3+/V4+ played a synergistic role in the reduction of Hg(II), accompanied by the continuous supply of electrons from zero-valent Co to expedite the valence cycle. The Co/Co2VO4/GCE presented remarkable selectivity towards Hg(II), with excellent stability, reproducibility, and anti-interference capability. The electrode also exhibited minimal sensitivity fluctuations towards Hg(II) in real water samples, underscoring its practicality for environmental applications. This study elucidates the mechanism underlying the surface redox reaction of metal oxides facilitated by zero-valent metals, providing us with new strategies for further design of efficient and practical sensors.

4.
Anal Chem ; 96(13): 5232-5241, 2024 Apr 02.
Article in English | MEDLINE | ID: mdl-38447030

ABSTRACT

Although utilizing nanomaterial-modified electrodes for lead ion detection has achieved great success, most of them are carried out under acidic conditions and ignore the variation of Pb(II) speciation at different pH conditions, leading to the potential inaccuracy of Pb(II) detection in a neutral natural water environment. Thus, designing a novel catalyst with high accuracy for the detection of various forms of the total amount of Pb(II) (Pb2+ and Pb(OH)+) in neutral waters is significant. Herein, Pt nanoclusters (Pt NCs) were elaborately constructed and stabilized on the Co single-atom-doped g-C3N4 with abundant N vacancies (Pt NCs/VN-C3N4), which achieved the ultrasensitive detection (102.16 µM µA-1) of Pb(II) in neutral conditions. The dynamic simulation and theoretical calculations reveal that the parallel deposition of Pb2+ and Pb(OH)+ occurs on the electrode surface modified by Pt NCs/VN-C3N4, and the current peaks of Pb(II) are cocontributed by Pb2+ and Pb(OH)+ species. An "electron inverse" phenomenon in Pt NCs/VN-C3N4 from the VN-C3N4 substrate to Pt NCs endows Pt NCs in an electron-rich state, serving as active centers to promote rapid and efficient reduction for both Pb2+ and Pb(OH)+, facilitating the accurate detection of the total amount of Pb(II) in all forms in the actual water environment.

5.
Sensors (Basel) ; 23(18)2023 Sep 07.
Article in English | MEDLINE | ID: mdl-37765794

ABSTRACT

In recent years, electric vehicles powered by lithium-ion batteries have developed rapidly, and the safety and reliability of lithium-ion batteries have been a paramount issue. Battery management systems are highly dependent on sensor measurements to ensure the proper functioning of lithium-ion batteries. Therefore, it is imperative to develop a suitable fault diagnosis scheme for battery sensors, to realize a diagnosis at an early stage. The main objective of this paper is to establish validated electrical and thermal models for batteries, and address a model-based fault diagnosis scheme for battery sensors. Descriptor proportional and derivate observer systems are applied for sensor diagnosis, based on electrical and thermal models of lithium-ion batteries, which can realize the real-time estimation of voltage sensor fault, current sensor fault, and temperature sensor fault. To verify the estimation effect of the proposed scheme, various types of faults are utilized for simulation experiments. Battery experimental data are used for battery modeling and observer-based fault diagnosis in battery sensors.

6.
Chem Sci ; 14(11): 2960-2970, 2023 Mar 15.
Article in English | MEDLINE | ID: mdl-36937602

ABSTRACT

Although the enhanced intrinsic activities of some nano-metal oxides are obtained by manufacturing oxygen vacancies (OVs), the effect of multiple roles of OVs is ambiguous. Herein, an interface catalytic regulation via electron rearrangement and hydroxyl radicals (˙OH) was proposed with the designed ZrO2 hollow sphere rich in OVs (Vo-rich ZrO2). Surprisingly, it was shown that the catalytic ability of Vo-rich ZrO2 was 9.9 times higher than that of ZrO2 with little OVs in electrochemical catalytic reduction of Pb(ii). It was found that the generation of Zr2+ and Zr3+ caused by OVs results in the rearrangement of abundant free electrons to facilitate the catalytic reaction rates. The longer bond length between Vo-rich ZrO2 and reactants, and the lower adsorption energy are beneficial for reactants to desorb, improving the conversion rates. Besides, the produced ˙OH were captured which were induced by OVs and trace divalent heavy metal ions in in situ electron paramagnetic resonance (EPR) experiments, contributing to lowering the energy barriers. This study not only revealed the enhanced interface catalytic effect of electron rearrangement and generated ˙OH triggered by OVs, but also provided unique insights into interface catalytic regulation on nano-metal oxides simulated by OVs.

