Mecp2 promotes the anti-inflammatory effect of alpinetin via epigenetic modification crosstalk.

In recent years, inflammatory disorders have emerged as a significant concern for human health. Through ongoing research on anti-inflammatory agents, alpinetin has shown promising anti-inflammatory properties, including involvement in epigenetic modification pathways. As a crucial regulator of epigenetic modifications, Mecp2 may play a role in modulating the epigenetic effects of alpinetin, potentially impacting its anti-inflammatory properties. To test this hypothesis, two key components, p65 (a member of NF-KB family) and p300 (a type of co-activator), were screened by the expression profiling microarray, which exhibited a strong correlation with the intensity of LPS stimulation in mouse macrophages. Meanwhile, alpinetin demonstrates the anti-inflammatory properties through its ability to disrupt the synthesis of p65 and its interaction with promoters of inflammatory genes, yet it did not exhibit similar effects on p300. Additionally, Mecp2 can inhibit the binding of p300 by attaching to the methylated inflammatory gene promoter induced by alpinetin, leading to obstacles in promoter acetylation and subsequently impacting the binding of p65, ultimately enhancing the anti-inflammatory capabilities of alpinetin. Similarly, in a sepsis mouse model, it was observed that homozygotes overexpressing Mecp2 showed a greater reduction in organ damage and improved survival rates compared to heterozygotes when administered by alpinetin. However, blocking the expression of DNA methyltransferase 3A (DNMT3A) resulted in the loss of Mecp2's anti-inflammatory assistance. In conclusion, Mecp2 may augment the anti-inflammatory effects of alpinetin through epigenetic 'crosstalk', highlighting the potential efficacy of a combined therapeutic strategy involving Mecp2 and alpinetin for anti-inflammatory intervention.

Construction of Ge-Stereogenic Center by Desymmetric Carbene Insertion of Dihydrogermanes.

We developed a method for the enantioselective synthesis of germanium-stereogenic compounds by the desymmetric carbene insertion of dihydrogermanes. A chiral rhodium phosphate catalyst decomposes diaryldiazo-methanes to generate rhodium carbenes that insert enantioselectively into one of the two Ge-H bonds of dihydrogermanes to form germanium-stereogenic compounds under mild reaction conditions. By this method, a variety of chiral germanes with germanium-stereogenic centers were synthesized in high yields and excellent enantioselectivities. Kinetic studies of the reaction showed that the diazo decomposition process was the rate-determining step. The remaining Ge-H bond of the chiral germane products provides a possibility for preparing chiral tetra-substituted germanium-stereogenic compounds.

Ligand-Controlled Regiodivergent Nickel-Catalyzed Hydroaminoalkylation of Unactivated Alkenes.

Ligand modulation of transition-metal catalysts to achieve optimal reactivity and selectivity in alkene hydrofunctionalization is a fundamental challenge in synthetic organic chemistry. Hydroaminoalkylation, an atom-economical approach for alkylating amines using alkenes, is particularly significant for amine synthesis in the pharmaceutical, agrochemical, and fine chemical industries. However, the existing methods usually require specific substrate combinations to achieve precise regio- and stereoselectivity, which limits their practical utility. Protocols allowing for regiodivergent hydroaminoalkylation from the same starting materials, controlling both regiochemical and stereochemical outcomes, are currently absent. Herein, we report a ligand-controlled, regiodivergent nickel-catalyzed hydroaminoalkylation of unactivated alkenes with N-sulfonyl amines. The reaction initiates with amine dehydrogenation and involves aza-nickelacycle intermediates. Tritert-butylphosphine promotes branched regioselectivity and syn diastereoselectivity, whereas ethyldiphenylphosphine enables linear selectivity, yielding regioisomers with inverse orientation. Systematic evaluation of diverse monodentate phosphine ligands reveals distinct regioselectivity cliffs, and % Vbur (min), a ligand steric descriptor, was established as a predictive parameter correlating ligand structure to regioselectivity. Computational investigations supported experimental findings, offering mechanistic insights into the origins of regioselectivity. Our method provides an efficient and predictable route for amine synthesis, demonstrating broad substrate scope, excellent tolerance toward various functional groups, and practical advantages. These include the use of readily available starting materials and cost-effective nickel(II) salts as precatalysts.

