Molecular Design of Highly Efficient Heavy-Atom-free NpImidazole Derivatives for Two-Photon Photodynamic Therapy and ClO- Detection.

Two-photon photodynamic therapy (TP-PDT), as a treatment technology with deep penetration and less damage, provides a broad prospect for cancer treatment. Nowadays, the development of TP-PDT suffers from the low two-photon absorption (TPA) intensity and short triplet state lifetime of photosensitizers (PSs) used in TP-PDT. Herein, we propose some novel modification strategies based on the thionated NpImidazole (the combination of naphthalimide and imidazole) derivatives to make efforts on those issues and obtain corresponding fluorescent probes for detecting ClO- and excellent PSs for TP-PDT. Density functional theory (DFT) and time-dependent DFT (TD-DFT) are used to help us characterize the photophysical properties and TP-PDT process of the newly designed compounds. Our results show that the introduction of different electron-donating groups at the position 4 of NpImidazole can effectively improve their TPA and emission properties. Specifically, 3s with a N,N-dimethylamino group has a large triplet state lifetime (τ = 699 µs) and TPA cross section value (δTPA = 314 GM), which can effectively achieve TP-PDT; additionally, 4s (with electron-donating group 2-oxa-6-azaspiro[3.3]heptane in NpImidazole) effectively realizes the dual-function of a PS for TP-PDT (τ = 25,122 µs, δTPA = 351 GM) and a fluorescent probe for detecting ClO- (Φf = 29% of the product 4o). Moreover, an important problem is clarified from a microscopic perspective, that is, why the transition property of 3s and 4s (1π-π*) from S1 to S0 is different from that of 1s and 2s (1n-π*). It is hoped that our work can provides valuable theoretical clues for the design and synthesis of heavy-atom-free NpImidazole-based PSs and fluorescent probes for the detection of hypochlorite.

Theoretical Investigation of Ru(II) Complexes with Long Lifetime and a Large Two-Photon Absorption Cross-Section in Photodynamic Therapy.

Two-photon photodynamic therapy (TP-PDT), as a new method for cancer, has shown unique advantages in tumors. A low two-photon absorption cross-section (δ) in the biologic spectral window and a short triplet state lifetime are the important issues faced by the current photosensitizers (PSs) in TP-PDT. In this paper, the photophysical properties of a series of Ru(II) complexes were studied by density functional theory and time-dependent density functional theory methods. The electronic structure, one- and two-photon absorption properties, type I/II mechanisms, triplet state lifetime, and solvation free energy were calculated. The results showed that the substitution of methoxyls by pyrene groups greatly improved the lifetime of the complex. Furthermore, the addition of acetylenyl groups subtly enhanced δ. Overall, complex 3b possess a large δ(1376 GM), a long lifetime (136 µs), and better solvation free energy. It is hoped that it can provide valuable theoretical guidance for the design and synthesis of efficient two-photon PSs in the experiment.

Photophysical Exploration of Zn(II) Polypyridine Photosensitizers in Two-Photon Photodynamic Therapy: Insights from Theory.

The high incidence and difficulties of treatment of cancer have always been a challenge for mankind. Two-photon photodynamic therapy (TP-PDT) as a less invasive technique provides a new perspective for tumor treatment due to its low-energy near-infrared excitation, high targeting, and minor damage. At present, the emerging metal complexes used as the photosensitizers (PSs) in TP-PDT have aroused great interest. However, most metal complexes as PSs in TP-PDT still face some problems, such as slow clearance, unsatisfactory two-photon absorption (TPA) characteristics, high price, low reactivity, and poor solubility. In this work, density functional theory and time-dependent density functional theory were used to characterize the one/two-photon response, solvation free energy, and lipophilicity of a series of novel PSs applied in TP-PDT. The results suggest that based on complex 1, replacing Ru(II) center with Zn(II) (complex 2) can effectively prolong the triplet excited state lifetime while reducing the cost and environmental pollution, and the azetidine heterospirocycles were introduced into the ligand scaffold (complex 3), which effectively reduced the vibration relaxation of the ligand group and improved the water solubility; further, the addition of acetylenyl groups subtly enhanced the light absorption and significantly improved the two-photon response (complex 4). In addition, all complexes met the requirement of a PS and could be used as potential candidates for TP-PDT. In particular, complex 4 has the advantages of high solvation free energy, a large TPA cross-section (1413 GM), a long triplet state lifetime (671 µs), good chemical reactivity, and low cost, and it is easy to be scavenged by organisms. Overall, this contribution may provide an important clue to formulate clear design principles for type I/II PSs and rational design of PSs with high intersystem crossing rates, a long lifetime, and therapeutic excitation wavelengths.