7.
Anal Chem ; 95(7): 3666-3674, 2023 Feb 21.
Article in English | MEDLINE | ID: mdl-36656141

ABSTRACT

Traditional nanomodified electrodes have made great achievements in electrochemical stripping voltammetry of sensing materials for As(III) detection. Moreover, the intermediate states are complicated to probe because of the ultrashort lifetime and complex reaction conditions of the electron transfer process in electroanalysis, which seriously hinder the identification of the actual active site. Herein, the intrinsic interaction of highly sensitive analytical behavior of nanomaterials is elucidated from the perspective of electronic structure through density functional theory (DFT) and gradient boosting regression (GBR). It is revealed that the atomic radius, d-band center (εd), and the largest coordinative TM-N bond length play a crucial role in regulating the arsenic reduction reaction (ARR) performance by the established ARR process for 27 sets of transition-metal single atoms supported on N-doped graphene. Furthermore, the database composed of filtered intrinsic electronic structural properties and the calculated descriptors of the central metal atom in TM-N4-Gra were also successfully extended to oxygen evolution reaction (OER) systems, which effectively verified the reliability of the whole approach. Generally, a multistep workflow is developed through GBR models combined with DFT for valid screening of sensing materials, which will effectively upgrade the traditional trial-and-error mode for electrochemical interface designing.

9.
Acta Pharmacol Sin ; 43(4): 1091-1099, 2022 Apr.
Article in English | MEDLINE | ID: mdl-34341512

ABSTRACT

HDAC inhibitors (HDACis) have been intensively studied for their roles and potential as drug targets in T-cell lymphomas and other hematologic malignancies. Bisthianostat is a novel bisthiazole-based pan-HDACi evolved from natural HDACi largazole. Here, we report the preclinical study of bisthianostat alone and in combination with bortezomib in the treatment of multiple myeloma (MM), as well as preliminary first-in-human findings from an ongoing phase 1a study. Bisthianostat dose dependently induced acetylation of tubulin and H3 and increased PARP cleavage and apoptosis in RPMI-8226 cells. In RPMI-8226 and MM.1S cell xenograft mouse models, oral administration of bisthianostat (50, 75, 100 mg·kg-1·d-1, bid) for 18 days dose dependently inhibited tumor growth. Furthermore, bisthianostat in combination with bortezomib displayed synergistic antitumor effect against RPMI-8226 and MM.1S cell in vitro and in vivo. Preclinical pharmacokinetic study showed bisthianostat was quickly absorbed with moderate oral bioavailability (F% = 16.9%-35.5%). Bisthianostat tended to distribute in blood with Vss value of 0.31 L/kg. This distribution parameter might be beneficial to treat hematologic neoplasms such as MM with few side effects. In an ongoing phase 1a study, bisthianostat treatment was well tolerated and no grade 3/4 nonhematological adverse events (AEs) had occurred together with good pharmacokinetics profiles in eight patients with relapsed or refractory MM (R/R MM). The overall single-agent efficacy was modest, stable disease (SD) was identified in four (50%) patients at the end of first dosing cycle (day 28). These preliminary in-patient results suggest that bisthianostat is a promising HDACi drug with a comparable safety window in R/R MM, supporting for its further phase 1b clinical trial in combination with traditional MM therapies.


