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Waldenström Macroglobulinemia (WM) is a rare type of non-Hodgkin lymphoma with no standard first-line treatment, and the disease is still incurable. This study evaluated the clinical efficacy, safety, and prognostic factors of bortezomib-based chemotherapy as initial treatment in WM patients. We retrospectively analyzed the clinical data collected from 44 newly diagnosed WM patients treated with bortezomib-based regimens at the Affiliated Hospital of Nantong University from December 2011 to June 2021. Univariate and multivariate analyses were used to assess prognostic factors for overall survival (OS) and progression-free survival (PFS). The median age was 67 years old, with an overall response rate (ORR) of 93.2%, complete response (CR) rate of 6.8%, and very good partial response (VGPR) rate of 29.5%. With a median follow-up of 39 months, the 2-year overall survival (OS) and 2-year PFS rates were 88.0% and 59.0%, respectively. By the last follow-up, eight patients (18.2%) had died. Univariate analysis showed patients with B symptoms, elevated LDH, international prognostic stage system of WM (IPSSWM) stage III, high Revised IPSSWM (R-IPSSWM) score, and those who did not achieve VGPR were associated with shorter PFS. And patients with B symptoms, with high R-IPSSWM score, and who do not achieve VGPR also had shorter OS than their counterparts. Multivariate analysis confirmed that failure to achieve VGPR was an independent adverse prognostic factor for OS and PFS. In conclusion, we showed that bortezomib-based chemotherapy effectively treated newly diagnosed patients with WM. However, combinations of drugs with different mechanisms are recommended for patients with a high tumor burden. In addition, deep remission can improve patients' survival.

Assessment of sphingosine-1-phosphate receptor 1 (S1PR1) expression could be a unique tool to determine the neuroinflammatory status for central nervous system (CNS) disorders. Our preclinical results indicate that PET imaging with [(11)C]CS1P1 radiotracer can quantitatively measure S1PR1 expression changes in different animal models of inflammatory diseases. Here we developed a multiple step F-18 labeling strategy to synthesize the radiotracer [(18)F]FS1P1, sharing the same structure with [(11)C]CS1P1. We explored a wide range of reaction conditions for the nucleophilic radiofluorination starting with the key ortho-nitrobenzaldehyde precursor 10. The tertiary amine additive TMEDA proved crucial to achieve high radiochemical yield of ortho-[(18)F]fluorobenzaldehyde [(18)F]12 starting with a small amount of precursor. Based on [(18)F]12, a further four-step modification was applied in one-pot to generate the target radiotracer [(18)F]FS1P1 with 30∼50% radiochemical yield, >95% chemical and radiochemical purity, and a high molar activity (37∼166.5 GBq/μmol, decay corrected to end of synthesis, EOS). Subsequently, tissue distribution of [(18)F]FS1P1 showed a high brain uptake (ID%/g) of 0.48 ± 0.06 at 5 min, and bone uptake of 0.27 ± 0.03, 0.11 ± 0.02 at 5, and 120 min respectively, suggesting no in vivo defluorination. MicroPET studies showed [(18)F]FS1P1 has high macaque brain uptake with a standard uptake value (SUV) of ~2.3 at 120 min. Radiometabolite analysis in nonhuman primate plasma samples indicated that [(18)F]FS1P1 has good metabolic stability, and no major radiometabolite confounded PET measurements of S1PR1 in nonhuman primate brain. Overall, [(18)F]FS1P1 is a promising F-18 S1PR1 radiotracer worthy of further clinical investigation for human use.

Hantzsch ester, a widely used base or electron-donor compound, was found to act as a catalyst in the deaminative difluoroalkylation reaction utilizing Katritzky salts and difluoroenoxysilane as substrates; this represents a rare catalytic example of electron donor–acceptor (EDA) photochemistry. In addition, a substrate-induced pathway was also observed, especially for substrates derived from amino acids. This mild and convenient approach provides a highly valuable method for the convenient installation of a diverse range of alkyl-CF2COPh products.

The sphingosine-1-phosphate receptor 1 (S1PR1) is an important biomarker for imaging inflammation in the central nervous system (CNS). Herein, we report our recent evaluation of four 18F-labeled S1PR1 tracers (18F-TZ43113, 18F-TZ35104, 18F-TZ4877, and 18F-TZ4881) in a rat model of multiple sclerosis (MS). MicroPET studies of each tracer’s uptake and kinetics were performed in an experimental autoimmune encephalomyelitis (EAE) rat model of MS to quantify upregulated S1PR1 expression in the lumbar spinal cord of EAE rats. Western blot analysis was conducted to confirm the differences in the expression of S1PR1 protein level between EAE and sham rats. Radiometabolite analysis was performed for the most promising candidate in rats. All four S1PR1 tracers detected increased S1PR1 levels in response to neuroinflammation in the lumbar spinal cord of EAE rats, which was supported by western blot results. The ranked order of tracer uptake in rat spinal cord was 18F-TZ4877 > 18F-TZ4881 > 18F-TZ35104 > 18F-TZ43113. 18F-TZ4877 had the highest uptake of the four tracers and showed good kinetic modeling fits in rat spinal cord using an image-based method of arterial blood input function. Radiometabolite analysis of 18F-TZ4877 showed good in vivo stability with no major radiometabolite accumulation in the rat brain. Among these four new PET tracers, 18F-TZ4877 showed the most favorable profile for assessing S1PR1 expression in the EAE rat model of MS. Further characterization of these radiotracers in other models of neuroinflammation is warranted to identify a promising 18F-labeled tracer for imaging S1PR1 in vivo.

