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The intestinal flora of the human body is closely related to health. Gut microbiota dysbiosis will lead to intestinal dysfunction and, consequently, a variety of intestinal diseases. In this study, subjects with different diseases were requested to take one of three microecological agents, stachyose, composite probiotics (CPb) and synbiotic MF-13. An Ion Torrent PGM™ sequencing platform was used to analyze the structure of intestinal microflora and the contents of cholesterol and bile acid in the feces of the subjects were measured. Our aim was to investigate the regulatory effect of intervention with microecological agents on the intestinal microflora structure and lipid metabolism. The results showed that 1 067 operational taxonomic units (OUT) were obtained from the fecal microbial samples from all subjects. The dominant bacteria were Firmicutes and Bacteroidetes, altogether accounting for 91.65%, and Bacteroidetes accounting for about 70.10% of the total number of sequences. Bacteroides and Prevotella were the dominant genera, accounting for 33.1% and 33.8% of the total sequences, respectively. At the phylum level, stachyose promoted the proliferation of Bacteroidetes, but inhibited the proliferation of Firmicutes. CPb had no significant effect on the abundance of each phylum, while MF-13 promoted the proliferation of Proteobacteria and Actinobacteria. Stachyose significantly decreased the abundance of Sutterella in subjects with constipation and insomnia, CPb significantly decreased the abundance of Sutterella in subjects with diarrhea, and MF-13 increased the abundance of Parabacteroides. The analysis of intestinal microflora diversity showed that Chao1 index significantly increased during the early period of MF-13 intervention, while there were no significant changes in other diversity indexes. Cluster analysis and non-metric multi-dimensional scaling (NMDS) analysis showed that microecological preparation intervention changed the intestinal microbiota structure in most of the samples, and the microflora structure of all populations showed an overlapping tendency. The intestinal microflora species that significantly differed between individuals were analyzed using Metastat statistics, and it was found that there was no significant change in the abundance of OTUs before and after intervention with each microecological agent, while there was a significant difference between individual subjects. MF-13 significantly promoted the fecal excretion of cholesterol and bile acids (P < 0.05). In conclusion, stachyose has an obvious influence on the intestinal microflora structure of volunteers, while CPb and MF-13 do not. However, MF-13 can increase the intestinal excretion of cholesterol and bile acid, which is beneficial to the metabolism of intestinal cholesterol, but the durability of this effect is poor.

Abstract Background As digital medicine has exerted profound influences upon diagnosis and treatment of hepatobiliary diseases, our study aims to investigate the accuracy of three-dimensional visualization and evaluation (3DVE) system in assessing the resectability of hilar cholangiocarcinoma (hCCA), and explores its potential clinical value. Materials and methods The discovery cohort, containing 111 patients from April 2013 to December 2019, was retrospectively included to determine resectability according to revised criteria for unresectability of hCCA. 3D visualization models were reconstructed to evaluate resectability parameters including biliary infiltration, vascular involvement, hepatic atrophy and metastasis. Evaluation accuracy were compared between contrast-enhanced CT and 3DVE. Logistic analysis was performed to identify independent risk factors of R0 resection. A new comprehensive 3DVE classification of hCCA based on factors influencing resectability was proposed to investigate its role in predicting R0 resection and prognosis. The main outcomes were also analyzed in cohort validation, including 34 patients from January 2020 to August 2022. Results 3DVE showed an accuracy rate of 91% (95%CI 83.6–95.4%) in preoperatively evaluating hCCA resectability, significantly higher than 81% (95%CI 72.8–87.7%) of that of CT (p = 0.03). By multivariable analysis, hepatic artery involvement in 3DVE was identified an independent risk factor for R1 or R2 resection (OR = 3.5, 95%CI 1.4,8.8, P

BackgroundImmune checkpoint inhibitor (ICI)-based combination therapy has opened a new avenue for the treatment of multiple malignancies including hepatocellular carcinoma (HCC). However, considering the unsatisfactory efficacy, biomarkers are urgently needed to identify the patients most likely to benefit from ICI-based combination therapy.MethodsA total of 194 patients undergoing ICI-based combination therapy for unresectable HCC were retrospectively enrolled and divided into a training cohort (n = 129) and a validation cohort (n = 65) randomly. A novel circulating immune index (CII) defined as the ratio of white blood cell count (×109/L) to lymphocyte proportion (%) was constructed and its prognostic value was determined and validated.ResultsPatients with CII ≤ 43.1 reported prolonged overall survival (OS) compared to those with CII > 43.1 (median OS: 24.7 vs 15.1 months; 6-, 12-, 18-month OS: 94.2%, 76.7%, 66.1% vs 86.4%, 68.2%, 22.8%, P = 0.019), and CII was identified as an independent prognostic factor for OS (hazard ratio, 2.24; 95% confidence interval, 1.17-4.31; P = 0.015). These results were subsequently verified in the validation cohort. Additionally, patients with low CII levels had improved best radiological tumor response (complete response, partial response, stable disease, progressive disease: 3%, 36%, 50%, 11% vs 0%, 27%, 46%, 27%; P = 0.037) and disease control rate (89% vs 73%; P = 0.031) in the pooled cohort and better pathologic response (pathologic complete response, major pathologic response, partial pathologic response, no pathologic response: 20%, 44%, 28%, 8% vs 0%, 0%, 40%, 60%; P = 0.005) in the neoadjuvant cohort. Detection of lymphocyte subsets revealed that an elevated proportion of CD4+ T cells was related to better OS, while the proportion of CD8+ T cells was not.ConclusionsWe constructed a novel circulating immune biomarker that was capable of predicting OS and therapeutic efficacy for HCC patients undergoing ICI and lenvatinib combination therapy.

