A mitochondrion-targeted cyanine agent for NIR-II fluorescence-guided surgery combined with intraoperative photothermal therapy to reduce prostate cancer recurrence.

Poorly identified tumor boundaries and nontargeted therapies lead to the high recurrence rates and poor quality of life of prostate cancer patients. Near-infrared-II (NIR-II) fluorescence imaging provides certain advantages, including high resolution and the sensitive detection of tumor boundaries. Herein, a cyanine agent (CY7-4) with significantly greater tumor affinity and blood circulation time than indocyanine green was screened. By binding albumin, the absorbance of CY7-4 in an aqueous solution showed no effects from aggregation, with a peak absorbance at 830 nm and a strong fluorescence emission tail beyond 1000 nm. Due to its extended circulation time (half-life of 2.5 h) and high affinity for tumor cells, this fluorophore was used for primary and metastatic tumor diagnosis and continuous monitoring. Moreover, a high tumor signal-to-noise ratio (up to ~ 10) and excellent preferential mitochondrial accumulation ensured the efficacy of this molecule for photothermal therapy. Therefore, we integrated NIR-II fluorescence-guided surgery and intraoperative photothermal therapy to overcome the shortcomings of a single treatment modality. A significant reduction in recurrence and an improved survival rate were observed, indicating that the concept of intraoperative combination therapy has potential for the precise clinical treatment of prostate cancer.

Reactive Matrices for MALDI-MS of Cholesterol.

Cholesterol is a critical molecule whose dysregulation in certain brain regions is related to multiple neurological disorders. It is of pathological importance to map the distribution of cholesterol in brain. Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) has been widely used in the molecular imaging of metabolites at a high spatial resolution. However, it is challenging to analyze cholesterol by MALDI-MS due to its difficulty in ionization. Herein, we present for the first time a type of reactive matrix for MALDI-MS of cholesterol. Methylpyridinium carboxaldehydes react with cholesterol and other hydroxyl-containing sterols, which greatly enhanced both desorption and ionization and improved the limits of detection to the low µg/mL range. Compared with previous methods, our reactive matrix requires only one step of chemical derivatization and avoids time-consuming enzymatic reaction, which simplified the sample pretreatment. The reactive matrix was successfully used in mapping the distribution of cholesterol in brain tissue sections using MALDI-MS imaging. In summary, this work has provided a sensitive and simple method for the MALDI-MS analysis of cholesterol, has proposed a novel solution to visualize the distribution of sterol metabolites, and has great potential for applications in neurological and pathological studies.

Stereocontrolled Preparation of Diversely Trifunctionalized Cyclobutanes.

The expedient and stereoselective syntheses of small libraries of trifunctionalized cyclobutane scaffolds bearing an acid, an amine, and a third functional group are described. Starting from a single precursor, the readily available protected derivative of all-cis-2-amino-3-hydroxycyclobutane-1-carboxylic acid, cis-trans stereoisomers are obtained following an SN2-type reaction, while all-trans stereoisomers are obtained using the same strategy preceded by a C1 epimerization reaction.

MicroRNA-193b-3p regulates matrix metalloproteinase 19 expression in interleukin-1ß-induced human chondrocytes.

Micro(mi)RNAs are small, non-coding RNA molecules known to play a significant role in osteoarthritis (OA) initiation and development, and similar to matrix metalloproteinases (MMPs), they participate in cartilage degeneration and cleave multiple extracellular matrices. The aim of this study was to determine whether the expression of MMP-19 in interleukin (IL)-1ß-induced human chondrocytes is directly regulated by miR-193b-3p. Expression levels of miR-193b-3p and MMP-19 in normal and osteoarthritis (OA) human cartilage, and interleukin-1 ß (IL-1ß)-induced human chondrocytes were determined by real-time polymerase chain reaction. Additionally, expression level of MMP-19 in IL-1ß-induced human chondrocytes was estimated by Western blotting and immunohistochemistry analyses. The effect of miR-193b-3p on MMP-19 expression was evaluated using transient transfection of normal human chondrocytes with miR-193b-3p mimic or its antisense inhibitor (miR-193b-3p inhibitor), and siMMP-19. The putative binding site of miR-193b-3p in the 3'-untranslated region (UTR) of MMP-19 mRNA was validated by luciferase reporter assay. miR-193b-3p expression was reduced in OA cartilage compared to that in normal chondrocytes, while the opposite was observed for MMP-19. Upregulation of MMP-19 expression was correlated with downregulation of miR-193b-3p in IL-1ß-stimulated normal chondrocytes. Increase in miR-193b-3p levels was associated with silencing of MMP-19. Overexpression of miR-193b-3p suppressed the activity of the reporter construct containing the 3'-UTR of human MMP-19 mRNA and inhibited the IL-1ß-induced expression of MMP-19 and iNOS in chondrocytes, while treatment with miR-193b-3p inhibitor enhanced MMP-19 expression. MiR-193b-3p is an important regulator of MMP-19 in human chondrocytes and may relieve the inflammatory response in OA.

