Site-Selective C-O Bond Editing of Unprotected Saccharides.

Glucose and its polyhydroxy saccharide analogs are complex molecules that serve as essential structural components in biomacromolecules, natural products, medicines, and agrochemicals. Within the expansive realm of saccharides, a significant area of research revolves around chemically transforming naturally abundant saccharide units to intricate or uncommon molecules such as oligosaccharides or rare sugars. However, partly due to the presence of multiple hydroxyl groups with similar reactivities and the structural complexities arising from stereochemistry, the transformation of unprotected sugars to the desired target molecules remains challenging. One such formidable challenge lies in the efficient and selective activation and modification of the C-O bonds in saccharides. In this study, we disclose a modular 2-fold "tagging-editing" strategy that allows for direct and selective editing of C-O bonds of saccharides, enabling rapid preparation of valuable molecules such as rare sugars and drug derivatives. The first step, referred to as "tagging", involves catalytic site-selective installation of a photoredox active carboxylic ester group to a specific hydroxyl unit of an unprotected sugar. The second step, namely, "editing", features a C-O bond cleavage to form a carbon radical intermediate that undergoes further transformations such as C-H and C-C bond formations. Our strategy constitutes the most effective and shortest route in direct transformation and modification of medicines and other molecules bearing unprotected sugars.

The association of post-embryo transfer SARS-CoV-2 infection with early pregnancy outcomes in in vitro fertilization: a prospective cohort study.

BACKGROUND: The influence of SARS-CoV-2 infection after embryo transfer on early pregnancy outcomes in in vitro fertilization or intracytoplasmic sperm injection-embryo transfer treatment remains inadequately understood. This knowledge gap endures despite an abundance of studies investigating the repercussions of preceding SARS-CoV-2 infection on early pregnancy outcomes in spontaneous pregnancies. OBJECTIVE: This study aimed to investigate the association between SARS-CoV-2 infection within 10 weeks after embryo transfer and early pregnancy outcomes in patients undergoing in vitro fertilization/intracytoplasmic sperm injection treatment. STUDY DESIGN: This prospective cohort study was conducted at a single public in vitro fertilization center in China. Female patients aged 20 to 39 years, with a body mass index ranging from 18 to 30 kg/m2, undergoing in vitro fertilization/intracytoplasmic sperm injection treatment, were enrolled between September 2022 and December 2022, with follow-up extended until March 2023. The study tracked SARS-CoV-2 infection time (≤14 days, ≤28 days, and ≤10 weeks after embryo transfer), symptoms, vaccination status, the interval between vaccination and embryo transfer, and early pregnancy outcomes, encompassing biochemical pregnancy rate, implantation rate, clinical pregnancy rate, and early miscarriage rate. The study used single-factor analysis and multivariate logistic regression to examine the association between SARS-CoV-2 infection status, along with other relevant factors, and the early pregnancy outcomes. RESULTS: A total of 857 female patients undergoing in vitro fertilization/intracytoplasmic sperm injection treatment were analyzed. In the first stage, SARS-CoV-2 infection within 14 days after embryo transfer did not have a significant negative association with the biochemical pregnancy rate (adjusted odds ratio, 0.74; 95% confidence interval, 0.51-1.09). In the second stage, SARS-CoV-2 infection within 28 days after embryo transfer had no significant association with the implantation rate (36.6% in infected vs 44.0% in uninfected group; P=.181). No statistically significant association was found with the clinical pregnancy rate after adjusting for confounding factors (adjusted odds ratio, 0.69; 95% confidence interval, 0.56-1.09). In the third stage, SARS-CoV-2 infection within 10 weeks after embryo transfer had no significant association with the early miscarriage rate (adjusted odds ratio, 0.77; 95% confidence interval, 0.35-1.71). CONCLUSION: Our study suggests that SARS-CoV-2 infection within 10 weeks after embryo transfer may not be negatively associated with the biochemical pregnancy rate, implantation rate, clinical pregnancy rate, and early miscarriage rate in patients undergoing in vitro fertilization/intracytoplasmic sperm injection treatment. It is important to note that these findings are specific to the target population of in vitro fertilization/intracytoplasmic sperm injection patients aged 20 to 39 years, without previous SARS-CoV-2 infection, and with a body mass index of 18 to 30 kg/m2. This information offers valuable insights, addressing current concerns and providing a clearer understanding of the actual risk associated with SARS-CoV-2 infection after embryo transfer.