BackgroundLenvatinib monotherapy and combination therapy with immune checkpoint inhibitors (ICI) were widely applied for unresectable hepatocellular carcinoma (uHCC). However, many patients failed to benefit from the treatments. A prognostic model was needed to predict the treatment outcomes and guide clinical decisions.Methods304 patients receiving lenvatinib monotherapy or lenvatinib plus ICI for uHCC were retrospectively included. The risk factors derived from the multivariate analysis were used to construct the predictive model. The C-index and area under the receiver-operating characteristic curve (AUC) were calculated to assess the predictive efficiency.ResultsMultivariate analysis revealed that protein induced by vitamin K absence or antagonist-II (PIVKA-II) (HR, 2.05; P=0.001) and metastasis (HR, 2.07; P600 mAU/mL) and PIMET-high group (with metastasis and PIVKA-II>600 mAU/mL). The C-index of PIMET score for the survival prediction was 0.63 and 0.67 in the training and validation cohort, respectively. In the training cohort, the AUC of 12-, 18-, and 24-month OS was 0.661, 0.682, and 0.744, respectively. The prognostic performances of the model were subsequently validated. The AUC of 12-, 18-, and 24-month OS was 0.724, 0.726, and 0.762 in the validation cohort. Subgroup analyses showed consistent predictive value for patients receiving lenvatinib monotherapy and patients receiving lenvatinib plus ICI. The PIMET score could also distinguish patients with different treatment responses. Notably, the combination of lenvatinib and ICI conferred survival benefits to patients with PIMET-int or PIMET-high, instead of patients with PIMET-low.ConclusionThe PIMET score comprising metastasis and PIVKA-II could serve as a helpful prognostic model for uHCC receiving lenvatinib monotherapy or lenvatinib plus ICI. The PIMET score could guide the treatment decision and facilitate precision medicine for uHCC patients.

Abstract Pancreatic cancer is an increasingly common cause of cancer mortality with a tight correspondence between disease mortality and incidence. Furthermore, it is usually diagnosed at an advanced stage with a very dismal prognosis. Due to the high heterogeneity, metabolic reprogramming, and dense stromal environment associated with pancreatic cancer, patients benefit little from current conventional therapy. Recent insight into the biology and genetics of pancreatic cancer has supported its molecular classification, thus expanding clinical therapeutic options. In this review, we summarize how the biological features of pancreatic cancer and its metabolic reprogramming as well as the tumor microenvironment regulate its development and progression. We further discuss potential biomarkers for pancreatic cancer diagnosis, prediction, and surveillance based on novel liquid biopsies. We also outline recent advances in defining pancreatic cancer subtypes and subtype-specific therapeutic responses and current preclinical therapeutic models. Finally, we discuss prospects and challenges in the clinical development of pancreatic cancer therapeutics.

BackgroundTumor recurrence after hepatectomy is high for hepatocellular carcinoma (HCC), and minimal residual disease (MRD) could be the underlying mechanism. A predictive model for recurrence and presence of MRD is needed.MethodsCommon inflammation-immune factors were reviewed and selected to construct novel models. The model consisting of preoperative aspartate aminotransferase, C-reactive protein, and lymphocyte count, named ACLR, was selected and evaluated for clinical significance.ResultsAmong the nine novel inflammation-immune models, ACLR showed the highest accuracy for overall survival (OS) and time to recurrence (TTR). At the optimal cutoff value of 80, patients with high ACLR (> 80) had larger tumor size, higher Edmondson’s grade, more vascular invasion, advanced tumor stage, and poorer survival than those with low ACLR (≤ 80) in the training cohort (5-year OS: 43.3% vs. 80.1%, P < 0.0001; 5-year TTR: 74.9% vs. 45.3%, P < 0.0001). Multivariate Cox analysis identified ACLR as an independent risk factor for OS [hazard ratio (HR) = 2.22, P < 0.001] and TTR (HR = 2.36, P < 0.001). Such clinical significance and prognostic value were verified in validation cohort. ACLR outperformed extant models, showing the highest area under receiver operating characteristics curve for 1-, 3-, and 5-year OS (0.737, 0.719, and 0.708) and 1-, 3-, and 5-year TTR (0.696, 0.650, and 0.629). High ACLR correlated with early recurrence (P < 0.001) and extremely early recurrence (P < 0.001). In patients with high ACLR, wide resection margin might confer survival benefit by decreasing recurrence (median TTR, 25.5 vs. 11.4 months; P = 0.037).ConclusionsThe novel inflammation-immune model, ACLR, could effectively predict prognosis, and the presence of MRD before hepatectomy and might guide the decision on resection margin for patients with HCC.