A Photochemical Route to 3- and 4-Hydroxy Derivatives of 2-Aminocyclobutane-1-carboxylic Acid with an all-cis Geometry.

Short gram-scale syntheses of both enantiomers of 2-amino-3-hydroxycyclobutane-1-carboxylic acid and of 2-amino-4-hydroxycyclobutanecarboxylic acid with an all-cis geometry are described. The sequences feature highly endo-selective [2 + 2]-photocycloaddition reactions followed by fully regioselective ring opening/Hofmann rearrangement/nitrogen protection, in a consecutive or one-pot protocol, followed by efficient resolution using a chiral oxazolidinone.

Preparation of Cyclobutene Acetals and Tricyclic Oxetanes through Photochemical Tandem and Cascade Reactions.

We describe a photochemical reaction using two starting materials, a cyclopent-2-enone and an alkene, which are transformed in a controlled manner via the initial [2+2]-photocycloaddition adducts into cyclobutene aldehydes (conveniently trapped as stable acetals) or unprecedented angular tricyclic 4:4:4 oxetane-containing skeletons. These compounds are formed through tandem or triple cascade photochemical reaction processes, respectively. Small libraries of each compound class were prepared, thus suggesting that this photochemistry approach opens new opportunities for synthesis design and for widening molecular diversity.

Amorphous Albumin Gadolinium-Based Nanoparticles for Ultrahigh-Resolution Magnetic Resonance Angiography.

Magnetic resonance angiography (MRA) contrast agents are extensively utilized in clinical practice due to their capability of improving the image resolution and sensitivity. However, the clinically approved MRA contrast agents have the disadvantages of a limited acquisition time window and high dose administration for effective imaging. Herein, albumin-coated gadolinium-based nanoparticles (BSA-Gd) were meticulously developed for in vivo ultrahigh-resolution MRA. Compared to Gd-DTPA, BSA-Gd exhibits a significantly higher longitudinal relaxivity (r1 = 76.7 mM-1 s-1), nearly 16-fold greater than that of Gd-DTPA, and an extended blood circulation time (t1/2 = 40 min), enabling a dramatically enhanced high-resolution imaging of microvessels (sub-200 µm) and low dose imaging (about 1/16 that of Gd-DTPA). Furthermore, the clinically significant fine vessels were successfully mapped in large mammals, including a circle of Willis, kidney and liver vascular branches, tumor vessels, and differentiated arteries from veins using dynamic contrast-enhanced MRA BSA-Gd, and have superior imaging capability and biocompatibility, and their clinical applications hold substantial promise.

Single-dye NIR-II chemiluminescence system for H2O2 imaging.

An efficient single-dye NIR-II CL system was proposed for the first time with the longest emission peak around 1000 nm. Biocompatible CL nanoparticles were developed and a surprising CL intensity enhancement was found in the presence of the BASZn nanoenzyme by about three orders of magnitude. Such an NIR-II CL system was demonstrated for glucose sensing, tumor therapy and in vivo H2O2 imaging. Via theoretical and experimental analyses, a novel electron transfer model was established for such a chemiluminescence system rather than the generally considered HOMODye-LUMODOD model. These findings provide useful guidelines for designing efficient single-dye NIR-II CL systems.

Human influence on the population decline and loss of genetic diversity in a small and isolated population of Sichuan snub-nosed monkeys (Rhinopithecus roxellana).

Human activities have caused worldwide loss and fragmentation of natural habitats, resulting in the decline and isolation of wild populations, consequently increasing their risks of extinctions. We investigated the genetic consequences of anthropogenic effects on the Sichuan snub-nosed monkeys (Rhinopithecus roxellana) in the Shennongjia Nature Reserve (SNR), which is a small and isolated distribution of R. roxellana in China and would continue to be threatened by habitat degradation and loss, using extensive sampling and 16 microsatellite loci. High level of genetic variation was observed from 202 individuals collected from three R. roxellana populations (SNR population, Sichuan-Gansu population and Shaanxi population). However, R. roxellana in SNR showed the lowest genetic diversity. The likelihood analysis of migration/drift equilibrium indicated that the SNR population suffered much stronger effect of drift than the other two populations, indicating that small populations are prone to be affected by drift. The STRUCTURE analysis identified two clusters, separating the SNR population from the other two populations, suggesting an increasing drift-induced differentiation between SNR and the other two populations. Bottleneck tests revealed that R. roxellana in SNR experienced a severe population decline (37-fold) during the past 500 years as a consequence of human population expansion. The current effective population size (Ne) in SNR is less than 100 and the ratio of Ne to the census population size is approximately 0.08. Based on our findings, we suggest that the SNR population should be monitored systematically and considered as an important conservation and management unit.