Regioselective and Enantioselective Nickel-Catalyzed Intermolecular Reductive Coupling of Aliphatic Alkenes with Imines.

Unactivated aliphatic alkenes are particularly desirable as starting materials because they are readily accessible in large quantities, but the enantioselective intermolecular reductive coupling of unactivated alkenes with imines is challenging. In this paper, we report a method for nickel-catalyzed intermolecular reductive coupling reactions between aliphatic alkenes and imines to yield chiral amines with excellent enantioselectivities and good linear selectivities. The reaction conditions are compatible with a broad range of aliphatic alkenes, including those derived from bioactive molecules. The success of this method can be attributed to the use of newly developed monodentate chiral spiro phosphine ligands.

Trade-off in genome turnover events leading to adaptive evolution of Microcystis aeruginosa species complex.

BACKGROUND: Numerous studies in the past have expanded our understanding of the genetic differences of global distributed cyanobacteria that originated around billions of years ago, however, unraveling how gene gain and loss drive the genetic evolution of cyanobacterial species, and the trade-off of these evolutionary forces are still the central but poorly understood issues. RESULTS: To delineate the contribution of gene flow in mediating the hereditary differentiation and shaping the microbial evolution, a global genome-wide study of bloom-forming cyanobacterium, Microcystis aeruginosa species complex, provided robust evidence for genetic diversity, reflected by enormous variation in gene repertoire among various strains. Mathematical extrapolation showed an 'open' microbial pan-genome of M. aeruginosa species, since novel genes were predicted to be introduced after new genomes were sequenced. Identification of numerous horizontal gene transfer's signatures in genome regions of interest suggested that genome expansion via transformation and phage-mediated transduction across bacterial lineage as an evolutionary route may contribute to the differentiation of Microcystis functions (e.g., carbohydrate metabolism, amino acid metabolism, and energy metabolism). Meanwhile, the selective loss of some dispensable genes at the cost of metabolic versatility is as a mean of adaptive evolution that has the potential to increase the biological fitness. CONCLUSIONS: Now that the recruitment of novel genes was accompanied by a parallel loss of some other ones, a trade-off in gene content may drive the divergent differentiation of M. aeruginosa genomes. Our study provides a genetic framework for the evolution of M. aeruginosa species and illustrates their possible evolutionary patterns.

Sweroside attenuates podocyte injury and proteinuria in part by activating Akt/BAD signaling in mice.

In this study, we investigated the effects of sweroside on podocyte injury in diabetic nephropathy (DN) mice and elucidated its molecular mechanisms. We conducted in vivo experiments using a C57BL/6 mice model of DN to explore the effects of sweroside on proteinuria and podocyte injury in DN mice. In in vitro experiments, conditionally immortalized mouse podocytes were treated with high glucose and sweroside, and the protective effects of sweroside on podocyte injury were analyzed. In vitro, Akt/BAD pathways were detected using gene siRNA silencing assays and found to be involved in the protective roles of sweroside in high glucose-mediated podocyte injury. In vivo, sweroside significantly decreased albuminuria in DN mice (p < 0.01). periodic acid-Schiff staining showed that sweroside alleviated the glomerular volume and mesangium expansion in DN mice. Consistently, western blot and reverse transcription-polymerase chain reaction analyses showed that the profibrotic molecule expression in the glomeruli declined in sweroside-treated DN mice. Immunofluorescent results showed that sweroside preserved nephrin and podocin expression, and transmission electron microscopy showed that sweroside attenuated podocyte injury. In DN mice, sweroside decreased podocyte apoptosis, and increased nephrin, podocin expression and decreased desmin and HIF1α expression. These results confirmed that sweroside ameliorated albuminuria, glomerulomegaly, and glomerulosclerosis in these mice. Experiments in vitro revealed that sweroside improved HG-induced podocyte injury and apoptosis. Sweroside stimulated activation of the Akt/BAD pathway and upregulated Bcl-2-associated death promoter (BAD) and p-Akt. Overall, sweroside protected podocytes from injury and prevented the progression of DN, providing a novel strategy for the treatment of DN.