Preoperative risk prediction models for acute kidney injury after noncardiac surgery: an independent external validation cohort study.

BACKGROUND: Numerous models have been developed to predict acute kidney injury (AKI) after noncardiac surgery, yet there is a lack of independent validation and comparison among them. METHODS: We conducted a systematic literature search to review published risk prediction models for AKI after noncardiac surgery. An independent external validation was performed using a retrospective surgical cohort at a large Chinese hospital from January 2019 to October 2022. The cohort included patients undergoing a wide range of noncardiac surgeries with perioperative creatinine measurements. Postoperative AKI was defined according to the Kidney Disease Improving Global Outcomes creatinine criteria. Model performance was assessed in terms of discrimination (area under the receiver operating characteristic curve, AUROC), calibration (calibration plot), and clinical utility (net benefit), before and after model recalibration through intercept and slope updates. A sensitivity analysis was conducted by including patients without postoperative creatinine measurements in the validation cohort and categorising them as non-AKI cases. RESULTS: Nine prediction models were evaluated, each with varying clinical and methodological characteristics, including the types of surgical cohorts used for model development, AKI definitions, and predictors. In the validation cohort involving 13,186 patients, 650 (4.9%) developed AKI. Three models demonstrated fair discrimination (AUROC between 0.71 and 0.75); other models had poor or failed discrimination. All models exhibited some miscalibration; five of the nine models were well-calibrated after intercept and slope updates. Decision curve analysis indicated that the three models with fair discrimination consistently provided a positive net benefit after recalibration. The results were confirmed in the sensitivity analysis. CONCLUSIONS: We identified three models with fair discrimination and potential clinical utility after recalibration for assessing the risk of acute kidney injury after noncardiac surgery.

Luteimonas suaedae sp. nov., a novel bacterium isolated from rhizosphere of Suaeda aralocaspica (Bunge) Freitag & Schütze.

Light yellowish-white colonies of a bacterial strain, designated LNNU 24178T, were isolated from the rhizosphere soil of halophyte Suaeda aralocaspica (Bunge) Freitag and Schütze grown at Shihezi district, Xinjiang, PR China. Cells were Gram-stain-negative, non-flagellum-forming, rod-shaped and non-motile. The results of phylogenetic analysis based on the 16S rRNA gene sequence indicated that LNNU 24178T represented a member of the genus Luteimonas and shared the highest sequence similarity with Luteimonas yindakuii CGMCC 1.13927T (97.1 %) and lower sequence similarity (< 97.0 %) to other known species. The genomic DNA G+C content of LNNU 24178T was 68.8 %. The average nucleotide identity (ANI) values between LNNU 24178T and Luteimonas yindakuii CGMCC 1.13927T, Luteimonas mephitis DSM 12574T, Luteimonas arsenica 26-35T and Luteimonas huabeiensis HB2T were 78.7, 78.6, 78.4 and 80.0 %, respectively. The digital DNA-DNA hybridisation (dDDH) values between LNNU 24178T and L. yindakuii CGMCC 1.13927T, L. mephitis DSM 12574T, L. arsenica 26-35T and L. huabeiensis HB2T were 22.0, 22.3, 22.2 and 23.5 %, respectively. The respiratory quinone detected in LNNU 24178T was ubiquinone-8 (Q-8). The major fatty acids (> 5.0 %) of LNNU 24178T were identified as iso-C15 : 0 (33.9 %), iso-C17 : 0 (8.7 %), iso-C11 : 0 (6.2 %), iso-C16 : 0 (5.7 %), C16 : 0 (5.3 %) and summed feature 9 (iso-C17 : 1ω9c/10-methyl C16 : 0) (21.1 %). The major polar lipids of LNNU 24178T were diphosphatidylglycerol (DPG), phosphatidylglycerol (PG), phosphatidylethanolamine (PE), one unidentified phospholipid (PL), one unidentified glycolipid (GL) and three unidentified lipids. According to the data obtained from phenotypic, chemotaxonomic and phylogenetic analyses, strain LNNU 24178T represents a novel species of the genus Luteimonas, for which the name Luteimonas suaedae sp. nov. is proposed, with LNNU 24178T (= CGMCC 1.17331T= KCTC 62251T) as the type strain.