Hepatocellular carcinoma (HCC) accounts for the predominant form of liver malignancy and presents a leading cause of cancer-related death globally. Sorafenib (SOR), a first-line targeted drug for advanced HCC treatment, has a battery of untoward side effects. Photothermal therapy (PTT) has been utilized as an effective adjuvant in synergy with other approaches. However, little is known about the tumoricidal efficacy of combining SOR with PTT for HCC. Herein, a novel versatile nanoparticle, Cu2−xSe@SOR@PEG (CSP), that is based on a photothermal Cu2−xSe core and SOR for simultaneously reinforcing PTT and reducing the adverse effects of SOR was constructed. The synthesized CSP exhibited a remarkably enhanced therapeutic effect upon 808 nm laser irradiation via dampening HCC cell propagation and metastasis and propelling cell apoptosis. The intravenous administration of CSP substantially suppressed tumor growth in a xenograft tumor mouse model. It was noted that the CSP manifested low toxicity and excellent biocompatibility. Together, this work indicates a promising and versatile tool that is based on synergistic PTT and molecular-targeted therapy for HCC management.

A series of bifunctional phase-transfer catalysts with a quaternary onium center and a hydrogen-bonding donor group were prepared for the fixation of CO2 with commercially available epoxides under mild conditions by using a CO2 balloon (1 atm). In the presence of 2.5 mol% of achiral bifunctional phase-transfer catalysts, cyclic carbonates were obtained in good to excellent yields (up to 95%). Additionally, optical carbonates and epoxides were obtained through the kinetic resolution of rac-epoxides by 1 mol% of chiral bifunctional phase-transfer catalysts with low enantioselectivities. These catalysts featured a simple synthetic route, good modularity and high efficiency. [ABSTRACT FROM AUTHOR]

A series of heterometallic magnesium diruthenium(ii,iii) carbonates, namely K{Mg(H2O)6}2[Ru2(CO3)4Cl2]·4H2O (1), K2[{Mg(H2O)4}2Ru2(CO3)4(H2O)Cl]Cl2·2H2O (2), K[Mg(H2O)5Ru2(CO3)4]·5H2O (3) and K[Mg(H2O)4Ru2(CO3)4]·H2O (4), were synthesized from the reaction of Ru2(CO3)43− and Mg2+ in aqueous solution. Compound 1 is composed of ionic crystals with the Ru2(CO3)4Cl25− : Mg(H2O)62+ : K+ ratio of 1 : 2 : 1. Compound 2 consists of two dimensional layer structures, in which each octahedral environment Mg(H2O)42+ bonds to two [Ru2(CO3)4(H2O)Cl]4− units in a cis manner forming a neutral square-grid layer {Mg(H2O)4Ru2(CO3)4(H2O)Cl}n. For compound 3, one water molecule of each Mg(H2O)62+ is substituted by an oxygen atom of Ru2(CO3)43− forming [Mg(H2O)5Ru2(CO3)4]−, and then the neighboring Ru2 dimers are linked together by the rest of the two oxygen atoms of carbonates to form a layer structure {Mg(H2O)5Ru2(CO3)4}nn−. In compound 4, the neighboring squared-grid layers {Ru2(CO3)4}n3n−, similar to those in compound 3, are linked by each octahedral environment Mg(H2O)42+ in a cis manner forming the three-dimensional network {Mg(H2O)4Ru2(CO3)4}nn−. Compound 3 shows ferromagnetic coupling between Ru2 dimers, and a long-range ordering is observed below 3.8 K. Compound 4 displays a magnetic ordering below 3.5 K, and a systematic study of the size-dependent magnetic properties of compound 4 reveals that the coercivity of 4 has been improved with reduced sample particle size from the micrometer to the nanometer scale. [ABSTRACT FROM AUTHOR]