Subject(s)
Histone Deacetylase Inhibitors , Multiple Myeloma , Acetylation , Animals , Antineoplastic Combined Chemotherapy Protocols , Bortezomib/therapeutic use , Histone Deacetylase Inhibitors/pharmacokinetics , Histone Deacetylase Inhibitors/therapeutic use , Humans , Hydroxamic Acids/therapeutic use , Mice , Multiple Myeloma/drug therapy , Multiple Myeloma/pathology
10.
Exp Ther Med ; 21(4): 290, 2021 Apr.
Article in English | MEDLINE | ID: mdl-33717233

ABSTRACT

The present study aimed to explore the pathogenesis behind post-traumatic epilepsy (PTE). In the present study, a chloride ferric injection-induced rat PTE model was established. The expression levels of apoptosis-antagonizing transcription factor (AATF), cleaved caspase-3, p53, Bcl-2 and Bax were measured by western blotting or immunofluorescence staining (IF). The expression of AATF in vivo was downregulated by microinjection of lentiviral-mediated short-hairpin RNA. Compared with control and sham groups, at day 5 after PTE, neuron apoptosis was significantly increased and the expression levels of AATF, p53, cleaved caspase-3 and Bax were significantly upregulated. In addition, IF revealed co-localization of AATF and cleaved caspase-3 in the cortex. Additionally, AATF was expressed mainly in neurons and astrocytes. Following AATF inhibition, the expression levels of p53 and cleaved caspase-3 were significantly reduced as compared with the control group. Taken together, these findings suggested that following PTE, AATF is involved in neuronal apoptosis and may serve as a potential target for its alleviation.

11.
Eur J Med Chem ; 209: 112913, 2021 Jan 01.
Article in English | MEDLINE | ID: mdl-33109399

ABSTRACT

In various human cancers, PI3Ks pathway is ubiquitously dysregulated and thus become a promising anti-cancer target. To discover new potent and selective PI3K inhibitors as potential anticancer drugs, new pyrrolo[2,1-f][1,2,4]triazines were designed, leading to the discovery of compound 37 (CYH33), a selective PI3Kα inhibitor (IC50 = 5.9 nM, ß/α, δ/α,γ/α = 101-, 13-, 38-fold). Western blot analysis confirmed that compound 37 could inhibit phosphorylation of AKT in human cancer cells to modulate the cellular PI3K/AKT/mTOR pathway. And further evaluation in vivo against SKOV-3 xenograft models demonstrated that a dose-dependent antitumor efficacy was achieved.


Subject(s)
Angiogenesis Inhibitors/chemical synthesis , Antineoplastic Agents/chemical synthesis , Morpholines/chemical synthesis , Phosphatidylinositol 3-Kinases/metabolism , Phosphoinositide-3 Kinase Inhibitors/chemical synthesis , Piperazines/chemical synthesis , Pyrroles/chemical synthesis , Angiogenesis Inhibitors/pharmacology , Animals , Antineoplastic Agents/pharmacology , Drug Screening Assays, Antitumor , Female , Humans , Mice, Inbred BALB C , Molecular Docking Simulation , Molecular Targeted Therapy , Morpholines/pharmacology , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Phosphorylation/drug effects , Piperazines/pharmacology , Protein Binding , Proto-Oncogene Proteins c-akt/metabolism , Pyrroles/pharmacology , Structure-Activity Relationship , TOR Serine-Threonine Kinases/metabolism
12.
Yi Chuan ; 42(10): 929-948, 2020 Oct 20.
Article in Chinese | MEDLINE | ID: mdl-33229320

ABSTRACT

Knowledge of the origin of eukaryotes is key to broadening our understanding of the eukaryotic genome and the relationship among internal structures within a eukaryotic cell. Since the discovery of archaea in 1977 and the proposal of three-domain tree of life by the American microbiologist Carl Woese, the intimate relationship in evolution between eukaryotes and archaea has been demonstrated by considerable experiments and analyses. From the beginning of the 21st century, with the development of phylogenetic methods and the discovery of new archaeal phyla more related to eukaryotes, increasing evidence has shown that Eukarya and Archaea should be merged into one domain, leading to a two-domain tree of life. Nowadays, the Asgard superphylum discovered via metagenomic analysis is regarded as the closest prokaryotes to eukaryotes. Nevertheless, several key questions are still under debate, such as what the ancestors of the eukaryotes were and when mitochondria emerged. Here, we review the current research progress regarding the changes of the tree of life and the detailed eukaryotic evolutionary mechanism. We show that the recent findings have greatly improved our knowledge on the origin of eukaryotes, which will pave the way for future studies.