A visible light promoted deaminative strategy for the difluoroalkylation reaction utilizing pyridinium-activated aliphatic primary amines and difluoroenoxysilane as substrates has been developed. This protocol is characteriazed by its mild reaction conditions and broad substrate scope, which converted a diverse array of amine-containing molecules to the alkyl-CF2COPh products. Moreover, the resulting products can be easily transformed into a vast array of structurally novel and interesting difluoro-containing moieties, therefore providing a facile route for applications in medicinal chemistry and the life sciences.

Receptor-interacting protein kinase 1 (RIPK1) has emerged as a crucial regulator of necroptosis and the inflammatory response by activating a group of downstream immune receptors. It has been recognized as a pivotal contributor to cell death and inflammation in various physiological and pathological processes. RIPK1 deficiency or dysregulation in humans can cause severe immunodeficiency and neurodegenerative diseases such as multiple sclerosis and amyotrophic lateral sclerosis. Recently, diverse structures of RIPK1 inhibitors have been developed as potential therapeutics for neurodegenerative diseases and other pathological inflammatory processes. 7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine (Compound 5 or TZ7774) was reported as a novel RIPK1 inhibitor with a KSynthesis of the desmethyl precursor TZ7790 was performed and optimized. The radiosynthesis of [The radiosynthesis of [

Abdominal aortic aneurysm (AAA) is a life-threatening disorder that occurs in the aorta. The inflammatory thickness of the aneurysm wall and perianeurysmal fibrosis are two main causes of AAA pathogenesis; however, the molecular mechanisms involved in these two processes are still unclear. We discovered that C-terminal binding protein 1 (CtBP1) and CtBP2 were overexpressed in the aortas of AAA-model mice created by treatment with CaCl

G3139 is an antisense oligodeoxyribonucleotide (ODN) developed as a Bcl-2 down-regulating agent for the treatment of acute myelogenous leukemia (AML). However, the clinical efficacy of G3139 has been shown to be limited due to its rapid plasma clearance and low permeability. To enhance the effective delivery of G3139, this work prepared a novel nano gene delivery vector (aCD33-NKSN) consisting of a CD33 antigbody (aCD33), a nuclear localization signal (NLS), gene fusion peptides (KALA), and stearic acid (SA) for CD33 antigen targeting and nuclear localization. The aCD33-NKSN/G3139 nanoparticles were spherical and uniformly sized with a positive charge and sustained release. They had an excellent G3139 loading capacity and colloidal stability. The aCD33-NKSN/G3139 delivered G3139 into the nucleus of Kasumi-1 cells and aCD33-NKSN/G3139 could more effectively inhibited Bcl-2 expression and induced apoptosis in Kasumi-1 cells versus free G3139. The aCD33-NKSN/G3139 administration was more effective at inhibiting tumor growth, and significantly prolonged the survival time of mice in contrast to free G3139. The results illustrate that aCD33-NKSN/G3139 nanoparticles could improve the antitumor activity of encapsulated G3139 due to aCD33 targeting and the ability to perform nuclear localization, The results offer a promising clinical application potential for the treatment of acute myeloid leukemia.

Automated synthesis of a radiopharmaceutical 3-((2-fluoro-4-(5-(2′-methyl-2-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl) (methyl-11C)amino)propanoic acid ([11C]CS1P1) for PET imaging sphingosine-1 phosphate receptor 1 (S1P1) was accomplished by a two-step-one-pot procedure in a Siemens CTI methylation automated module using TR-19 cyclotron. The synthesis of [11C]CS1P1 was successfully validated under current Good Manufacturing Practices (cGMP) conditions, resulting in a consistent average radiochemical yield of ∼15%, molar activity of ∼3129 GBq/μmol (decay corrected to end of bombardment, EOB), and radiochemical purity > 95%. The radiopharmaceutical product meets all quality control criteria for human use for an Investigational New Drug (IND) application to permit human studies.

Atom transfer radical addition and Heck-type reaction between alkenes and ethyl iododifluoroacetate by using organophosphine compounds as catalysts have been developed. The reaction proceeds under mild reaction conditions with excellent functional group tolerance and high chemo- and regioselectivities. Mechanistic study indicates that the reaction might be initiated via noncovalent interactions between an organophosphine catalyst and a carbon-iodine bond.

Cardiac hypertrophy is a frequent pathological reaction to hypertension, pulmonary hypertension, and other cardiovascular diseases. A typical feature of myocardial remodeling, cardiac hypertrophy can lead to heart failure and ultimately death. In recent years, studies have found some factors circulating within the blood of young mice can improve symptoms of heart hypertrophy in aged mice. GDF11 in the blood was once considered a key factor to extenuate cardiac hypertrophy, but subsequent studies question this conclusion. Recent genomic advances have revealed that non-coding RNA, including circular RNA, piRNAs, microRNAs and long non-coding RNAs, play an important role in gene expression and regulation, directly affecting pathophysiological mechanisms. The involvement of microRNAs within the myocardium and aortic valve in the regulation of pathophysiology may lead to the development of cardiovascular disease. Exosome-derived microRNA molecules in the heart are related to heart hypertrophy and failure. This article reviews the relevance of microRNAs to heart hypertrophy and the transported mechanism, which is helpful to discover new therapy and biomarkers for cardiac hypertrophy.