In this study, we assessed the efficacy and safe usage of the oral contraceptive, Diane-35, in the treatment of polycystic ovary syndrome (PCOS) when combined with the drug metformin. Eighty-two patients with PCOS were randomly divided into two equal groups: Diane-35 treatment group and Diane-35 plus metformin group. Three treatment cycles were administered. Patients’ biomedical data such as height, weight, waist circumference, hip circumference, body fat percentage, acne score, hirsutism score and serum hormone levels were selected, which were tested between the second and the fifth day of the menstrual cycle and follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T), blood glucose, blood lipids and insulin levels(IR) were analyzed. Significant reduction in body mass index (BMI), acne score, LH and T levels were observed in both groups after three months of treatment; on the other hand, high-density lipoprotein cholesterol (HDL) concentration elevated (p < 0.05). Combined treatment group had a significant change in BMI index and fasting blood glucose levels compared to Diane-35 alone treatment group (p < 0.05). With personalized nutrition and exercise program, Diane-35 only group or Diane-35 plus metformin group had both significantly lowered their serum testosterone levels and had improved acne symptoms. Diane-35 plus metformin combination had shown reduced fat percentage levels in patients with PCOS, and had shown improved glucose and lipid metabolism. [ABSTRACT FROM PUBLISHER]

Isostructural heterometallic diruthenium carbonates KM(H2O)6[M(H2O)2Ru2(CO3)4Cl2]·4H2O [M = Zn (1) and Mn (2)] were synthesized from the reaction of the precursors [Ru2(CO3)4Cl2]5− and transitional metal ions in aqueous solution. Complexes 1 and 2 show layered structures in which Ru2(ii,iii) units are linked by four octahedral environment M(H2O)22+ ions in a cross fashion and vice versa giving a negative bimetallic square grid layer {M(H2O)2Ru2(CO3)4Cl2}n3n−. M(H2O)62+ ions, linked by K+ forming zigzag chain {KM(H2O)6}n3+, are located in the void spaces between the layers. The adjacent bimetallic carbonate layers are connected with K–O and K–Cl bonds, and hydrogen bonding, forming a supramolecular 3D framework structure. Their magnetic properties were characterized in detail, and intralayer ferromagnetic coupling between the Ru2 dimer and Mn2+ ion, as well as long-range ordering (Tc = 5.2 K) coexistence of domain movement behavior were observed for complex 2. [ABSTRACT FROM AUTHOR]

Self-assembly of Ru2(CO3)43− units and Cu2+ ions in the presence of halogen (Cl− or Br−) has resulted in two novel isomeric layered structural heterometallic carbonates, K2Li[Cu(H2O)2Ru2(CO3)4X2]·5H2O [X = Cl (1), Br (2)]. X-ray structural analysis reveals that complexes 1 and 2 contain a similar square-grid negative layer [Cu(H2O)2Ru2(CO3)4X2]n5n−, in which each Ru2(CO3)4X25− unit is linked by four Jahn–Teller distorted Cu(H2O)22+ ions in a cross mode and vice versa. The adjacent negative layers are connected by K–O, Li–O bonds, and hydrogen bonding, which led to the formation of a supramolecular 3D network structure. The two complexes show ferromagnetic coupling between the Ru2 dimer and the Cu2+ ion. Detailed magnetism measurement demonstrates that complex 1 exhibits soft magnetic ordering below 2.9 K coexistent with domain movement, and complex 2 shows long-range ferromagnetic ordering below 3.8 K. [ABSTRACT FROM AUTHOR]

Two hetero-metallic carbonates, namely KCd(H2O)3Ru2(CO3)4·4H2O (1) and KCd(H2O)3Ru2(CO3)4·3.5H2O (2), have been synthesized in a neutral aqueous solution. Both of the 3D dimensional structured complexes contain mixed-valent diruthenium(ii,iii) carbonate paddlewheel cores of Ru2II,III(CO3)43− that are connected to each other in trans- or cis-modes by carbonate oxygen atoms, forming rectangular square-grid and isomeric parallelogram layers [Ru2(CO3)4]n3n− in 1 and 2, respectively. The reaction temperature is found to play an important role in directing the final products with particular topologies and their layered structural diversity is due to the various linking modes between the Ru2(CO3)43− units. The magnetic studies show that ferromagnetic interactions are propagated between the diruthenium units in both complexes 1 and 2 but their magnetic properties differ at low temperatures, in which the trans linking mode parallelogram layer [Ru2(CO3)4]n3n− in complex 2 leads to long-range magnetic ordering below 4.0 K. However, no Curie ordering down to 1.8 K is detected for complex 1 containing the isomeric rectangle square-grid layer linking in the cis mode. [ABSTRACT FROM AUTHOR]