Subject(s)
Biological Evolution , Eukaryota , Archaea/classification , Archaea/genetics , Eukaryota/classification , Eukaryota/genetics , Research/trends
13.
Zhongguo Zhong Yao Za Zhi ; 45(15): 3575-3583, 2020 Aug.
Article in Chinese | MEDLINE | ID: mdl-32893546

ABSTRACT

Myricetin and its glycosides are important flavonols commonly found in plants, and they are natural organic compounds with diverse pharmacological activities. Numerous studies have demonstrated that myricetin and its glycosides are strong antioxidants that have great potential in preventing, alleviating and assisting the treatment of chronic non-infectious diseases such as cancer, diabetes, and cardiovascular diseases. In addition, myricetin and its glycosides also have antiviral, antibacterial, anti-inflammatory, analgesic, liver protection and other pharmacological activities. Myricetin contains more hydroxyl groups in the parent ring structure than other flavonoids, so myricetin and its glycosides have stronger pharmacological activities than other flavonols or flavonoids such as quercetin and kaempferol. Therefore, myricetin and its glycosides have great development and application prospects. In this paper, the classification and distribution of myricetin and its glycosides, their pharmacological activity and mechanism, as well as comparison with other flavonoids were reviewed. In addition, limitations of the current research and application of myricetin and its glycosides were analyzed, and the further studies on pharmacological activities as well as their dose-activity relationship, structure-activity relationship, chemical modification, biosynthesis and application prospects of myricetin and its glycosides were discussed and proposed.


Subject(s)
Flavonoids , Glycosides , Flavonols , Quercetin
14.
Psychogeriatrics ; 20(4): 501-509, 2020 Jul.
Article in English | MEDLINE | ID: mdl-31976614

ABSTRACT

Even after successful hip arthroplasty, elderly patients who have undergone this procedure remain subject to cognitive decline and may collectively develop postoperative cognitive dysfunction (POCD). However, no consensus exists as to the risk factors resulting in a higher likelihood that a patient may present with this complication, and the aetiology of POCD is not well understood. We conducted a systematic review of papers concerning the influence of POCD-related risk factors in patients undergoing hip arthroplasty but limited the literature search to papers in English. A systematic and electronic search for manuscripts in the PubMed database was performed in order to identify all studies in which the risk factors for POCD were investigated. Articles were also obtained from the authors' files. Keywords for the search were postoperative cognitive dysfunction/change/impairment/decline/deficit, elderly/older/aged patients, and hip arthroplasty/replacement surgery. The evidence published to date suggests that POCD is a multifactorial disease, which includes an individual patient's characteristics, surgery, type of anaesthesia, and pain levels. All of these factors can increase the risk of POCD incidence. There are a number of factors that appear to influence the risk of early cognitive dysfunction after hip arthroplasty. Nevertheless, the specific mechanism and explicit risk factors associated with this cognitive dysfunction are not completely understood. Hip arthroplasty has made it possible for older patients to find relief from pain and improve their function, whereas it also increases the risk for suffering POCD that may affect these patients' quality of life and increase their mortality. Therefore, it is worthwhile investigating the mechanism of POCD in future studies in order to prevent and treat this condition.