Diastereodivergent and Enantioselective Synthesis of Homoallylic Alcohols via Nickel-Catalyzed Borylative Coupling of 1,3-Dienes with Aldehydes.

We present the first enantioselective nickel-catalyzed borylative coupling of 1,3-dienes with aldehydes, providing an efficient route to highly valuable homoallylic alcohols in a single step. The reaction involves the 1,4-carboboration of dienes, leading to the formation of C-C and C-B bonds accompanied by the construction of two continuous stereogenic centers. Enabled by a chiral spiro phosphine-oxazoline nickel complex, this transformation yields products with exceptional diastereoselectivity, E-selectivity, and enantioselectivity. The diastereoselectivity of the reaction can be controlled by employing either (Z)-1,3-dienes or (E)-1,3-dienes.

VASERP: An Adaptive, Lightweight, Secure, and Efficient RFID-Based Authentication Scheme for IoV.

With the rapid growth in wireless communication and IoT technologies, Radio Frequency Identification (RFID) is applied to the Internet of Vehicles (IoV) to ensure the security of private data and the accuracy of identification and tracking. However, in traffic congestion scenarios, frequent mutual authentication increases the overall computing and communication overhead of the network. For this reason, in this work, we propose a lightweight RFID security fast authentication protocol for traffic congestion scenarios, designing an ownership transfer protocol to transfer access rights to vehicle tags in non-congestion scenarios. The edge server is used for authentication, and the elliptic curve cryptography (ECC) algorithm and the hash function are combined to ensure the security of vehicles' private data. The Scyther tool is used for the formal analysis of the proposed scheme, and this analysis shows that the proposed scheme can resist typical attacks in mobile communication of the IoV. Experimental results show that, compared to other RFID authentication protocols, the calculation and communication overheads of the tags proposed in this work are reduced by 66.35% in congested scenarios and 66.67% in non-congested scenarios, while the lowest are reduced by 32.71% and 50%, respectively. The results of this study demonstrate a significant reduction in the computational and communication overhead of tags while ensuring security.

Intermolecular Enantioselective Benzylic C(sp3 )-H Amination by Cationic Copper Catalysis.

Chiral benzylic amines are privileged motifs in pharmacologically active molecules. Intramolecular enantioselective radical C(sp3 )-H functionalization by hydrogen-atom transfer has emerged as a straightforward, powerful tool for the synthesis of chiral amines, but methods for intermolecular enantioselective C(sp3 )-H amination remain elusive. Herein, we report a cationic copper catalytic system for intermolecular enantioselective benzylic C(sp3 )-H amination with peroxide as an oxidant. This mild, straightforward method can be used to transform an array of feedstock alkylarenes and amides into chiral amines with high enantioselectivities, and it has good functional group tolerance and broad substrate scope. More importantly, it can be used to synthesize bioactive molecules, including chiral drugs. Preliminary mechanistic studies indicate that the amination reaction involves benzylic radicals generated by hydrogen-atom transfer.

The effects of REG4 expression on chemoresistance of ovarian cancer.