Sphingosine-1-phosphate receptor 1 (S1PR1) plays a crucial role in infectious diseases. Targeting S1PR1 provides protection against pathogens, such as influenza viruses. This study is aimed at investigating S1PR1 in response to bacterial infection by assessing S1PR1 expression in S. aureus-infected mice. A rodent local muscle bacterial infection model was developed by injecting S. aureus to the lower hind limb of Balb/c mice. The changes of S1PR1 expression in response to bacterial infection and blocking treatment were assessed using ex vivo biodistribution and in vivo positron emission tomography (PET) after intravenous injection of an S1PR1-specific radiotracer [18F]TZ4877. The specificity of [18F]TZ4877 was assessed using S1PR1-specific antagonist, NIBR-0213, and S1PR1-specific DsiRNA pretreated the animals. Immunohistochemical studies were performed to confirm the increase of S1PR1 expression in response to infection. Ex vivo biodistribution data showed that the uptake of [18F]TZ4877 was increased 30.6%, 54.3%, 74.3%, and 115.3% in the liver, kidney, pancreas, and thymus of the infected mice, respectively, compared to that in normal control mice, indicating that S1PR1 is involved in the early immune response to bacterial infection. NIBR-0213 or S1PR1-specific DsiRNA pretreatment reduced the tissue uptake of [18F]TZ4877, suggesting that uptake of [18F]TZ4877 is specific. Our PET/CT study data also confirmed that infected mice have increased [18F]TZ4877 uptake in several organs comparing to that in normal control mice. Particularly, compared to control mice, a 39% increase of [18F]TZ4877 uptake was observed in the infected muscle of S. aureus mice, indicating that S1PR1 expression was directly involved in the inflammatory response to infection. Overall, our study suggested that S1PR1 plays an important role in the early immune response to bacterial infection. The uptake of [18F]TZ4877 is tightly correlated with the S1R1 expression in response to S. aureus infection. PET with S1PR1-specific radiotracer [18F]TZ4877 could provide a noninvasive tool for detecting the early S1PR1 immune response to infectious diseases.

Doxorubicin (DOX) is a potent chemotherapeutic drug but the clinical use was limited by its dose-dependent cardiotoxicity. Pinocembrin (PCB), a flavonoid originally isolated from honeybee propolis and rhizomes of Boesenbergia pandurate displays diverse biological activities. However, the role of PCB in DOX-induced cardiac injury and its underlying molecular mechanism are not fully elucidated. The present study was designed to evaluate the protective role of PCB in a DOX-induced cardiotoxicity in vivo and in vitro. Our results revealed that PCB administration greatly improved cardiac function and reduced cardiac fibrosis manifested by LVEF, LVFS, LVIDd, LVIDs, and myocardial fibrotic area which were impaired by DOX treatment. The cardiac injury evidenced by LDH and CK-MB activities were reduced while the levels of IL-1β and IL-18 were decreased following PCB treatment compared to DOX-treated mice. Mechanically, our present results showed that PCB significantly inhibited DOX-induced cardiomyocyte pyroptosis via activating Nrf2/Sirt3 signal pathway. Furthermore, the inhibition of Nrf2 in H9c2 cells abolished the protective role of PCB against DOX-induced cell toxicity, which was at least partly via upregulation of NLRP3-mediated pyroptosis. In conclusion, our study clearly demonstrated that PCB reduced cardiomyocyte pyroptosis to protect hearts from DOX-induced cardiotoxicity through activation of Nrf2/Sirt3 signal pathway.

In this study, we designed a novel nucleus-targeted nanocarrier (NLS-KALA-SA, NKSN) consisting of Kala peptide (KALA), nuclear localization signal (NLS) and stearic acid (SA) using Fmoc solid phase synthesis method. We chose Curcumin (CUR), Paclitaxel (PTX), Ginsenoside compound K(CK) as models of poorly water-soluble antitumor drugs, The drugs loaded NLS-KALA-SA nanoparticles (CUR/NKSN, PTX/NKSN, CK/NKSN) were obained by the dialysis method, their physicochemical properties were determined and antitumor activity were evaluated. The NLS-KALA-SA nanoparticles were spherical shaped with an average size of 76.4 ± 7.6 mm and a zeta potential of 43.7 ± 5.8 mV. The drug-loaded NLS-KALA-SA nanoparticles were above 86.1% and 17.1% in entrapment efficiency and drug loading capacity, and had sustained drug release behavior. Biodistribution and cellular uptake study exhibited that PTX/NKSN mainly distributed in tumor site of A549-bearing mice, and coumarin-6(C6) loaded NLS-KALA-SA nanoparticle (C6/NKSN) was predominantly accumulated in the nucleus of A549 cells. Western blot analysis indicated that PTX/NKSN could more remarkably inhibit Bcl-2 expression and enhance the expression of Bax and Caspase-3 as compared to the controls in A549 cells. Cell apoptosis and antitumor activity study showed that PXT/NKSN could more obviously induce apoptosis of A549 cells compared with free PXT, the PTX/NKSN administration was more effective than free PTX for lung cancer treatment and displayed mild toxicity in A549-bearing mice. The results demonstrates that the NLS-KALA-SA nanoparticles system could enhance the antitumor effects of the encapsulated drug and reduce tissue toxicity due to its long circulating properties and tumor targeting, which might provide a promising strategy for lung cancer treatment.