Enantioselective Synthesis of Bispiro[indanedione-oxindole-cyclopropane]s through Organocatalytic [2+1] Cycloaddition.

A series of compounds featuring a novel bispiro[indanedione-oxindole-cyclopropane] moiety have been synthesized through a squaramide-catalyzed [2+1] cycloaddition reaction. The tandem Michael-alkylation reaction of 2-arylidene-1,3-indanediones with 3-bromooxindoles furnished the cycloadducts in high yields with excellent diastereo- and enantioselectivities. The ammonium ylide in the catalytic process, as a key intermediate, was revealed by the high-resolution mass spectrometry study.

A highly efficient metal-free selective 1,4-addition of difluoroenoxysilanes to chromones.

A highly efficient metal-free selective 1,4-addition reaction of difluoroenoxysilanes to chromones was developed using the low-cost and readily available HOTf as the catalyst, which is a facile and straightforward method to access valuable C2-difluoroalkylated chroman-4-one derivatives. Interestingly, the products could be readily converted to the difluorinated bioisostere of the natural product (S)-2,6-dimethylchroman-4-one and a difluorinated benzo-seven-membered heterocycle via the Schmidt rearrangement reaction. In addition, the in vitro anti-proliferative activities of these synthesized derivatives against human colon carcinoma cells (HCT116) revealed that compound 3g exhibited potent inhibitory effect on HCT116 cancer cells with an IC50 value of 6.37 µM, representing a novel lead compound for further structural optimization and biological evaluation.

Magnetic semiconducting borophenes and their derivatives.

Two semiconducting borophenes with layer-dependent magnetism are predicted based on spin-polarized density functional theory. Both monolayer borophenes are ferromagnetic. One is composed of B3 and B15 triangular motifs, exhibiting bipolar spin polarization and a magnetic moment of 1.00 µB per primitive cell. The other consists of B15 triangular motifs, possessing a Curie temperature of about 437 K and a magnetic moment of 3.00 µB per primitive cell. B atoms located between the triangular motifs are essential for inducing ferromagnetism in monolayer borophenes. However, bilayer borophenes with high-symmetry stacking orders are nonmagnetic. Furthermore, magnetic boron nanotubes and fullerenes could be made of monolayer borophenes. Finally, we propose to fabricate these magnetic semiconducting borophenes from the buckled triangular structure of borophenes via selective electron beam ionization of B atoms by scanning transmission electron microscopy.

[Comparison of in vivo plasma pharmacokinetics and urine excretion of main components in Xihuang Formula in rats with precancerous lesions of breast cancer].