Subject(s)
Arthroplasty, Replacement, Hip , Cognitive Dysfunction , Postoperative Complications , Aged , Arthroplasty, Replacement, Hip/adverse effects , Cognitive Dysfunction/epidemiology , Cognitive Dysfunction/etiology , Humans , Incidence , Postoperative Cognitive Complications , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Quality of Life
15.
Front Biosci (Landmark Ed) ; 24(3): 576-596, 2019 01 01.
Article in English | MEDLINE | ID: mdl-30468675

ABSTRACT

The molecular mechanism of how airway inflammation develops is not fully understood. Withaferin A (WA) is a natural phytochemical isolated from the plant Withania somnifera. It is a well-investigated bioactive compound that possesses a variety of health-promoting effects, including anti-inflammatory and anti-oxidative activities. In the present study, the effect of WA on ovalbumin (OVA)-induced airway inflammation in mice was investigated. The results indicated that pre-treatment with WA inhibited OVA-induced lung injury and fibrosis progression in mice. Furthermore, WA significantly downregulated inflammatory cell infiltration into the bronchoalveolar lavage fluid and significantly reduced pro-inflammatory cytokine expression in the lung tissue specimens. Additionally, WA significantly suppressed transforming growth factor-b1 expression in lung tissues. WA also caused the downregulation of collagen I, collagen III, α-smooth muscle actin and tissue inhibitor of metalloproteinase-1, as well as SMADs and extracellular signal related kinase 1/2 inactivation. Notably, WA significantly reduced the activation of the NLRP3 inflammasome. The results indicate that WA may be an effective novel candidate for the treatment of airway inflammation.


Subject(s)
Inflammation/prevention & control , Ovalbumin/toxicity , Respiratory System/drug effects , Withanolides/pharmacology , Animals , Cell Line , Collagen/genetics , Collagen/metabolism , Cytokines/genetics , Cytokines/metabolism , Gene Expression/drug effects , Humans , Inflammasomes/drug effects , Inflammasomes/genetics , Inflammasomes/metabolism , Inflammation/genetics , Inflammation/metabolism , Male , Mice, Inbred C57BL , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Pulmonary Fibrosis/genetics , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/prevention & control , Respiratory System/metabolism , Respiratory System/pathology
16.
Acta Cardiol Sin ; 33(6): 567-577, 2017 Nov.
Article in English | MEDLINE | ID: mdl-29167607

ABSTRACT

BACKGROUND: This study aimed to evaluate the impact of intra-aortic balloon counterpulsation (IABP) on the prognosis of patients with acute myocardial infarction (AMI). METHODS: We identified and included in this study AMI cases treated with IABP from January 1970 to May 2014. For statistical analysis, we utilized RevMan 5.0 software. RESULTS: Fourteen RCTs with a total population of 2538 were included in this study. The in-hospital and 30-day mortality rate in the IABP group was not significantly lower than those in the non-IABP group. Subgroup analysis according to the type of revascularization, OR values of TT subgroup, PCI subgroup, and CABG subgroup were 0.64 (95% CI 0.25-1.61, p = 0.34), 0.85 (95% CI 0.65-1.11, p = 0.23) and 0.46 (95% CI 0.13-1.63, p = 0.23). And OR values of AMI patients in the before and after PCI subgroup were 0.43 (95% CI 0.21-0.91, p = 0.03) and 1.36 (95% CI 0.76-2.41, p = 0.30). The 6-month mortality in the IABP group was not significantly lower than that in the non-IABP group. And OR values of 6-month mortalities of the before and after PCI subgroup were 0.47 (95% CI 0.26-0.86, p = 0.01) and 1.40 (95% CI 0.57-3.45, p = 0.47). CONCLUSIONS: IABP did not reduce the in-hospital and 30-day mortality of AMI patients, and did not reduce the 6-month mortality. But IABP used in AMI patients before PCI was associated not only with reduced in-hospital and 30-day mortality, but also reduced 6-month mortality.