PURPOSE: The sphingosine-1-phosphate receptor 1 (S1PR1) is an important biomarker for imaging inflammation in the central nervous system (CNS). Herein we report our recent evaluation of four (18)F-labeled S1PR1 tracers ((18)F-TZ43113, (18)F-TZ35104, (18)F-TZ4877, and (18)F-TZ4881) in a rat model of multiple sclerosis (MS). PROCEDURES: MicroPET studies of each tracer’s uptake and kinetics were performed in the experimental autoimmune encephalomyelitis (EAE) rat model of MS to quantify upregulated S1PR1 expression in the lumbar spinal cord of EAE rats. Western blot analysis was conducted to confirm the differences in the expression of S1PR1 protein level in EAE and sham rats. Radiometabolite analysis was performed for the most promising candidate in rats. RESULTS: All four S1PR1 tracers detected increased S1PR1 levels in response to neuroinflammation in the lumbar spinal cord of EAE rats, which was supported by western blot results. The ranked order of tracer uptake in rat spinal cord was (18)F-TZ4877>(18)F-TZ4881>(18)F-TZ35104>(18)F-TZ43113. (18)F-TZ4877 had the highest uptake of the four tracers and showed good kinetic modeling fits in rat spinal cord using an image-based method of arterial blood input function. Radiometabolite analysis of (18)F-TZ4877 showed good in vivo stability with no major radiometabolite accumulation in the brain. CONCLUSION: Among these four new PET tracers, (18)F-TZ4877 showed the most favorable profile for assessing S1PR1 expression in the EAE rat model of MS. Further characterization of these radiotracers in other models of neuroinflammation is warranted to identify a promising (18)F-labeled tracer for imaging S1PR1 in vivo.

The nonselective Ca2+ -permeable transient receptor potential channel subfamily member 5 (TRPC5) belongs to the transient receptor potential canonical (TRPC) superfamily and is widely expressed in the brain. Compelling evidence reveals that TRPC5 plays crucial roles in depression and other psychiatric disorders. To develop a TRPC5 radioligand, following up on our previous effort, we synthesized the iodine compound TZ66127 and its iodine-125-labeled counterpart [125 I]TZ66127. The synthesis of TZ66127 was achieved by replacing chloride with iodide in the structure of HC608, and the [125 I]TZ66127 was radiosynthesized using its corresponding tributylstannylated precursor. We established a stable human TRPC5-overexpressed HEK293-hTRPC5 cell line and performed Ca2+ imaging and a cell-binding assay study of TZ66127; these indicated that TZ66127 had good inhibition activity for TRPC5, and the inhibitory efficiency of TZ66127 toward TRPC5 presented in a dose-dependent manner. An in vitro autoradiography and immunohistochemistry study of rat brain sections suggested that [125 I]TZ66127 had binding specificity toward TRPC5. Altogether, [125 I]TZ66127 has high potential to serve as a radioligand for screening the binding activity of other new compounds toward TRPC5. The availability of [125 I]TZ66127 might facilitate the development of therapeutic drugs and PET imaging agents that target TRPC5.

Leukocyte reduced NADP (NADPH) oxidase plays a key role in host defense and immune regulation. Genetic defects in NADPH oxidase result in chronic granulomatous disease (CGD), characterized by recurrent bacterial and fungal infections and aberrant inflammation. Key drivers of hyperinflammation induced by fungal cell walls in CGD are still incompletely defined. In this study, we found that CGD (CYBB−) neutrophils produced higher amounts of leukotriene B4 (LTB4) in vitro after activation with zymosan or immune complexes, compared with wild-type (WT) neutrophils. This finding correlated with increased calcium influx in CGD neutrophils, which was restrained in WT neutrophils by the electrogenic activity of NADPH oxidase. Increased LTB4 generation by CGD neutrophils was also augmented by paracrine cross talk with the LTB4 receptor BLT1. CGD neutrophils formed more numerous and larger clusters in the presence of zymosan in vitro compared with WT cells, and the effect was also LTB4- and BLT1-dependent. In zymosan-induced lung inflammation, focal neutrophil infiltrates were increased in CGD compared with WT mice and associated with higher LTB4 levels. Inhibiting LTB4 synthesis or antagonizing the BLT1 receptor after zymosan challenge reduced lung neutrophil recruitment in CGD to WT levels. Thus, LTB4 was the major driver of excessive neutrophilic lung inflammation in CGD mice in the early response to fungal cell walls, likely by a dysregulated feed-forward loop involving amplified neutrophil production of LTB4. This study identifies neutrophil LTB4 generation as a target of NADPH oxidase regulation, which could potentially be exploited therapeutically to reduce excessive inflammation in CGD.

The first example of visible light promoted fluoroalkylation reactions initiated via noncovalent interactions between acetone and fluoroalkyl iodides is presented. The reaction system features synthetic simplicity, mild reaction conditions without any photoredox catalyst, and high functional group tolerance. A wide range of substrate scopes such as alkenes, alkynes and (hetero)arenes were all compatible with the reaction system.