• ECH ameliorated motor deficit induced by MPTP in a mouse PD model. • ECH promoted DA neurons survival upon MPTP injury. • ECH interacts with TH predicted by the molecular docking simulation. • ECH inhibited the activated microglia-mediated NLRP3/CASP-1/IL-1β inflammatory signaling. Persistent microglia-mediated neuroinflammation contributes to the progressive loss of dopaminergic (DA) neurons in Parkinson's disease (PD). Recently, NOD-like receptor protein 3 (NLRP3) inflammasome-mediated neuroinflammation is considered to influence the pathogenesis of PD profoundly. Promoting DA neuron survival and/or inhibiting neuroinflammation may offer neuroprotection for PD. In the present study, we found that echinacoside (ECH), a phenylethanoid glycoside derived from Cistanche Deserticola, ameliorated motor deficit induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in a mouse PD model, characterized as decreased mobility distance in open field test and average time in rotarod test, as well as increased turn time and total time in pole test. ECH administration promoted the reduction of tyrosine hydroxylase (TH) expression and the number of TH-positive neurons in the substantia nigra (SN) under MPTP injury as the molecular docking simulation predicted that ECH would interact with TH. Moreover, ECH improved cell viability in MPP+-damaged SH-SY5Y cell, a cell line for DA neuron, in vitro. Furthermore, ECH administration alleviated MPTP-triggered microglial activation, thus downregulated the expression and activation of NLRP3 inflammasomes in mice SN, along with the involved proteins including Caspase (CASP)-1 and interleukin-1β (IL-1β). The inhibition of NLRP3/CASP-1/IL-1β neuroinflammatory signaling was further confirmed in murine N9 microglia activated by MPP+ insult after ECH treatment in vitro. Furthermore, MCC950, a selective inhibitor for NLRP3 activation, reduced the enhancive expression of NLRP3/CASP-1/IL-1β in MPP+-insulted N9, and also facilitated the inhibition of inflammation synergistically mediated by ECH treatment. All the collected data revealed that ECH ameliorated PD mice neuroethology through promoting DA neuron survival and inhibiting the activated microglia-mediated NLRP3/CASP-1/IL-1β inflammatory signaling. These findings highlight the crucial roles of NLRP3 inflammasome involved in PD neuropathology and ECH exertes neuroprotection for PD as double-targeting neuroinflammation and DA neuronal survival. [ABSTRACT FROM AUTHOR]

Highlights • Triple-layer scales occur in both the fine-grained and coarse-grained specimens. • Fine-grained specimens possess the thicker outer layer and the discrete inner layer. • Fine-grained specimens possess the shallower Te permeation along grain boundaries. • Fine-grained specimens possess the shallower Cr 3 Te 4 existence along grain boundaries. • Fine-grained specimens provide more paths for the outward diffusion of Cr. Abstract The effects of grain size on the tellurium corrosion behaviors have been investigated systematically in GH3535 alloy. After the exposure to Te vapor, the triple-layer scales, which consist of Ni 3 Te 2 , Cr 3 Te 4 , MnTe, M 6 C carbides and Fe-riched γ phase, occur in both the fine-grained and coarse-grained specimens. The thicker outer layer, the more discrete inner layer, the shallower Te permeation and Cr 3 Te 4 existence along grain boundaries can be observed in the fine-grained specimens. By comparing the Gibbs free energies and calculating the effective diffusion coefficients, the tellurization mechanism and the role of grain size were discussed. [ABSTRACT FROM AUTHOR]

This study assessed the effects of different cutting traits on bud emergence and early growth of the Chinese vegetable Toona sinensis . This work, including two indoor box experiments, was conducted in 2013 and 2014 at Nanjing University, Jiangsu Province, China. The plant characteristics include survival rate, number of buds, number of branches, maximum length of new shoot, number of new leaves, biomass, OD (Optical Density) value of soluble sugar and soluble protein, and concentration of chlorophyll. These characteristics were quantified with seedling age (1-year to 4-year-old seedlings), cutting position (apex, middle, base of the seedling stem) and cultivation methods (hydroponics and cuttage) in the age experiment, and cutting season (spring, summer, autumn, winter), cutting position (apex, middle, base of the seedling stem) and cultivation methods (hydroponics and cuttage) in the season experiment. Results showed that cuttings derived from 1-year-old seedling stems displayed better morphological and physiological characteristics than from other seedling ages. Cuttings of newly obtained from 1-year-old fresh seedling stems and derived from four seasons were all sprouted well in two cultivation methods (hydroponics and cuttage). Cuttings derived from apical and middle positions in spring and basal positions in autumn displayed better performance than the other treatments. Cuttings cultivated by cuttage exhibited better physiological characteristics than by hydroponics. We concluded that the cuttings of Chinese toon could be cultivated all year round for vegetable production. To obtain faster and more even stands of Chinese toon sprouts in plant factory, we recommended the use of cuttings from 1-year-old Chinese toon seedling stems, apical and middle parts from spring and basal positions from autumn, and use of cuttage method. [ABSTRACT FROM AUTHOR]