The UPLC-MS/MS was established for the determination of acetyl-11-keto-beta-boswellic acid(AKBA) and ß-boswellic acid(ß-BA), the main active components of Olibanum and Myrrha extracts in Xihuang Formula, in rat plasma and urine. The effects of compatibility on the pharmacokinetic behaviors of AKBA and ß-BA in rats were investigated, and the differences in pharmacokinetic behaviors between healthy rats and rats with precancerous lesions of breast cancer were compared. The results showed that compared with RM-NH and RM-SH groups, the AUC_(0-t) and AUC_(0-∞) of ß-BA increased(P<0.05 or P<0.01), T_(max) decreased(P<0.05 or P<0.01), and C_(max) increased(P<0.01) after compatibility. The trends of AKBA and ß-BA were the same. Compared with RM-SH group, the T_(max) decreased(P<0.05), C_(max) increased(P<0.01), and the absorption rate increased in the normal group of Xihuang Formula. The results of urinary excretion showed that there was a decreasing trend in the urinary excretion rate and total urinary excretion of ß-BA and AKBA after compatibility, but there was no statistical difference. Compared with normal group of Xihuang Formula, the AUC_(0-t) and AUC_(0-∞) of ß-BA increased(P<0.05), T_(max) increased(P<0.05), and the clearance rate decreased in the breast precancerous lesion group. AUC_(0-t) and AUC_(0-∞) of AKBA showed an increasing trend, the in vivo retention time was prolonged, and the clearance rate was reduced, but there was no significant difference compared with the normal group. The cumulative urinary excretion and urinary excretion rate of ß-BA and AKBA decreased under pathological conditions, indicating that pathological conditions could affect the in vivo process of ß-BA and AKBA, and reduce their excretion in the form of prototype drugs, showing different pharmacokine-tic characteristics from normal physiological conditions. In this study, UPLC-MS/MS analysis method was established, which was sui-table for in vivo pharmacokinetic analysis of ß-BA and AKBA. This study laid a foundation for the development of new dosage forms of Xihuang Formula.

[Effect and mechanism of Xihuang Pills on rats with precancerous lesions of breast].

The purpose of this study was to explore the effect and mechanism of Xihuang Pills on rats with precancerous lesions of the breast. Of 48 healthy female rats, 8 were randomly selected as blank group, and the other 40 were treated with 7,12-dimethylbenzanthracene(DMBA) combined with estrogen and progestin to establish a model of precancerous lesions of the breast. The successfully modeled rats were randomly divided into a model group, a tamoxifen group(1.8 mg·kg~(-1)·d~(-1)), a Xihuang Pills low-dose group(0.3 g·kg~(-1)·d~(-1)), a medium-dose group(0.6 g·kg~(-1)·d~(-1)) and a high-dose group(1.2 g·kg~(-1)·d~(-1)). After 30 days of admi-nistration, the histopathological changes of viscera and breast were observed by haematoxylin and eosin(HE) staining, and the visceral index was calculated. Enzyme linked immunosorbent assay(ELISA) was used to detect the contents of estradiol(E_2) and progesterone(P) in serum. The protein expressions of vascular endothelial growth factor(VEGF) and fibroblast growth factor 2(FGF2) were detected by immunohistochemistry. The protein expressions of VEGF, vascular endothelial growth factor receptor 2(VEGFR2), phosphorylated-vascular endothelial growth factor receptor 2(p-VEGFR2), B-cell lymphoma-2(Bcl-2), and Bcl-2 associated X protein(Bax) were detected by Western blot and the mRNA expressions of VEGF, FGF2, CXC-chemokine receptor 4(CXCR4), cysteine aspartic acid-specific protease(caspase-3), and stromal cell-derived factor 1(SDF-1) were detected by real-time polymerase chain reaction(RT-PCR). HE staining revealed that the model group had some liver and kidney damages and severe hyperplastic mammary tissue, while the Xihuang Pills high-dose group had mild hyperplasia. Compared with the model group, the Xihuang Pills groups had lo-wer ovarian coefficient(P<0.05 or P<0.01) and Xihuang Pills high-dose group had lower uterine coefficient(P<0.01). ELISA results showed that compared with the model group, expressions of E_2 and P in Xihuang Pills high-dose group were significantly decreased(P<0.05 or P<0.01). Immunohistochemistry, Western blot and RT-PCR indicated that compared with the conditions in the model group, the protein and mRNA expressions of VEGF and FGF2 in the Xihuang Pills groups were down-regulated(P<0.05 or P<0.01), and the protein expression of Bcl-2 was lowered(P<0.01); there was a decrease in the protein expressions of VEGFR2 and p-VEGFR2(P<0.01), a down-regulation in the mRNA expressions of CXCR4 and SDF-1(P<0.01), while an increase in the mRNA expression of caspase-3(P<0.01) in both Xihuang Pills medium-dose and high-dose groups; the protein expression of Bax in Xihuang Pills high-dose group was increased(P<0.01). The above results indicated that Xihuang Pills can effectively intervene in precance-rous lesions of the breast, and the mechanism may be related to the regulation of E_2 and P secretion as well as the inhibition of angiogenesis and chemokine receptor expression, thus controlling the occurrence of precancerous lesions of the breast in rats.