Sixteen new sulfur-containing compounds targeting the vesicular acetylcholine transporter (VAChT) were synthesized and assessed for in vitro binding affinities. Enantiomers (-)-(1-(3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)piperidin-4-yl)(4-(methylthio)phenyl)methanone [(-)-8] and (-)-(4-((2-fluoroethyl)thio)phenyl)(1-(3-hydroxy-1,2,3,4-tetrahydronaph-thalen-2-yl)piperidin-4-yl)methanone [(-)-14 a] displayed high binding affinities, with respective Ki values of 1.4 and 2.2 nm for human VAChT, moderate and high selectivity for human VAChT over σ1 (≈13-fold) and σ2 receptors (>420-fold). Radiosyntheses of (-)-[11 C]8 and (-)-[18 F]14 a were achieved using conventional methods. Ex vivo autoradiography and biodistribution studies in Sprague-Dawley rats indicated that both radiotracers have the capacity to penetrate the blood-brain barrier, with high initial brain uptake at 5 min and rapid washout. The striatal region had the highest accumulation for both radiotracers. Pretreating the rats with the VAChT ligand (-)-vesamicol decreased brain uptake for both radiotracers. Pretreating the rats with the σ1 ligand YUN-122 (N-(4-benzylcyclohexyl)-2-(2-fluorophenyl)acetamide) also decreased brain uptake, suggesting these two radiotracers also bind to the σ1 receptor in vivo. The microPET study of (-)-[11 C]8 in the brain of a non-human primate showed high striatal accumulation that peaked quickly and washed out rapidly. Although preliminary results indicated these two sulfur-containing radiotracers have high binding affinities for VAChT with rapid washout kinetics from the striatum, their σ1 receptor binding properties limit their potential as radiotracers for quantifying VAChT in vivo.

Studies have indicated that high levels of ethanol exposure impaired spermatogenesis in mice. However, the effects of chronic and low-dose alcohol consumption on susceptible populations remain unclear. The previous studies have confirmed that Immp2l mutant mice (Immp2lTg(Tyr)979Ove or Immp2l-/- ) suffered from increased levels of oxidative stress(OS) and male infertility, heterozygous lmmp2l mice (Immp2l+/- ) showed no altered ROS levels under physiological condition. Lycium barbarum polysaccharide (LBP) significantly scavenge oxygen free radicals and enhance antioxidant enzyme activity. The objectives of present study were to research the effects of chronic and low-dose alcohol-induced damage on Immp2l+/- , explore the protective function of LBP and possible mechanism. The results indicated that chronic ethanol exposure leads to spermatogenic impairment and triggered a toxic effect on germ cell, 10 mg/kg LBP administration improved the quality of spermatozoon, decreased the ratio of apoptotic germ cells and the expression of Col1a1 and Col1a2, while increased the level of TNP2 and RPL31. In conclusion, the study may provide basic knowledge about LBP's important role against ethanol-induced spermiotoxicity and testicular degeneration in Immp2l+/- mice, and the mechanism may be that LBP influenced the state of the spermatogenic epithelium by decreasing the expression of Collagen level leading to alterations in protein biosynthesis during the process of spermatogenesis.

The objective of this study was to develop a novel type of an antisense oligonucleotide (OGX-011) loaded Tat-tagged and folate-modified N-succinyl-chitosan (Tat-Suc-FA) nanoparticles (NPs) for improving tumor targetability. In this study, Tat-Suc-FA/OGX-011NPs were prepared and its physicochemical characterizations were also evaluated. The nanoparticles showed an average diameter of 73 ± 16.6 nm, the zeta potential of +23.6 ± 0.3 mV, and a high entrapment efficiency of 89.6 ± 6.6%. Transmission electron microscopy analysis showed the nanoparticles were mostly spherical and well dispersed. The delivery efficiency of this system was investigated both in vitro and in vivo. In comparison with nontargeted Lipofectamin2000/OGX-011 and free OGX-011, Tat-Suc-FA/GOX-011 showed the highest apoptosis rate of 14.2% ± 1.8% and significant uptake in A549 cells. Tat-Suc-FA NPs loaded with GOX-011 induced significant down-regulation of s-CLU mRNA and protein levels in A549 cells. In A549 tumor-bearing mice model, Tat-Suc-FA/GOX-011 produced a more efficient down-regulation of s-CLU compared to Lipofectamin2000/OGX-011. Furthermore, the combined use of Tat-Suc-FA/OGX-011 with DDP chemotherapy showed a most significant inhibition of tumor growth and greatly enhanced the survival rate of A549 tumor-bearing mice. These findings suggested successful application of Tat-Suc-FA NPs for the high efficiency and specificity in therapeutic delivery of OGX-011 to A549 cells.

In search of an effective and less toxic absorption enhancer, we synthesized primary amine acetylation of generation 2 polyamidoamine (G2 PAMAM) dendrimer (Ac-G2) by the reaction of G2 PAMAM dendrimer with acetic anhydride, and evaluated the effects of Ac-G2 on the intestinal absorption of poorly absorbable water-soluble drugs using an in situ closed-loop method in rats. The results indicated that Ac50-G2 had a greatest absorption enhancing effect for 5(6)-carboxyfluorescein (CF) in various acetylation levels of G2 PAMAM dendrimers. Ac50-G2 with various concentrations (0.1-1.0%, w/v) could significantly improve the intestinal absorption of alendronate, CF, and fluorescein isothiocyanate-labeled dextrans (FD4), although they did not enhance the absorption of macromolecular drug of FD10, and the absorption enhancement effect of Ac50-G2 was concentration-dependent. Furthermore, we examined the intestinal membrane damage with or without Ac50-G2. The results displayed Ac50-G2 at lower concentrations (0.1-0.5%, w/v) did not cause any observed toxic effect to the intestinal membranes. These findings suggested Ac50-G2 at lower concentrations (below 0.5%, w/v) might be promising as an effective and safe absorption enhancers to promote the intestinal absorption of poorly absorbable drugs.