A Theoretical Investigation into the Homo- and Hetero-leptic Cu(I) Phosphorescent Complexes Bearing 2,9-dimethyl-1,10-phenanthroline and bis [2-(diphenylphosphino)phenyl]ether Ligand.

Cu(I) complexes have received widespread attention as a promising alternative to traditional noble-metal complexes. Herein, we systematically study the properties of Cu(I) complexes from homo- to hetero-ligands, and found the following: (1) hetero-ligands are beneficial to regulate phosphorescent efficiency; (2) when the hetero-ligands in a tetracoordinated Cu(I) complex are 1:1, the ligands coordinate along the dx2-y2 direction of Cu(I) ion, which can observably suppress structural deformation; (3) unlike the P^P ligand, the N^N ligand can enhance the participation of Cu(I) during the transition process; (4) the addition of an appropriate amount of P^P ligand can effectively raise the energy level of HOMO (highest occupied molecular orbital), enhance the proportion of LLCT (ligand-ligand charge transfer), and thereby increase the available singlet emission transition moments which can be borrowed, thus promoting the radiative decay process. As a result, this work provides a detailed understanding of the effects of different ligands in Cu(I) complexes, and provides a valuable reference and theoretical basis for regulating and designing the phosphorescent properties of Cu(I) complexes in the future.

Theoretical study and application of 2-phenyl-1,3,4-thiadiazole derivatives with optical and inhibitory activity against SHP1.

Src homology-2 domain-containing protein tyrosine phosphatase 1 (SHP1) is mainly restricted to hematopoietic and epithelial cells and widely accepted as a convergent node for oncogenic cell-signaling cascades. The development of efficient methods for rapidly tracing and inhibiting the SHP1 activity in complex biological systems is of considerable significance for advancing the integration of diagnosis and treatment of the related disease. With this aim, we designed and synthesized five 2-phenyl-1,3,4-thiadiazole derivatives (PT2, PT5, PT8, PT9 and PT10) here based on the reported SHP1 inhibitors (PT1, PT3, PT4, PT6 and PT7). The photophysical properties and inhibitory activities of these 2-phenyl-1,3,4-thiadiazole derivatives (PT1-PT10) against SHP1 were thoroughly studied from the theoretical simulation and experimental application aspects. The representative compound PT10 exhibited a larger quantum yield than the other molecules because of the smaller geometric relaxation and reorganization energy of the excited state, which was consistent with the results from the fluorescence experiments in organic solvents. In addition, PT10 showed a selective fluorescence response for SHP1 activity and low cytotoxicity in HeLa cells. Lastly, it indicated the potential application in two-photon cell fluorescence imaging in the future according to the calculated excellent two-photon absorption properties. In this contribution, firstly, we offered the fluorescent and activated molecule PT10 against SHP1, which achieved the integration of visualization and inhibitory activity of SHP1 preliminarily at the enzyme molecular level.

Theoretical design and investigation of 1,8-naphthalimide-based two-photon fluorescent probes for detecting cytochrome P450 1A with separated fluorescence signal.