Insect gustatory systems play important roles in food selection and feeding behaviors. In spite of the enormous progress in understanding gustation in Drosophila , for other insects one of the key elements in gustatory signaling, the gustatory receptor (GR), is still elusive. In this study, we report that fructose elicits behavioral and physiological responses in Helicoverpa armigera (Harm) to fructose and identify the gustatory receptor for this sugar. Using the proboscis extension reflex (PER) assays we found that females respond to fructose following stimulation of the distal part of the antenna, where we have identified contact chemosensilla tuned to fructose in tip recording experiments. We isolated three full-length cDNAs encoding candidate HarmGRs based on comparison with orthologous GR sequences in Heliothis virescens and functionally characterized the responses of HarmGR4 to 15 chemicals when this receptor was expressed in Xenopus oocytes with two-electrode voltage-clamp recording. Among the tastants tested, the oocytes dose-dependently responded only to d -fructose (EC 50 = 0.045 M). By combining behavioral, electrophysiological and molecular approaches, these results provide basic knowledge for further research on the molecular mechanisms of gustatory reception. [ABSTRACT FROM AUTHOR]

Aim and Objective: The direct β-functionalization of trans-β-nitroolefins by Michael reaction is regarded as an efficient way to provide precursors for β-functional amines. However, Michael additions by grinding means with solvent-free conditons are rarely reported. We have developed facile access to β-functional nitroalkanes by grinding means under solvent-free conditions., Materials and Methods: From commercially available materials including ethyl 2-nitroacetate, alkyl 2-cyanoacetates and malononitrile, the grinding reactions between these above-mentioned activated methylenecompounds and various trans-β-nitroolefins were performed at room temperature and solvent-free conditions., Results: A highly efficient direct Michael reaction of nitroolefins by simple grinding means has been developed. Various trans-nitrostyrenes were easily converted into corresponding β-functional nitroalkanes in excellent yields within 5~10 min (up to 36 examples)., Conclusion: Herein, we have developed a simple and efficient way to β-functional nitroalkanes through Michael reactions by grinding means. The grinding Michael reaction is fast, clean and stable and these Michael adducts could be easily converted into the other amino compounds served as building blocks in organic synthesis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Newcastle disease virus (NDV) and Salmonella Pullorum have significant damaging effects on the poultry industry, but no previous vaccine can protect poultry effectively. In this study, a recombinant-attenuated S. Pullorum strain secreting the NDV hemagglutinin-neuraminidase (HN) protein, C79-13Δ crp Δ asd (pYA-HN), was constructed by using the suicide plasmid pRE asd -mediated bacteria homologous recombination method to form a new bivalent vaccine candidate against Newcastle disease (ND) and S . Pullorum disease (PD). The effect of this vaccine candidate was compared with those of the NDV LaSota and C79-13Δ crp Δ asd (pYA) strains. The serum hemagglutination inhibition antibody titers, serum immunoglobulin G (IgG) antibodies, secretory IgA, and stimulation index in lymphocyte proliferation were increased significantly more ( p < 0.01) in chickens inoculated with C79-13Δ crp Δ asd (pYA-HN) than with C79-13Δ crp Δ asd (pYA) but were not significantly increased compared with the chickens immunized with the LaSota live vaccine ( p > 0.05). Moreover, the novel strain provides 60% and 80% protective efficacy against the NDV virulent strain F48E9 and the S . Pullorum virulent strain C79-13. In summary, in this study, a recombinant-attenuated S . Pullorum strain secreting NDV HN protein was constructed. The generation of the S . Pullorum C79-13Δ crp Δ asd (pYA-HN) strain provides a foundation for the development of an effective living-vector double vaccine against ND and PD.

Attenuated Listeria monocytogenes ( L. monocytogenes , LM) induces specific CD8 + and CD4 + T cell responses, and has been identified as a promising cancer vaccine vector. Cervical cancer is the third most common cancer in women worldwide, with human papillomavirus (HPV), particularly type 16, being the main etiological factor. The therapeutic HPV vaccines are urgently needed. The E7 protein of HPV is necessary for maintaining malignancy in tumor cells. Here, a genetically modified attenuated LM expressing HPV16 E7 protein was constructed. Intraperitoneal vaccination of LM4Δ hly ::E7 significantly reduced tumor size and even resulted in complete regression of established tumors in a murine model of cervical cancer. We provided evidence that recombinant LM strains could enter the tumor tissue and induce non-specific tumor cell death, probably via activation of reactive oxygen species and increased intracellular Ca 2+ levels. LM4Δ hly ::E7 effectively triggered a strong antigen-specific cellular immunity in tumor-bearing mice, and elicited significant infiltration of T cells in the intratumoral milieu. In summary, these data showed LM4Δ hly ::E7 to be effective in a cervical cancer model and LM4Δ hly ::E7 induced an antitumor effect by antigen-specific cellular immune responses and direct killing of tumor cells, indicating a potential application against cervical cancer.