17.
Int J Syst Evol Microbiol ; 67(6): 1943-1948, 2017 Jun.
Article in English | MEDLINE | ID: mdl-28629491

ABSTRACT

A Gram-staining-negative, non-motile, non-spore-forming bacterium designated Y3L14T was isolated from the saline-alkaline soil of a farmland, Inner Mongolia, northern China. Strain Y3L14T could grow at 10-40 °C (optimally at 30 °C), pH 6.0-10.0 (optimally at pH 8.0), and in the presence of 0-6.0 % (w/v) NaCl (optimally with 0-2.0 %). Phylogenetic analysis based on the 16S rRNA gene and DNA gyrase subunit B (gyrB) gene sequences revealed that strain Y3L14T clustered with strains belonging to the genus Sphingobacterium, sharing the highest 16S rRNA gene sequence similarity with Sphingobacterium lactis WCC 4512T (94.99 %). Its major cellular fatty acids contained iso-C15 : 0, C16 : 0, iso-C17 : 0 3-OH and summed feature 3 (iso-C15 : 0 2-OH and/or C16 : 1ω7c). Menaquinone-7 (MK-7) was the only isoprenoid quinone. Strain Y3L14T contained phosphatidylethanolamine, sphingophospholipid, two unknown phospholipids and three unknown lipids as the major polar lipids. The genomic DNA G+C content of strain Y3L14T was 36.0 mol%. Based on the phenotypic, phylogenetic and genotypic characteristics, strain Y3L14T represents a novel species within the genus Sphingobacterium, for which Sphingobacterium alkalisoli sp. nov. is proposed; the type strain is Y3L14T (=CGMCC 1.15782T=KCTC 52379T).


Subject(s)
Alkalies , Phylogeny , Salinity , Soil Microbiology , Sphingobacterium/classification , Bacterial Typing Techniques , Base Composition , China , DNA, Bacterial/genetics , Fatty Acids/chemistry , Hydrogen-Ion Concentration , Phospholipids/chemistry , RNA, Ribosomal, 16S/genetics , Sequence Analysis, DNA , Sphingobacterium/genetics , Sphingobacterium/isolation & purification , Vitamin K 2/analogs & derivatives , Vitamin K 2/chemistry
18.
Oncotarget ; 8(3): 4156-4168, 2017 Jan 17.
Article in English | MEDLINE | ID: mdl-27926532

ABSTRACT

The approval of poly(ADP-ribose) polymerase (PARP) inhibitor AZD2281 in 2014 marked the successful establishment of the therapeutic strategy targeting homologous recombination repair defects of cancers in the clinic. However, AZD2281 has poor water solubility, low tissue distribution and relatively weak in vivo anticancer activity, which appears to become limiting factors for its clinical use. In this study, we found that mefuparib hydrochloride (MPH) was a potent PARP inhibitor, possessing prominent in vitro and in vivo anticancer activity. Notably, MPH displayed high water solubility (> 35 mg/ml) and potent PARP1/2 inhibition in a substrate-competitive manner. It reduced poly(ADP-ribose) (PAR) formation, enhanced γH2AX levels, induced G2/M arrest and subsequent apoptosis in homologous recombination repair (HR)-deficient cells. Proof-of-concept studies confirmed the MPH-caused synthetic lethality. MPH showed potent in vitro and in vivo proliferation and growth inhibition against HR-deficient cancer cells and synergistic sensitization of HR-proficient xenografts to the anticancer drug temozolomide. A good relationship between the anticancer activity and the PARP inhibition of MPH suggested that PAR formation and γH2AX accumulation could serve as its pharmacodynamic biomarkers. Its high bioavailability (40%~100%) and high tissue distribution in both monkeys and rats were its most important pharmacokinetic features. Its average concentrations were 33-fold higher in the tissues than in the plasma in rats. Our work supports the further clinical development of MPH as a novel PARP1/2 inhibitor for cancer therapy.