The Kandelia obovata transcription factor KoWRKY40 enhances cold tolerance in transgenic Arabidopsis.

BACKGROUND: WRKY transcription factors play key roles in plant development processes and stress response. Kandelia obovata is the most cold-resistant species of mangrove plants, which are the important contributors to coastal marine environment. However, there is little known about the WRKY genes in K. obovata. RESULTS: In this study, a WRKY transcription factor gene, named KoWRKY40, was identified from mangrove plant K. obovata. The full-length cDNA of KoWRKY40 gene was 1420 nucleotide bases, which encoded 318 amino acids. The KoWRKY40 protein contained a typical WRKY domain and a C2H2 zinc-finger motif, which were common signatures to group II of WRKY family. The three-dimensional (3D) model of KoWRKY40 was formed by one α-helix and five ß-strands. Evolutionary analysis revealed that KoWRKY40 has the closest homology with a WRKY protein from another mangrove plant Bruguiera gymnorhiza. The KoWRKY40 protein was verified to be exclusively located in nucleus of tobacco epidermis cells. Gene expression analysis demonstrated that KoWRKY40 was induced highly in the roots and leaves, but lowly in stems in K. obovata under cold stress. Overexpression of KoWRKY40 in Arabidopsis significantly enhanced the fresh weight, root length, and lateral root number of the transgenic lines under cold stress. KoWRKY40 transgenic Arabidopsis exhibited higher proline content, SOD, POD, and CAT activities, and lower MDA content, and H2O2 content than wild-type Arabidopsis under cold stress condition. Cold stress affected the expression of genes related to proline biosynthesis, antioxidant system, and the ICE-CBF-COR signaling pathway, including AtP5CS1, AtPRODH1, AtMnSOD, AtPOD, AtCAT1, AtCBF1, AtCBF2, AtICE1, AtCOR47 in KoWRKY40 transgenic Arabidopsis plants. CONCLUSION: These results demonstrated that KoWRKY40 conferred cold tolerance in transgenic Arabidopsis by regulating plant growth, osmotic balance, the antioxidant system, and ICE-CBF-COR signaling pathway. The study indicates that KoWRKY40 is an important regulator involved in the cold stress response in plants.

Merger and Postmerger of Binary Neutron Stars with a Quark-Hadron Crossover Equation of State.

Fully general-relativistic binary-neutron-star (BNS) merger simulations with quark-hadron crossover (QHC) equations of state (EOS) are studied for the first time. In contrast to EOS with purely hadronic matter or with a first-order quark-hadron phase transition (1PT), in the transition region QHC EOS show a peak in sound speed and thus a stiffening. We study the effects of such stiffening in the merger and postmerger gravitational (GW) signals. Through simulations in the binary-mass range 2.5

Rhodium-Catalyzed Azine-Directed C-H Amidation with N-Methoxyamides.

Using N-methoxyamide reagents as an amide source, C-H amidation was realized at the ortho position of azine under the action of rhodium and boric acid. The method has mild reaction conditions, high atomic utilization, excellent yield, and wide adaptability to amidation reagents (both aromatic amides and fatty amides are applicable). Amide-substituted ketones can be obtained by a simple treatment and can be further transformed into bioactive substances. This provides a good supplement for the C-H bond amidation of aromatic rings.

C-H acylation of aniline derivatives with α-oxocarboxylic acids using ruthenium catalyst.

An efficient and convenient synthetic strategy for ruthenium(II)-catalyzed ortho-acylation of N-(2-pyridyl)-anilines using α-oxycarboxylic acids as acyl sources is described. The procedure can smoothly proceed under mild conditions, showing good functional group tolerance. Valuable ortho-acylated aniline products have been obtained with moderate to good yields. Furthermore, the reaction could be easily scaled up to the gram scale.