OBJECTIVES: Postoperative new-onset atrial fibrillation (POAF) in cardiac surgery is associated with increased morbidity and mortality. Because n-3 polyunsaturated fatty acids (n-3 PUFA) have an antiarrhythmic effect, we hypothesized that a high content of marine n-3 PUFA in the atrial wall was associated with a reduced risk of POAF.DESIGN: Venous blood and tissue from the right atrial appendage were obtained from 50 patients undergoing elective cardiac surgery. We determined the content of marine n-3 PUFA in atrial tissue and in plasma phospholipids using gas chromatography.RESULTS: The mean age of the patients (results available from 49 patients) was 66.0±10.4years, and 22, 14, 10 and 3 patients underwent coronary artery bypass surgery, valve, combined or other cardiac surgery, respectively. Eighteen patients (36.7%) developed POAF. Concentrations of n-3 PUFA in the atrial wall and in plasma phospholipids did not predict the development of POAF, but there were significant correlations between marine n-3 PUFA in atrial tissue and plasma.CONCLUSION: Levels of marine n-3 PUFA in the atrial wall was not associated with the risk of POAF following cardiac surgery, despite significant correlations of marine n-3 PUFA in the atrium and in plasma phospholipids.

We aimed to investigate the absorption-enhancing effect (AEE) of caproyl-modified G2 PAMAM dendrimer (G2-AC) on peptide and protein drugs via the pulmonary route. In this study, G2 PAMAM dendrimer conjugates modified with caproic acid was synthesized, the pulmonary absorption of insulin as models with or without G2-AC were evaluated. The results indicated that G2-AC6 exhibited a greatest AEE for insulin in various caproylation levels of G2-AC. G2-AC6 could significantly enhance the absorption of insulin, and the AEE of G2-AC6 was concentration-dependent. In toxicity tests, G2-AC6 displayed no measurable cytotoxicity to the pulmonary membranes over a concentration range from 0.1% (w/v) to 1.0% (w/v). Measurements of the TEER and permeability showed that G2-AC6 significantly reduced the TEER value of CF and increased its Papp value. The results suggested that G2-AC6 could cross epithelial cells by means of a combination of paracellular and transcellular pathways. These findings suggested G2-AC6 at lower concentrations (below 1.0%, w/v) might be promising absorption enhancers for increasing the pulmonary absorption of peptide and protein drugs.

Vesicular acetylcholine transporter (VAChT) is a promising target for a PET measure of cholinergic deficits which contribute to cognitive impairments. Dopamine D(2)-like agonists and antagonists are frequently used in the elderly and could alter cholinergic function and VAChT level. Therefore, pretreatment with dopamine D(2)-like drugs may interfere with PET measures using [(18)F]VAT, a specific VAChT radioligand. Herein, we investigated the impact of dopaminergic D(2)-like antagonist/agonist on VAChT level in the brain of macaques using [(18)F]VAT PET. PET imaging studies were carried out on macaques at baseline or pretreatment conditions. For pretreatment, animals were injected using a VAChT inhibitor (−)-vesamicol, a D(2)-like antagonist (−)-eticlopride, and a D(2)-like agonist (−)-quinpirole, separately. (−)-Vesamicol was injected at escalating doses of 0.025, 0.05, 0.125, 0.25 and 0.35 mg/kg; (−)-eticlopride was injected at escalating doses of 0.01, 0.10 and 0.30 mg/kg; (−)-quinpirole was injected at escalating doses of 0.20, 0.30, and 0.50 mg/kg. PET data showed [(18)F]VAT uptake declined in a dose-dependent manner by (−)-vesamicol pretreatment, demonstrating [(18)F]VAT uptake is sensitive to reflect the availability of VAChT binding sites. Furthermore, (−)-eticlopride increased [(18)F]VAT striatal uptake in a dose-dependent manner, while (−)-quinpirole decreased its uptake, suggesting striatal VAChT levels can be regulated by D(2)-like drug administration. Our findings confirmed [(18)F]VAT offers a reliable tool to in vivo assess the availability of VAChT binding sites. More importantly, PET with [(18)F]VAT successfully quantified the impact of dopaminergic D(2)-like drugs on striatal VAChT level, suggesting [(18)F]VAT has great potential for investigating the interaction between dopaminergic and cholinergic systems in vivo.

Automated synthesis of a radiopharmaceutical 3-((2-fluoro-4-(5-(2′-methyl-2-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)(methyl-(11)C)amino)propanoic acid ([(11)C]CS1P1) for PET imaging sphingosine-1 phosphate receptor 1 (S1P1) was accomplished by a two-step-one-pot procedure in a Siemens CTI methylation automated module using TR-19 cyclotron. The synthesis of [(11)C]CS1P1 was successfully validated under current Good Manufacturing Practices (cGMP) conditions, resulting in a consistent average radiochemical yield of ~ 15%, molar activity of ~ 3129 GBq/μmol (decay corrected to end of bombardment, EOB), and radiochemical purity > 95%. The radiopharmaceutical product meets all quality control criteria for human use for an Investigational New Drug (IND) application to permit human studies.