Although ovarian cancer usually responds well to platinum- and taxane-based first-line chemotherapy, most patients develop recurrence and chemoresistance. Regenerating gene 4 (REG4) is a secretory protein involved in cell differentiation and proliferation. We found higher REG4 expression in ovarian cancer than in normal tissues (p < .05). Regenerating gene 4 expression was negatively associated with overall, progression-free or post-progression survival rates of patients with ovarian cancer receiving platinum or paclitaxel treatment (p < .05) according to a Kaplan-Meier plotter. Regenerating gene 4 overexpression resulted in either cisplatin or paclitaxel resistance, and apoptosis resistance in CAOV3 ovarian cancer cells (p < .05). REG4-transfected ovarian cancer cells showed stronger migration and invasion treated with cisplatin or paclitaxel (p < .05). Additionally, cisplatin or paclitaxel exposure led to the overexpression of phosphorylated phosphoinositide 3-kinase (p-PI3K), p-Akt, phosphorylated mammalian target of rapamycin (p-mTOR), glutathione S-transferase-π, survivin, and B-cell lymphoma 2 in REG4 transfectants compared with control cells (p < .05). These findings suggested that REG4 expression was up-regulated in ovarian cancer, and associated with poor survival and chemotherapy resistance. REG4 promoted the occurrence, development, and chemotherapy resistance of ovarian cancer by regulating cell proliferation, apoptosis, migration, and invasion, and PI3K/Akt/m-TOR signalling pathways. IMPACT STATEMENTWhat is already known on this subject? REG4 mRNA expression is up-regulated in many digestive cancers. High REG4 expression was associated with an adverse prognosis, high tumour and nodal stages, poor differentiation, and hepatic and peritoneal metastases of digestive cancers. REG4 expression conferred cancer cells with increased resistance to chemoradiotherapy, especially 5-FU-based treatment, by activating the MAPK/Erk/Bim signalling pathway.What do the results of this study add? REG4 was highly expressed in ovarian cancer. The expression of p-PI3K, p-AKT, p-mTOR, GST-π, survivin, and Bcl-2 was increased in REG4-overexpressing cells. High REG4 expression was significantly associated with inferior OS, PFS, and PPS rates in patients with ovarian cancer receiving platinum chemotherapy. REG4 mediated cisplatin and paclitaxel resistance in CAOV3 ovarian cancer cells. The percentage of apoptotic cells was markedly lower in REG4-transfected compared to mock-transfected cells after cisplatin or paclitaxel treatment.What are the implications of these findings for clinical practice and/or further research? This study aimed to evaluate the prognostic significance of REG4 expression in ovarian cancer treated with platinum and paclitaxel, to explore REG4 chemoresistance mechanisms to platinum and paclitaxel, and to provide a scientific experimental basis for the clinical treatment and outcome evaluation of ovarian cancer. In order to provide comprehensive clinical treatment of ovarian cancer, it is helpful to improve our understanding of multi-drug resistance and identify new cancer diagnostic biomarkers.

Practice and exploration of the "student-centered" multielement fusion teaching mode in human anatomy.

PURPOSE: Human anatomy is a core course of basic medicine and the first professional course for medical students. Traditional teaching includes "teacher-centered" instruction, passive learning, and a lack of interaction between teachers and students as well as between students. The aim of this study was to develop a "student-centered" multielement fusion teaching mode to address the mentioned drawbacks. METHODS: A total of 141 clinical medical students from grades 2016 and 2017 of Chengde Medical University participated in this study. The students were randomly divided into four classes: two experimental classes and two control classes. The experimental classes experienced a "student-centered" multielement fusion teaching mode, while the control classes experienced a traditional teaching method. Formative assessments and questionnaires were used to assess the students' preferences and obtain feedback. Theoretical and experimental tests were carried out to detect the students' scores at the end of the semester. RESULTS: The results of the questionnaires demonstrated that 100% of the students agreed that the multielement teaching mode was better. In the experimental test, the students in the experimental group achieved a mean score of 16.50 ± 0.3203, which was significantly higher than that of the control group 12.65 ± 0.4731 (P < 0.01). In the theoretical test, the average score of the experimental group was 45.86 ± 0.6273 and that of the control group was 46.59 ± 0.6636; thus, there was no significant difference between the two groups (P > 0.05). CONCLUSION: The application of a "student-centered" multielement fusion teaching mode obtained strong approval from the students. This teaching mode not only improved students' interest in learning and increased the interaction between teachers and students as well as between students but also enhanced students' competence and will lay a solid foundation for their future careers.