Discovery and structural optimization of 9-O-phenylsulfonyl-berberines as new lipid-lowering agents.

Berberine is a quaternary isoquinoline alkaloid that exhibits potent hypoglycemic and hypolipidemic activity. Many medicinal chemists are currently working on structural modifications around the parent scaffold of berberine, expecting to further enhance its hypolipidemic activity and reducing its cytotoxicity. In this study, a focused berberine-like compound library containing 12,600 molecules was built via the introduction of various "drug-like" fragments at the C8 and C9 positions of berberine. Sixteen comopounds were hit by using the in-house QSAR models previously reported by our group. Considering synthesis feasibility and the cost of building-blocks, only four berberine analogs (library ID: 2028, 3847, 6033, and 12456) were selected and synthesized for investigating their lipid-lowering activities. Preliminary lipid-lowering study showed that compound 12456 with the phenylsulfonyl group at the C9 position had potent cholesterol inhibitory activity in HepG2 cells, superior to that of the parent compound berberine. Subsequently, a total of twenty-five 9-O-phenylsulfonyl-berberines (1a-1y) and twenty-four 9-O-phenylsulfonyl-tetrahydroberberine (2a-2x) were designed, synthesized, and evaluated by lipid-lowering experiments. The results displayed that most compounds exhibited more lipid-lowering activities than berberine. Among them, compound 1m inhibited cholesterol production close to 50% in both cell models when compared with the blank control; the inhibition of triglycerides exceeded 70%. Moreover, 1m also had significant pharmacological effects on the inhibition of LDLC and promotion of HDLC production, especially in the HepG2 cell model, in which the inhibitory rate against LDLC was close to 70% and the increase rate of HDLC was more than 75%. The hypolipidemic experiment of SD rats demonstrated that after 40 days of administration (1m, 15 mg/kg/d), blood cholesterol was reduced by 19.6%, triglycerides reduced by 34.52%, and LDLC reduced by 41.49%, when compared with the high-fat diet model (HFD). In addition, after 80 days of administration, the three indexes of 1m were still better than that of berberine. Oil Red O staining and H&E staining results showed that 1m exhibited potent lipid scavenging activity. All in all, 1m was discovered and identified as a potent lipid-lowering agent and a new berberine-like candidate, being evaluated by subsequent studies.

[Long-term intermittent fasting induces abnormal lipid accumulation in mouse liver].

Short-term intermittent fasting (IF) is beneficial to weight control in patients with nonalcoholic fatty liver disease, but the impact of long-term IF is not clear. In this study, healthy C57BL/6N mice with 4-month alternate day fasting (ADF) were used to study the effects of long-term IF on systemic and liver lipid metabolism. The results showed that, compared with the Ad Libitum group, the weight and food conversion rate of mice in the ADF group were markedly decreased and increased respectively, and the liver index and the liver content of triglyceride were significantly increased by pathological examination. qRT-PCR analysis revealed that the mRNA expression of the lipogenesis gene Pparγ and lipolysis gene Atgl was up-regulated in the ADF group (P < 0.05). Western blot analysis showed that the ratio of microtubule associated protein LC3-II/LC3-I was increased, while the abundance of autophagy adaptor protein p62 was decreased in the ADF group. In addition, autophagy signal positive regulation key factor AMPK phosphorylation was increased (P < 0.05), and negative regulation factor mTOR phosphorylation was decreased (P < 0.05) in the ADF group, indicating that hepatocyte autophagy activity was elevated. Taken together, ADF for 4 months results in an excessive liver triglyceride accumulation, accompanied by a marked decrease in liver mTOR phosphorylation and a significant increase in hepatic autophagy.

Selection of a pH- and temperature-stable laccase from Ganoderma australe and its application for bioremediation of textile dyes.