BSA-Coated Gold Nanorods for NIR-II Photothermal Therapy.

The second near infrared window is considered to be the optimal optical window for medical imaging and therapy as its capability of deep tissue penetration. The preparation of the gold nanorods with long wavelength absorption and low cytotoxicity is still a challenge. A series gold nanorods with large aspect ratio have been synthesized. Strong plasma absorption in the second near infrared window from 1000 to 1300 nm could be observed. The biocompatibility of the synthesized gold nanorods is dramatically improved via coating by bovine serum albumin (BSA), while the optical properties of which remains. The breast cancer tumor-bearing mouse could be well treated by the prepared gold nanorods with the NIR-II light intensity as low as 0.75 W/cm2. In summary, these results demonstrate the feasibility of using low illumination dose to treat tumor in the NIR-II region via the large aspect ratio gould nanoparticles.

Recent development of the mononuclear phagocyte system: in memory of Metchnikoff and Ehrlich on the 100th Anniversary of the 1908 Nobel Prize in Physiology or Medicine.

Monocytes/macrophages are critical for both immunity and homoeostasis. They are the outposts of the immune system in detecting invading pathogens or foreign antigens for homoeostatic clearance and antigen processing for the initiation and effector stages of both innate and adaptive immunity. In addition, monocytes/macrophages often function as control switches for immune system balance between pro- and anti-inflammatory reactions. In the beginning of this article, I would like to briefly introduce the achievements of Metchnikoff and Ehrlich in immunology, including Metchnikoff's cell theory, since they have both greatly influenced the advancement of modern immunology. Additionally, I will honour the 100th anniversary of the 1908 Nobel Prize in Physiology or Medicine. Next, I would like to emphasize the concept of the MPS (mononuclear phagocyte system) by examining recent developments regarding the MPS. Thus the article consists of three parts. The first part describes the regulation of growth and differentiation in the MPS. The second part addresses how the key macrophage transcription factor gene PU.1 and the csf1r (colony-stimulating factor-1 receptor gene) play a critical role in haematopoietic myelopoiesis, or the generation of the cells of the MPS. The third part describes PMA-induced monocyte/macrophage differentiation and immune modulation of suppressor macrophages. Finally, this review discusses the latest findings and implications regarding the MPS and macrophages.

General and chemoselective bisphosphonylation of secondary and tertiary amides.

With Tf2O as the activation reagent, a mild and general method has been developed for the bisphosphonylation of both secondary and tertiary amides. The protocol is highly efficient and chemoselective, and it tolerates a number of sensitive functional groups such as cyano, ester, and aldehyde groups.

Enantioselective total synthesis of (+)-methoxystemofoline and (+)-isomethoxystemofoline.

The first enantioselective total synthesis of (+)-methoxystemofoline (2) and (+)-isomethoxystemofoline (3) has been reported. The synthesis employed the halide-assisted bromotropanonation method that we developed recently to construct the core structure, and Overman's strategy for the implementation of the butenolide moiety. Through this work, the structure of methoxystemofoline was revised as with an E-alkene, and its absolute configuration was established.

IFN-gamma activates cAMP/PKA/CREB signaling pathway in murine peritoneal macrophages.

Interferon-gamma (IFN-gamma) is a macrophage-activating cytokine that serves critical functions in innate and adaptive immunity and is thought to be mediated by the Jak-Stat signaling pathway. The present study establishes for the first time that cyclic adenosine monophosphate, protein kinase A, and cAMP response element-binding protein (cAMP/PKA/CREB) are coregulators of the IFN-gamma signaling pathway. Experimental data indicate that exogenous IFN-gamma stimulated cAMP accumulation and PKA activation in time-dependent and dose-dependent manners in murine peritoneal macrophages. Moreover, IFN-gamma stimulated CREB phosphorylation and CREB DNA binding, which could be significantly attenuated by PKA inhibition with H89. It appears that a novel cAMP/PKA/CREB signaling pathway is activated by IFN-gamma in macrophages, suggesting that an alternate signaling pathway exists in macrophages in response to IFN-gamma.

cAMP elevators inhibit LPS-induced IL-12 p40 expression by interfering with phosphorylation of p38 MAPK in murine peritoneal macrophages.

cAMP mediated signaling may play a suppressive role in immune response. We previously found that the cAMP-elevators (CTx and 8-Br-cAMP) inhibited IL-12, IL-la, IL-6 gene expression, but increased the transcriptional levels of IL-10 and IL-1Ra in LPS-treated murine peritoneal macrophages. The present study examined a possible molecular mechanism involved in cAMP elevators-induced inhibition of IL-12 p40 expression in response to LPS. Our data demonstrated that cAMP elevators downregulated IL-12 p40 mRNA expression and IL-12 p70 production in murine peritoneal macrophages. Subsequent studies revealed that cAMP-elevators blocked phosphorylation of p38 MAPK, but did not affect the activity of NF-kappaB binding to IL-12 promoter (-136/-112). This is the first report that cAMP elevators inhibit LPS-induced IL-12 production by a mechanism that is associated, at least in part, with p38-dependent inhibition by cAMP signaling pathways.