Hepatocellular carcinoma (HCC) cells rapidly switch their energy source from oxidative phosphorylation to glycolytic metabolism in order to efficiently proliferate. However, the molecular mechanisms responsible for this switch remain unclear. In this study, we found that miR-592 was frequently downregulated in human HCC tissues and cell lines, and its downregulation was closely correlated with aggressive clinicopathological features and poor prognosis of HCC patients. Overexpression of miR-592 inhibited aerobic glycolysis and proliferation in HCC cells in vitro. Conversely, knockdown of miR-592 promoted HCC growth in both subcutaneous injection and orthotopic liver tumor implantation models in vivo. Mechanistically, miR-592 downregulation in human HCCs was correlated with an upregulation of WD repeat and SOCS box containing 1 (WSB1). We further showed that miR-592 directly binds to the 3'-UTR of the WSB1 gene, thus disrupting hypoxia inducible factor-1α (HIF-1α) protein stabilization. In turn, overexpression of WSB1 in HCC cells rescued decreased HIF-1α expression, glucose uptake, and HCC growth induced by miR-592. Collectively, our clinical data and functional studies suggest that miR-592 is a new robust inhibitor of the Warburg effect and a promising therapeutic target for HCC treatment., Competing Interests: All the authors declare no conflict of interest on the publication.

A series of heterometallic magnesium diruthenium(ii,iii) carbonates, namely K{Mg(H2O)6}2[Ru2(CO3)4Cl2]·4H2O (1), K2[{Mg(H2O)4}2Ru2(CO3)4(H2O)Cl]Cl2·2H2O (2), K[Mg(H2O)5Ru2(CO3)4]·5H2O (3) and K[Mg(H2O)4Ru2(CO3)4]·H2O (4), were synthesized from the reaction of Ru2(CO3)4(3-) and Mg(2+) in aqueous solution. Compound 1 is composed of ionic crystals with the Ru2(CO3)4Cl2(5-) : Mg(H2O)6(2+) : K(+) ratio of 1 : 2 : 1. Compound 2 consists of two dimensional layer structures, in which each octahedral environment Mg(H2O)4(2+) bonds to two [Ru2(CO3)4(H2O)Cl](4-) units in a cis manner forming a neutral square-grid layer {Mg(H2O)4Ru2(CO3)4(H2O)Cl}n. For compound 3, one water molecule of each Mg(H2O)6(2+) is substituted by an oxygen atom of Ru2(CO3)4(3-) forming [Mg(H2O)5Ru2(CO3)4](-), and then the neighboring Ru2 dimers are linked together by the rest of the two oxygen atoms of carbonates to form a layer structure {Mg(H2O)5Ru2(CO3)4}n(n-). In compound 4, the neighboring squared-grid layers {Ru2(CO3)4}n(3n-), similar to those in compound 3, are linked by each octahedral environment Mg(H2O)4(2+) in a cis manner forming the three-dimensional network {Mg(H2O)4Ru2(CO3)4}n(n-). Compound 3 shows ferromagnetic coupling between Ru2 dimers, and a long-range ordering is observed below 3.8 K. Compound 4 displays a magnetic ordering below 3.5 K, and a systematic study of the size-dependent magnetic properties of compound 4 reveals that the coercivity of 4 has been improved with reduced sample particle size from the micrometer to the nanometer scale.

Objective: The objective of this study was to evaluate the pharmacokinetic parameters of triflusal and its major active metabolite, 2-hydroxy-4-trifluoromethyl benzoic acid (HTB), following a single oral dose of 900 mg in healthy subjects under fed and fasting conditions., Methods: The study participants (n=12) were randomized to receive one 900 mg triflusal capsule in a fasting condition (no food for 12 hours) or a fed condition (after a high-fat meal); after a 2-week washout period, participants received the same dose of triflusal capsule under the converse condition. Pharmacokinetic parameters were calculated using WinNonlin 6.2 software. Safety was evaluated through assessment of adverse events, standard laboratory evaluations, vital signs, and 12-lead electrocardiography., Results: The mean Cmax of triflusal and HTB were 13.96, 110.2 ug/mL for the fasting state and 9.546, 97.15 ug/mL for the fed state, respectively. The AUC0-144 of triflusal and HTB were 19.66, 5,572 hxμg/mL for the fasting state and 22.20, 5,038 hxμg/mL for the fed state, the AUC0-∞ of triflusal and HTB were 19.79, 6,333 hxμg/mL for the fasting state and 22.44, 5,632 hxμg/mL for the fed state, respectively. The results showed that Cmax and AUCs for triflusal were outside the bioequivalency (BE) interval after food intake, but there was no statistically significant change for HTB., Conclusion: High-fat food intake may affect the pharmacokinetics of triflusal capsule in healthy subjects.

Well-defined unnatural dipeptide-alcohols based on a cis-2,5-disubstitued pyrrolidine backbone were synthesized from commercially available starting materials meso-diethyl-2,5-dibromoadipate, (S)-(-)-1-phenylethylamine, and phenylalaninol. The structures of these unnatural dipeptide-alcohols are supported by HRMS, 1H- and 13C-NMR spectroscopy. These unnatural dipeptide-alcohols can act as building blocks for peptidomimetics.