The absorption-enhancing effects of glycol chitosan modified by 5β-cholanic acid nanoparticles (5β-CHA/GC-NPs) on a drug with poor absorption in the intestine were studied by the method of in situ closed loop. We chose fluorescein isothiocyanate-labeled dextrans (FDs) and insulin as the model drugs. 5β-CHA/GC-NPs loaded to different drugs were prepared by the dialysis method, and the physicochemical characteristics and in vitro release profiles of nanoparticles were also estimated. The results showed that 5β-CHA/GC-NPs markedly increased the absorption of insulin and FDs in the jejunum, ileum, and colon. The ratios of absorption for all the drugs in the jejunum were higher than those in the ileum and colon. In addition, the enhancing effect of 5β-CHA/GC-NPs for the absorption of FDs from the jejunum was decreased with increasing molecular weights. In the toxicity test, 5β-CHA/GC-NPs did not significantly increase the release of protein and the activities of LDH, indicating that the nanoparticles did not cause any membrane damage to the intestine. These findings suggested that 5β-CHA/GC-NPs were safe and useful carriers for enhancing the absorption of the drug with poor absorption by intestinal membranes.

α-Trifluoromethyl alkenes can be used as peptide isosteres, moreover, the pre-installed vinyl group make it possible that transformation to diverse fluorine-containing unities. However, the cross-coupling of benzyl group with α-trifluoromethyl alkenes has yet to be developed. In this report, we describe a general method for the cross-coupling of benzylzinc reagents with 2-bromo-3,3,3-trifluoropropene (BTP) to afford diverse α-trifluoromethylalkene derivatives by using Pd(TFA)2 as catalyst. This method takes advantage of cheap industrial available fluorine building blocks and easily prepared benzylzinc reagents to generate α-trifluoromethylalkene derivatives, which features with mild reaction conditions, wide substrate scope and feasibility of product transformations.

Vesicular acetylcholine transporter (VAChT) is a promising target for a PET measure of cholinergic deficits which contribute to cognitive impairments. Dopamine D2-like agonists and antagonists are frequently used in the elderly and could alter cholinergic function and VAChT level. Therefore, pretreatment with dopamine D2-like drugs may interfere with PET measures using [18F]VAT, a specific VAChT radioligand. Herein, we investigated the impact of dopaminergic D2-like antagonist/agonist on VAChT level in the brain of macaques using [18F]VAT PET. PET imaging studies were carried out on macaques at baseline or pretreatment conditions. For pretreatment, animals were injected using a VAChT inhibitor (-)-vesamicol, a D2-like antagonist (-)-eticlopride, and a D2-like agonist (-)-quinpirole, separately. (-)-Vesamicol was injected at escalating doses of 0.025, 0.05, 0.125, 0.25 and 0.35 mg/kg; (-)-eticlopride was injected at escalating doses of 0.01, 0.10 and 0.30 mg/kg; (-)-quinpirole was injected at escalating doses of 0.20, 0.30, and 0.50 mg/kg. PET data showed [18F]VAT uptake declined in a dose-dependent manner by (-)-vesamicol pretreatment, demonstrating [18F]VAT uptake is sensitive to reflect the availability of VAChT binding sites. Furthermore, (-)-eticlopride increased [18F]VAT striatal uptake in a dose-dependent manner, while (-)-quinpirole decreased its uptake, suggesting striatal VAChT levels can be regulated by D2-like drug administration. Our findings confirmed [18F]VAT offers a reliable tool to in vivo assess the availability of VAChT binding sites. More importantly, PET with [18F]VAT successfully quantified the impact of dopaminergic D2-like drugs on striatal VAChT level, suggesting [18F]VAT has great potential for investigating the interaction between dopaminergic and cholinergic systems in vivo.

Here, we describe a mild, catalyst-free and operationally-simple strategy for the direct fluoroalkylation of olefins driven by the photochemical activity of an electron donor−acceptor (EDA) complex between DMA and fluoroalkyl iodides. The significant advantages of this photochemical transformation are high efficiency, excellent functional group tolerance, and synthetic simplicity, thus providing a facile route for further application in pharmaceuticals and life sciences.

BACKGROUND: Allogeneic red blood cell (RBC) transfusion has been associated with new-onset postoperative atrial fibrillation (POAF) following cardiac surgery. Prolonged storage time of RBC may increase the risk. The primary aim of the study was to evaluate whether the storage time of RBC is associated with development of POAF.MATERIALS AND METHODS: Pre-, per- and postoperative data were retrieved from the Western Denmark Heart Registry and local blood banks regarding patients who underwent coronary artery bypass surgery, valve surgery or combined procedures in Aalborg or Aarhus University Hospital during 2010-2014. Multiple logistic regression was used to determine the risk of POAF according to transfusion of RBC on the day of surgery. Furthermore, we determined trend in storage time of RBC according to risk of POAF using restricted cubic splines. Patients with a history of preoperative atrial fibrillation, patients who received transfusions preoperative and patients who died at the day of surgery were among excluded patients.RESULTS: A total of 2,978 patients with a mean age of 66.4 years were included and 609 patients (21%) received RBC transfusion on the day of surgery. POAF developed in 752 patients (25%) and transfused patients were at an increased risk compared with non-transfused patients (adjusted Odds Ratios for patients receiving RBC: 1.37; 95% CI: 1.11-1.69, P-value = 0.004). However, RBC transfusion was not necessarily the cause of POAF and may only be a marker for development of POAF. There was no significant association between storage time of RBC and POAF.CONCLUSIONS: In contrast to intraoperative allogeneic RBC transfusion in general, increased storage time of RBC is not associated with development of POAF in cardiac surgery.