Immunomodulated Signaling in Macrophages:Regulation of the MAPK Signaling Pathways by PKA and PKC.

Previous experimental investigation indicated that immuno-suppressor activities of suppressor macrophages on T B lymphocytes and NK cells could be prevented by treatment with LPS but the tumoricidal activities of those macrophages could be kept or even enhanced after the same treatment. During this complicated course LPS-mediated immuno-modulation was accompanied by activation of PKC and MAPK signal pathways. In order to explore the effect of another signal on MAPK pathway this model of immuno-modulated macrophage was utilized to study the regulatory effect on the activation of three family members of MAPK (ERK1/2 JNK and p38) by cAMP/PKA and PMA/PKC. The results showed that 1) LPS-mediated immuno-modulation was accompanied by dynamic changes of intracellular cAMP amount and PKA activity. 2) A specific PKC activator PMA induced strongly the activation of ERK1/2 JNK and p38 MAPK. 3) In contrast the activation of cAMP/PKA mediated a significant inhibiton of the phosphorylation of ERK1/2 JNK and p38 MAPK and ATF-2 but it enhanced the phosphorylation of CREB. These results suggest that a complicated "cross-talk" may exist among PKC and PKA and MAPK signaling pathways in the regulation of murine peritoneal suppressor macrophages by LPS.

[Association of the polymorphism of platelet membrane glycoprotein I a gene with myocardial infarction].

OBJECTIVE: Platelet membrane glycoprotein (GP) Ia/IIa complex is the major collagen receptor on platelets. Platelet activation by GP Ia/ IIa dependent adhesion leads to cellular events that catalyze prothrombin conversion and fibrin clot formation. Correlation between the polymorphism of platelet membrane GP Ia gene and myocardial infarction (MI) was explored. METHODS: A total of 137 patient s with myocardial infarction and 175 controls with no history of coronary heart disease, thrombogenic and hemorrhagenic diseases were studied by case-control. Platelet GP I a gene 807 C/T polymorphisms were checked by polymerase chain reaction-sequence specific primers. RESULTS: There were significant differences in the distribution of T and C alleles between MI and control groups (T:42.70% vs 32.00%, C:57.30% vs 68.00%, P<0.001). No matter among all subjects or among subjects aged

Versatile construction of functionalized tropane ring systems based on lactam activation: enantioselective synthesis of (+)-pervilleine B.

The halo-assisted intramolecular addition of silyl enol ethers with in situ activated lactams yielded (hydroxylated) 1-halo-8-azabicyclo[3,2,1]octane and 1-halo-9-azabicyclo[3,3,1]nonane ring systems, which provided an easy enantioselective access to 6ß-silyloxytropane-3-one, 3α,6ß-dihydroxytropane, and pervilleine B. The absolute configuration of the natural (-)-pervilleine B was determined to be 1R,3R,5S,6R.

Use of covered Cheatham-Platinum stent as the primary modality in the treatment for native coarctation of the aorta.

BACKGROUND: Bare stent implantation in the treatment for native and recurrent coarctation of the aorta (CoA) has become established as an alternative to surgery and balloon angioplasty. However, this modality still encounters significant complications during the procedure and/or follow-up. The covered Cheatham-Platinum (CP) stent commonly used to be chosen as a rescue treatment in these patients. The purpose of this study was to evaluate the use of covered CP stent as the primary modality in the treatment for native CoA. METHODS: Twenty-five covered CP stents and 2 bare CP stents were implanted in 25 patients with native CoA. All patients after the intervention were invited for follow-up examinations. RESULTS: The peak systolic gradient across the lesion decreased significantly from a median value of 67.5 mmHg (quartile range, 19.3 mmHg) to 2 mmHg (quartile range, 4.0 mmHg) (P < 0.0001). Stenotic segment diameter increased from a median value of 5.0 mm (quartile range, 1.5 mm) to 17.9 mm (quartile range, 2.5 mm) (P < 0.0001). The median ratio of diameter of the coarctation postprocedure to preprocedure was 4.2 (quartile range, 1.6). All of the CP stents were placed in the suitable position without any acute complications. During a follow-up period of up to 72 months, no complications were encountered. Most of the patients (21/25) were normotensive, apart from four patients requiring antihypertensive medication during the follow-up. CONCLUSION: The implantation of covered CP stent as the primary modality is safe and effective in the treatment for native CoA in adolescents and adults.