Subject(s)
Antineoplastic Agents/administration & dosage , Heterocyclic Compounds, 4 or More Rings/administration & dosage , Neoplasms/drug therapy , Poly(ADP-ribose) Polymerase Inhibitors/administration & dosage , Animals , Antineoplastic Agents/pharmacokinetics , Cell Cycle Checkpoints , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dacarbazine/administration & dosage , Dacarbazine/analogs & derivatives , Dacarbazine/pharmacology , Drug Synergism , Haplorhini , Heterocyclic Compounds, 4 or More Rings/pharmacokinetics , Humans , Mice , Neoplasms/enzymology , Poly(ADP-ribose) Polymerase Inhibitors/pharmacokinetics , Rats , Temozolomide , Tissue Distribution , Xenograft Model Antitumor Assays
19.
Cancer Lett ; 386: 47-56, 2017 02 01.
Article in English | MEDLINE | ID: mdl-27847302

ABSTRACT

Poly(ADP-ribose)polymerase (PARP)1/2 inhibitors have been proved to be clinically effective anticancer drugs. Here we report a new PARP1/2 inhibitor, simmiparib, displaying apparently improved preclinical anticancer activities relative to the first approved inhibitor olaparib. Simmiparib inhibited PARP1/2 approximately 2-fold more potently than olaparib, with more than 90-fold selectivity over the other tested PARP family members. Simmiparib and olaparib caused similar cellular PARP1-DNA trapping. Simmiparib selectively induced the accumulation of DNA double-strand breaks, G2/M arrest and apoptosis in homologous recombination repair (HR)-deficient cells. Consistently, simmiparib showed 26- to 235-fold selectivity in its antiproliferative activity against HR-deficient cells over the corresponding isogenic HR-proficient cells. Notably, its antiproliferative activity was 43.8-fold more potent than that of olaparib in 11 HR-deficient cancer cell lines. Simmiparib also potentiated the proliferative inhibition of several conventional anticancer drugs. Simmiparib reduced the poly(ADP-ribose) formation in HR-deficient cancer cells and xenografts. When orally administered to nude mice bearing xenografts, simmiparib revealed excellent pharmacokinetic properties. Simmiparib caused approximately 10-fold greater growth inhibition than olaparib against HR-deficient human cancer cell- or tissue-derived xenografts in nude mice. Collectively, these findings support the undergoing clinical trials of simmiparib.


Subject(s)
Breast Neoplasms/drug therapy , Phthalazines/pharmacology , Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Poly(ADP-ribose) Polymerases/metabolism , Administration, Oral , Animals , Apoptosis/drug effects , Breast Neoplasms/enzymology , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Clinical Trials as Topic , Cricetinae , DNA Breaks, Double-Stranded , Dose-Response Relationship, Drug , G2 Phase Cell Cycle Checkpoints/drug effects , Genes, BRCA1 , Genes, BRCA2 , Humans , Mice, Nude , Phthalazines/administration & dosage , Phthalazines/pharmacokinetics , Piperazines/pharmacology , Poly (ADP-Ribose) Polymerase-1/metabolism , Poly(ADP-ribose) Polymerase Inhibitors/administration & dosage , Poly(ADP-ribose) Polymerase Inhibitors/pharmacokinetics , Signal Transduction/drug effects , Time Factors , Tumor Burden/drug effects , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
20.
J Phys Condens Matter ; 28(5): 056003, 2016 Feb 10.
Article in English | MEDLINE | ID: mdl-26761786

ABSTRACT

We theoretically and numerically studied the band structure and spin transport of electrons subject to a superlattice structure where magnetic semiconductor layers lie between normal semiconductor layers to form periodic spin-filter tunnel barriers. In this alternately deposited superlattice structure, due to the induced periodicity of the envelope wavefunctions, there are additional allowed and forbidden energy regions established, i.e. forming minibands that are far narrower than the conventional conduction bands. The number and thickness of the stacked potential profiles can finely tune these minibands. The spin dependent potential barriers also induce spin splitting at the bottom of each miniband, which generates strongly spin-dependent miniband conduction. Most strikingly, the lowest lying miniband is 100% spin-polarized mimicking a half-metallic behavior on this conduction channel. The total transmission electron current carries thus near-perfectly polarized spin currents when the superlattice falls into suitable miniband conduction regime. This half-metallic miniband enhanced spin-filtering capability paves the way to generate highly polarized spin current without incurring exponentially increased device impedance, as usually happens when only a single spin-filter barrier is applied.

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