Background: Marine omega-3 fatty acids have antiarrhythmic effects, but whether the plant-derived omega-3 fatty acid alpha-linolenic acid (ALA) have similar effects is less documented. Some data suggest that intake of ALA may reduce sudden cardiac death (and presumably ventricular arrhythmias) but little is known about a possible effect of ALA on atrial arrhythmias including atrial fibrillation (AF). A possible effect of ALA on AF would probably be caused by incorporation of ALA into atrial tissue.Aim of study: To compare plasma phospholipid levels of ALA to levels in atrial muscle tissueMethods: Atrial tissue was obtained from 50 patients during cardiac surgery (valvular surgery and/or coronary artery bypass grafting) and plasma was sampled prior to skin incision. Fatty acid composition was determined in both atrial tissue and plasma phospholipids (49 samples available) by gas chromatography and ALA levels were compared by the Pearson correlation coefficient.Results: There was a statistical significant correlation (r=0.54, 95% confidence interval: 0.30-0.71) between levels of ALA in plasma phospholipids and atrial tissue.Conclusion: The content of ALA in plasma phospholipids is a short term indicator of intake of ALA and this correlated well with the content of ALA in atrial tissue. Atrial tissue is not readily available but this study shows that determination of plasma phospholipids may be useful to further investigate an antiarrhythmic effect of ALA on AF.

OBJECTIVES The content in adipose tissue of marine n-3 polyunsaturated fatty acids (PUFAs) is a marker of long-term fish consumption and data suggest an antiarrhythmic effect of n-3 PUFAs. We investigated the correlation between adipose tissue content of the major n-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), from three different adipose tissue compartments [epicardial (EAT), pericardial (PAT) and subcutaneous (SAT)]. Furthermore, we studied the correlation between the content of EPA and DHA in these compartments and in atrial tissue (AT). METHODS We obtained AT from auricles, EAT above the right ventricle, PAT, and SAT below the sternum from 50 patients undergoing cardiac surgery. Samples were frozen at -80°C and the content of n-3 PUFAs determined by gas chromatography with results given in relative weight%. RESULTS EPA and DHA were significantly correlated in EAT, PAT and SAT with high r-values from 0.70 to 0.87. There was a significant correlation between the content of EPA in adipose tissue and in AT from 0.49 to 0.59, with minor/no correlation between contents of DHA in adipose tissue and in AT. Correlations: DHA / EPA SAT PAT EAT AT SAT 1.00 / 1.00 PAT 0.84* / 0.87* 1.00 / 1.00 EAT 0.85* / 0.76* 0.71* / 0.74* 1.00 / 1.00 AT 0.19 / 0.49* 0.36* / 0.58* 0.28 / 0,59* 1.00 / 1.00 * P< 0.05 CONCLUSIONS: The content of EPA and DHA was very similar in EAT, PAT and SAT. There were significant correlations between the content of EPA, but not of DHA, in adipose tissues and in AT. This might be relevant when studying n-3 PUFAs and atrial arrhythmias.

Objective To investigate if electrocardiogram (ECG) markers from routine preoperative ECGs can be used in combination with clinical data to predict new-onset postoperative atrial fibrillation (POAF) following cardiac surgery. Design Retrospective observational case-control study. Setting Single-center university hospital. Participants One hundred consecutive adult patients (50 POAF, 50 without POAF) who underwent coronary artery bypass grafting, valve surgery, or combinations. Interventions Retrospective review of medical records and registration of POAF. Measurements and Main Results Clinical data and demographics were retrieved from the Western Denmark Heart Registry and patient records. Paper tracings of preoperative ECGs were collected from patient records, and ECG measurements were read by two independent readers blinded to outcome. A subset of four clinical variables (age, gender, body mass index, and type of surgery) were selected to form a multivariate clinical prediction model for POAF and five ECG variables (QRS duration, PR interval, P-wave duration, left atrial enlargement, and left ventricular hypertrophy) were used in a multivariate ECG model. Adding ECG variables to the clinical prediction model significantly improved the area under the receiver operating characteristic curve from 0.54 to 0.67 (with cross-validation). The best predictive model for POAF was a combined clinical and ECG model with the following four variables: age, PR-interval, QRS duration, and left atrial enlargement. Conclusion ECG markers obtained from a routine preoperative ECG may be helpful in predicting new-onset POAF in patients undergoing cardiac surgery.

* E-mail: zhusz@mail.sioc.ac.cn; Tel.: 0086-021-54925183 Received June 14, 2011; revised July 19, 2011; accepted July 26, 2011. Project supported by the National Natural Science Foundation of China (Nos. 21032006, 20972178) and Shanghai Natural Science Council. † Dedicated to Professor Weiyuan Huang on the occasion of his 90th birthday.

A catalyst free cycloaddition reaction of 3-oxo-1,2-pyrazolidinium ylides with β -trifluoroacetyl vinyl ethyl ether is reported, which proceeded smoothly at ambient temperature and afford the bicyclic pyrazolidinone products in good yield. This is the first report of synthesis of 6-trifluoroacetyl substituted bicyclic pyrazolidinones that are potentially anti-microbial and herbicidal.