The self-assembly of Ru2(CO3)4(3-) paddle-wheel precursors and Mn(2+) ions in aqueous solution yields various carbonate complexes. With appropriate selection of the synthetic conditions, we are able to intentionally tune the composition and structure of Mn-Ru2-carbonate assemblies to form infinite chain structural complexes, e.g., K[{Mn(H2O)4}2Ru2(CO3)4Br2]·H2O (1) and H[{Mn(H2O)4}2Ru2(CO3)4Br2]·6H2O (2). Complexes 1 and 2 are obtained at different temperatures (25 °C for 1 and 5 °C for 2, respectively), and their crystal structures consist of brick-wall stacked chains, in which neighboring Ru2(CO3)4Br2(5-) units are linked by two disubstituted octahedral Mn(H2O)4(2+) in a cis manner, resulting in two isomeric (twisted and zigzag) negative double-chain α- and β-{[Mn(H2O)4]2Ru2(CO3)4Br2}n(n-). The magnetic properties of complexes 1 and 2 were highly characterized. The alternating current (AC) susceptibility analysis of complex 1 reveals a two-step magnetism transition at T1 = 5.0 K and T2 = 2.6 K, respectively. Complex 2 exhibits metamagnetism behavior, with a transition field H(C) = ~1.2 kOe at 2.0 K.

Isostructural heterometallic diruthenium carbonates KM(H2O)6[M(H2O)2Ru2(CO3)4Cl2]·4H2O [M = Zn (1) and Mn (2)] were synthesized from the reaction of the precursors [Ru2(CO3)4Cl2](5-) and transitional metal ions in aqueous solution. Complexes 1 and 2 show layered structures in which Ru2(II,III) units are linked by four octahedral environment M(H2O)2(2+) ions in a cross fashion and vice versa giving a negative bimetallic square grid layer {M(H2O)2Ru2(CO3)4Cl2}n(3n-). M(H2O)6(2+) ions, linked by K(+) forming zigzag chain {KM(H2O)6}n(3+), are located in the void spaces between the layers. The adjacent bimetallic carbonate layers are connected with K-O and K-Cl bonds, and hydrogen bonding, forming a supramolecular 3D framework structure. Their magnetic properties were characterized in detail, and intralayer ferromagnetic coupling between the Ru2 dimer and Mn(2+) ion, as well as long-range ordering (Tc = 5.2 K) coexistence of domain movement behavior were observed for complex 2.

The aim of this study is to investigate a food effect on the single-dose pharmacokinetics and tolerability of clinofibrate tablets in 12 Chinese healthy volunteers. The authors evaluated the effect of being under a fasting or fed state at the time of drug intake on the single-dose of clinofibrate 400 mg tablets in a randomized, balanced, single-dose, two-treatment (fed and fasting), two-period, two-sequence study design with a 7-day washout period. The end points were the maximum plasma drug concentration (Cmax) and areas under the plasma-concentration curve (AUC) for 72 hours exposure (AUC0-72) and total exposure (AUC0-∞). All participants completed the whole study without side effects being observed. The Cmax mean of clinofibrate glucuronides and parent clinofibrate were 21.91, 17.85 μ/ml for the fasting state and 13.14, 11.25 μ/ml for the fed state, respectively. The AUC0-72 and AUC0-∞ of clinofibrate glucuronides and parent clinofibrate were 381.60, 307.07 μ/ ml and 404.55, 342.24 μ/ml for the fasting state and 379.02, 321.14 μ/ml and 432.24, 351.80 μ/ml for the fed state. The authors showed that food intake was associated with a significant decrease in Cmax, but no significant change in AUC values.

Two hetero-metallic carbonates, namely KCd(H2O)3Ru2(CO3)4·4H2O (1) and KCd(H2O)3Ru2(CO3)4·3.5H2O (2), have been synthesized in a neutral aqueous solution. Both of the 3D dimensional structured complexes contain mixed-valent diruthenium(II,III) carbonate paddlewheel cores of Ru2(II,III)(CO3)4(3-) that are connected to each other in trans- or cis-modes by carbonate oxygen atoms, forming rectangular square-grid and isomeric parallelogram layers [Ru2(CO3)4]n(3n-) in 1 and 2, respectively. The reaction temperature is found to play an important role in directing the final products with particular topologies and their layered structural diversity is due to the various linking modes between the Ru2(CO3)4(3-) units. The magnetic studies show that ferromagnetic interactions are propagated between the diruthenium units in both complexes 1 and 2 but their magnetic properties differ at low temperatures, in which the trans linking mode parallelogram layer [Ru2(CO3)4]n(3n-) in complex 2 leads to long-range magnetic ordering below 4.0 K. However, no Curie ordering down to 1.8 K is detected for complex 1 containing the isomeric rectangle square-grid layer linking in the cis mode.