By virtue of screening, purification, and properties characterization, this study captures a new pH- and temperature-stable laccase, designated Galacc-F, from Ganoderma australe for dye bioremediating applications. The enzyme was purified to homogeneity by salt precipitation, ionic exchange, and size exclusion chromatography with a final specific activity of 22.214 U mg-1, yielding a purification fold of 23.989 and recovery of 38.44%. Its molecular weight was estimated to be 48.0 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, zymography, Sephadex G-100 column, and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, which confirmed its monomeric nature. Galacc-F exhibited high levels of activity and stability over wide ranges of pH (5.0-8.0) and temperature (10-60 °C), which are highly valuable properties in industrial processes. Broad substrate specificity was observed, wherein a better affinity was found for 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) with a low value of Km (164.137 µM) and higher kcat/Km ratio (1.663 s-1 µM-1). Activity was stimulated by Cu2+ and ß-mercaptoethanol but inhibited by ethylenediaminetetraacetic acid, diethylpyrocarbonate, iodoacetic acid, phenylmethylsulfonyl fluoride, and Hg2+, indicating that Galacc-F is a metalloprotease containing a typical histidine-cysteine-serine catalytic triad. It had high tolerance to surfactants, oxidants, and salts. Additionally, a fabricated protocol for native Galacc-F immobilization onto Fe3O4@Chitosan composite nanoparticles using glutaraldehyde as a crosslinker was developed. Most importantly, the enzyme was determined to be ideal for use in efficient treatment of dye effluents as compared with the laccases requiring redox mediators.

[Study on effect of SuperTab 40LL on compression characteristics of musk sustained-release mini-tablets based on mathematical models].

In this paper, co-processed lactose SuperTab 40 LL was selected as fillers to study the preparation of musk sustained-release mini-tablets in the Xihuang multiple-unit drug release system. Musk sustained-release tablets containing different proportions of SuperTab 40 LL and MCC were prepared under various pressures, and then the compressibility and compactibility of these prescriptions were evaluated by Walker, Heckel and Ryshkewitch-Duckworth equations. In addition, the fluidity of the prescriptions was evaluated by parameters of Kawakita equation. There was a comprehensive analysis of the effect of SuperTab 40 LL on musk sustained-release mini-tablets combined with the appearance of SuperTab 40 LL and their tensile strength. The results shown that SuperTab 40 LL had better compression process through the Heckel equation, and the direct compression process of drug powders with excipients can be analyzed by the Kawakita and Ryshkewitch-Duckworth equations. As a new type of co-processed lactose, SuperTab 40 LL had a good fluidity and compactibility. SuperTab 40 LL may undergo particle crushing and plastic deformation during the compression process, which increased the contact area and bonding sites between the particles, and aggregated and shaped the mixed powder easy. Moreover, MCC showed a synergistic effect, and the combined application with SuperTab 40 ll could effectively improve the fluidity and compressibility of the musk sustained-release powder. When the ratio of SuperTab 40 LL and MCC was 2∶1, musk sustained-release mini-tablets had a high drug loading capacity and good compactibility in line with the design objectives.

Muscone suppresses inflammatory responses and neuronal damage in a rat model of cervical spondylotic myelopathy by regulating Drp1-dependent mitochondrial fission.

Cervical spondylotic myelopathy (CSM) is a common cause of disability with few treatments. Aberrant mitochondrial dynamics play a crucial role in the pathogenesis of various neurodegenerative diseases. Thus, regulation of mitochondrial dynamics may offer therapeutic benefit for the treatment of CSM. Muscone, the active ingredient of an odoriferous animal product, exhibits anti-inflammatory and neuroprotective effects for which the underlying mechanisms remain obscure. We hypothesized that muscone might ameliorate inflammatory responses and neuronal damage by regulating mitochondrial dynamics. To this end, the effects of muscone on a rat model of chronic cervical cord compression, as well as activated BV2 cells and injured neurons, were assessed. The results showed that muscone intervention improved motor function compared with vehicle-treated rats. Indeed, muscone attenuated pro-inflammatory cytokine expression, neuronal-apoptosis indicators in the lesion area, and activation of the nod-like receptor family pyrin domain-containing 3 inflammasome, nuclear transcription factor-κB, and dynamin-related protein 1 in Iba1- and ßIII-tubulin-labeled cells. Compared with vehicle-treated rats, compression sites of muscone-treated animals exhibited elongated mitochondrial morphologies in individual cell types and reduced reactive oxygen species. In vitro results indicated that muscone suppressed microglial activation and neuronal damage by regulating related-inflammatory or apoptotic molecules. Moreover, muscone inhibited dynamin-related protein 1 activation in activated BV2 cells and injured neurons, whereby it rescued mitochondrial fragmentation and reactive oxygen species production, which regulate a wide range of inflammatory and apoptotic molecules. Our findings reveal that muscone attenuates neuroinflammation and neuronal damage in rats with chronic cervical cord compression by regulating mitochondrial fission events, suggesting its promise for CSM therapy.