As a type of enzyme with a terminal oxygen, the CYP1A subfamily possesses the ability to catalyze the reactions of many environmental toxins, endogenous substrates and clinical drugs. The development of efficient methods for the rapid and real-time detection of CYP1A enzyme activity in complex biological systems is of considerable significance for identifying potential abnormalities in these cancer-related enzymes. With this goal, we firstly provided a series of 1,8-naphthalimide-based two-photon fluorescent chromophores with large two-photon absorption (TPA) cross-sections (500-7000 GM) and remarkable changes in fluorescence spectra upon recognizing the CYP1A enzyme from its theoretical aspect. Moreover, we have thoroughly studied the effects of cyclic acceptor (dichlorobenzene and benzothiadiazole) and donor (fluorene and carbazole) groups on the one-photon absorption (OPA), TPA, and fluorescence properties of CYP1A enzyme probes and the corresponding reaction products. The connection of a heterocycle as the donor group to a 1,8-naphthalimide-based molecule to form a D-π-A-π-D-type electronic structure can effectively cause red shifts in the absorption and emission wavelengths to facilitate bioimaging in the near infrared (NIR) region, which is attributed to the lower transition energy, larger transition dipole moment and amount of transferred charge. Docking analysis suggests that the two-photon fluorescent probes NCMN-3 and NCMN-5 that were designed will guarantee and achieve excellent selectivity for the CYP1A enzyme.

A ten-microRNA signature identified from a genome-wide microRNA expression profiling in human epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is the most common gynecologic malignancy. To identify the micro-ribonucleic acids (miRNAs) expression profile in EOC tissues that may serve as a novel diagnostic biomarker for EOC detection, the expression of 1722 miRNAs from 15 normal ovarian tissue samples and 48 ovarian cancer samples was profiled by using a quantitative real-time polymerase chain reaction (qRT-PCR) assay. A ten-microRNA signature (hsa-miR-1271-5p, hsa-miR-574-3p, hsa-miR-182-5p, hsa-miR-183-5p, hsa-miR-96-5p, hsa-miR-15b-5p, hsa-miR-182-3p, hsa-miR-141-5p, hsa-miR-130b-5p, and hsa-miR-135b-3p) was identified to be able to distinguish human ovarian cancer tissues from normal tissues with 97% sensitivity and 92% specificity. Two miRNA clusters of miR183-96-183 (miR-96-5p, and miR-182, miR183) and miR200 (miR-141-5p, miR200a, b, c and miR429) are significantly up-regulated in ovarian cancer tissue samples compared to those of normal tissue samples, suggesting theses miRNAs may be involved in ovarian cancer development.

[Effect of Tongfu granules and its constituents on barrier function of small intestine in rats with sepsis].

OBJECTIVE: To investigate the effects of Tongfu granules and its constituents on barrier function of small intestine in rats with sepsis. METHODS: The male rats were divided into model group, Tongfu granules group, Rhubarb group and Magnoliae cortex group by random digits table, normal rats as control group. Intraperitoneal injection of lipopolysaccharide (LPS, 6 mg/kg) was used to reproduce sepsis model. After establishment of model, rats in Tongfu granules group were given Tongfu granules 28 g×kg(-1)×d(-1) by gavage, and Rhubarb group and Magnoliae cortex group rats were given Rhubarb or Magnoliae cortex 5 g×kg(-1)×d(-1) by gavage, while the model group was given normal saline in same quantity, once a day. Blood samples of rats were collected at 24, 48, 72 hours for measuring tumor necrosis factor-α (TNF-α) and interleukin-8 (IL-8) with enzyme linked immunosorbent assay (ELISA). The pathological changes in intestinal mucosa were observed, and the pathological scores was estimated at 72 hours. RESULTS: The levels of TNF-α and IL-8 were significantly higher in model group than those in control group at different time points. The serum levels of TNF-α and IL-8 were significantly lower in treatment groups than those in model group, and the level of TNF-α (ng/L) in Tongfu granules group was significantly lower than that in Rhubarb and Magnoliae cortex groups at different time points (24 hours: 44.64±1.48 vs. 47.18±1.83 and 46.96±2.23, 48 hours: 51.38±1.36 vs. 57.17±2.23 and 59.41±2.01, 72 hours: 55.54±2.58 vs. 64.34±1.02 and 65.96±3.45, all P<0.05), and IL-8 (ng/L) level at 72 hours was significantly lower than that in Magnoliae cortex group (65.53±4.52 vs. 69.14±2.82,P<0.05). The scores of the lesions were significantly higher in model group than that in control group (3.90±0.17 vs. 0). The scores of Rhubarb group, Magnoliae cortex group and Tongfu granules group were 3.15±0.28, 3.18±0.08, and 2.95±0.15, respectively, which were lower than those of the model group (all P<0.01), and the Tongfu granules group descended obviously than other groups. In control group, the intercellular tight junctions were normal, and the morphology of microvilli and mitochondria was also normal. In model group, the microvilli of intestinal mucosa of the small intestine were absent or disintegrated. The intercellular tight junctions were seen to be blurred in Rhubarb and Magnoliae cortex groups, and they were close to normal state in Tongfu granules group. Their integrity was better preserved compared with that of the model group. CONCLUSION: Injury of barrier function of the small intestine was found in septic rat. It was found that traditional Chinese medicine Tongfu granules, Rhubarb and Magnoliae cortex could protect the barrier function of the small intestine by decreasing the TNF-α and IL-8 levels in septic rats. Above-mentioned effects of Tongfu granules were better than Rhubarb and Magnoliae cortex.