circCELSR1 facilitates ovarian cancer proliferation and metastasis by sponging miR-598 to activate BRD4 signals.

BACKGROUND: Ovarian cancer is one of the most common gynecologic cancers and has high mortality rate due to the lack of early diagnosis method and efficient therapeutic agents. circCELSR1 is up-regulated in ovarian cancer, but its role and mechanisms in ovarian cancer are unclear. METHODS: Gene expression of circCELSR1, miR-598 and BRD4 in ovarian cells was examined by qRT-PCR. Protein level was determined by Western blotting. Bioinformatic analysis and luciferase assay determined the molecular binding among circCELSR1, miR-598 and BRD4 3' UTR. Cell proliferation, migration, invasion and apoptosis were determined by colony formation, wound healing assay, transwell assay and flow cytometry analysis, respectively. An abdominal cavity metastasis nude mice model was used to determine the in vivo function of circCELSR1. RESULTS: circCELSR1 and BRD4 were promoted, but miR-598 was suppressed in various ovarian cancer cells. circCELSR1 bound to miR-598 and promoted expression of its downstream target BRD4. Knockdown of circCELSR1 suppressed proliferation, migration, invasion and epithelial-mesenchymal transition (EMT), but promoted apoptosis in ovarian cancer cells, and these effects were reversed by miR-598 inhibition or BRD4 overexpression. circCELSR1 inhibition decreased the expression of BRD4 and its downstream proliferation/migration related genes by targeting miR-598. Furthermore, knockdown of circCELSR1 suppressed ovarian cancer growth and metastasis in nude mice. CONCLUSION: Knockdown of circCELSR1 inhibited BRD4-mediated proliferation/migration related signaling via sponging miR-598, thereby repressing ovarian cancer progression. This study provides a new regulatory mechanism of ovarian cancer may facilitate the development of therapeutic agents for ovarian cancer.

A VIT-like transporter facilitates iron transport into nodule symbiosomes for nitrogen fixation in soybean.

Effective legume-rhizobia symbiosis depends on efficient nutrient exchange. Rhizobia need to synthesize iron-containing proteins for symbiotic nitrogen fixation (SNF) in nodules, which depends on host plant-mediated iron uptake into the symbiosome. We functionally investigated a pair of vacuolar iron transporter like (VTL) genes, GmVTL1a/b, in soybean (Glycine max) and evaluated their contributions to SNF, including investigations of gene expression patterns, subcellular localization, and mutant phenotypes. Though both GmVTL1a/b genes were specifically expressed in the fixation zone of the nodule, GmVTL1a was the lone member to be localized at the tonoplast of tobacco protoplasts, and shown to facilitate ferrous iron transport in yeast. GmVTL1a targets the symbiosome in infected cells, as verified by in situ immunostaining. Two vtl1 knockout mutants had lower iron concentrations in nodule cell sap and peribacteroid units than in wild-type plants, suggesting that GmVTL1 knockout inhibited iron import into symbiosomes. Furthermore, GmVTL1 knockout minimally affected soybean growth under nonsymbiotic conditions, but dramatically impaired nodule development and SNF activity under nitrogen-limited and rhizobia-inoculation conditions, which eventually led to growth retardation. Taken together, these results demonstrate that GmVTL1a is indispensable for SNF in nodules as a transporter of ferrous iron from the infected root cell cytosol to the symbiosome.