Theoretical investigation on the origin of yellow-green firefly bioluminescence by time-dependent density functional theory.

The question whether the emitter of yellow-green firefly bioluminescence is the enol or keto-constrained form of oxyluciferin (OxyLH(2)) still has no definitive answer from experiment or theory. In this study, Arg220, His247, adenosine monophosphate (AMP), Water324, Phe249, Gly343, and Ser349, which make the dominant contributions to color tuning of the fluorescence, are selected to simulate the luciferase (Luc) environment and thus elucidate the origin of firefly bioluminescence. Their respective and compositive effects on OxyLH(2) are considered and the electronic absorption and emission spectra are investigated with B3LYP, B3PW91, and PBE1KCIS methods. Comparing the respective effects in the gas and aqueous phases revealed that the emission transition is prohibited in the gas phase but allowed in the aqueous phase. For the compositive effects, the optimized geometry shows that OxyLH(2) exists in the keto(-1) form when Arg220, His247, AMP, Water324, Phe249, Gly343, and Ser349 are all included in the model. Furthermore, the emission maximum wavelength of keto(-1)+Arg+His+AMP+H(2)O+Phe+Gly+Ser is close to the experimental value (560 nm). We conclude that the keto(-1) form of OxyLH(2) is a possible emitter which can produce yellow-green bioluminescence because of the compositive effects of Arg220, His247, AMP, Water324, Phe249, Gly343, and Ser349 in the luciferase environment. Moreover, AMP may be involved in enolization of the keto(-1) form of OxyLH(2). Water324 is indispensable with respect to the environmental factors around luciferin (LH(2)).

Magnolol attenuates sepsis-induced gastrointestinal dysmotility in rats by modulating inflammatory mediators.

AIM: To investigate the protective effects of magnolol on sepsis-induced inflammation and intestinal dysmotility. METHODS: Sepsis was induced by a single intraperitoneal injection of lipopolysaccharide (LPS). Male Wistar rats were randomly assigned to one of three treatment groups: magnolol prior to LPS injection (LPS/Mag group); vehicle prior to LPS injection (LPS/Veh group); vehicle prior to injection of saline (Control/Veh). Intestinal transit and circular muscle mechanical activity were assessed 12 h after LPS injection. Tumor necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10), monocyte chemoattractant protein-1 (MCP-1) and inducible nitric oxide synthase (iNOS) mRNA in rat ileum were studied by RT-PCR 2 h after LPS injection. Nuclear factor-kappaB (NF-kappaB) activity in the intestine was also investigated at this time using electrophoretic mobility shift assay. In addition, antioxidant activity was determined by measuring malondialdehyde (MDA) concentration and superoxide dismutase (SOD) activity in the intestine 2 h after LPS injection. RESULTS: Magnolol significantly increased intestinal transit and circular muscle mechanical activity in LPS-treated animals. TNF-alpha, MCP-1 and iNOS mRNA expression in the small intestine were significantly reduced after magnolol treatment in LPS-induced septic animals, compared with untreated septic animals. Additionally, magnolol significantly increased IL-10 mRNA expression in septic rat ileum. Magnolol also significantly suppressed NF-kappaB activity in septic rat intestine. In addition, magnolol significantly decreased MDA concentration and increased SOD activity in rat ileum. CONCLUSION: Magnolol prevents sepsis-induced suppression of intestinal motility in rats. The potential mechanism of this benefit of magnolol appears to be modulation of self-amplified inflammatory events and block of oxidative stress in the intestine.