Nickel-Catalyzed Desymmetric Reductive Cyclization/Coupling of 1,6-Dienes: An Enantioselective Approach to Chiral Tertiary Alcohol.

We have developed a nickel-catalyzed desymmetric reductive cyclization/coupling of 1,6-dienes. The reaction provides an efficient method for constructing a chiral tertiary alcohol and a quaternary stereocenter by a single operation. The method has excellent diastereoselectivity and high enantioselectivity, a broad substrate scope, as well as good tolerance of functional groups. Preliminary mechanism studies show that alkyl nickel(I) species are involved in the reaction.

Palladium(II)-Catalyzed Selective Arylation of Tertiary C-H Bonds of Cyclobutylmethyl Ketones Using Transient Directing Groups.

We report the first example of selective PdII -catalyzed tertiary C-H activation of cyclobutylmethyl ketones using a transient directing group. An electron-deficient 2-pyridone ligand was identified as the optimal external ligand to enable tertiary C-H activation. A variety of cyclobutylmethyl ketones bearing quaternary carbon centers was readily accessed without preinstalling internal directing groups in up to 81 % yield and >95 : 5 regioisomeric ratios of tertiary C-H arylation to ß-methylene (ß-methyl) or γ-C-H arylation.

Palladium-Catalyzed Asymmetric Hydrosulfonylation of 1,3-Dienes with Sulfonyl Hydrazides.

A highly enantio- and regioselective hydrosulfonylation of 1,3-dienes with sulfonyl hydrazides has been realized by using a palladium catalyst containing a monodentate chiral spiro phosphoramidite ligand. The reaction provided an efficient approach to synthetically useful chiral allylic sulfones. Mechanistic studies suggest that the reaction proceeds through the formation of an allyl hydrazine intermediate and subsequent rearrangement to the chiral allylic sulfone product. The transformation of the allyl hydrazine intermediate to the product is the enantioselectivity-determining step.

Clinical significance of prognostic nutritional index in predicting the efficacy in patients with B-cell lymphoma. / é¢„åŽè¥å »æŒ‡æ•°åœ¨Bç»†èƒžæ·‹å·´ç˜¤æ‚£è€ ä¸­çš„ç–—æ•ˆé¢„æµ‹ä»·å€¼.

OBJECTIVES: To investigate the clinical significance of prognostic nutritional index (PNI) in predicting the efficacy in patients with B-cell lymphoma. METHODS: The clinical data from 111 patients with B-cell lymphoma (B-cell lymphoma group), who were newly diagnosed in the Third Xiangya Hospital of Central South University from February 2013 to September 2018, were retrospectively analyzed. A total of 93 volunteers selected from the Health Management Center in the Third Xiangya Hospital were set as control, The PNI was compared between the 2 groups. The PNI cut-off value was determined by receiver operating characteristic (ROC) curve analysis. According to the PNI values of patients before chemotherapy, the patients were also divided into a high PNI group (≥43.5) and a low PNI group (<43.5). The correlation of baseline characteristics was evaluated. The correlation between changes in PNI levels and efficacy were evaluated before and after chemotherapy. RESULTS: The PNI value in the B-cell lymphoma group was significantly lower than that in the healthy control group (P<0.05). Lactate dehydrogenase (LDH), presence or absence of B symptoms, international prognostic index (IPI), Eastern Cooperative Oncology Group (ECOG) performance status, source of germinal center, and the efficacy between the high PNI group and the low PNI group were significantly different (all P<0.05). The mean PNI in the effective patients in the low PNI group was increased from 38.10 before chemotherapy to 42.66 after chemotherapy, with significant difference (t=-2.562, P<0.05). The PNI value in the ineffective patients in the high PNI group was decreased from 50.50 before chemotherapy to 41.45 after chemotherapy, with significant difference (t=3.044, P<0.05). CONCLUSIONS: The level of PNI in patients with B-cell lymphoma is significantly lower than that in healthy people, and it is related to the baseline characteristics of prognosis. The change of PNI level before and after chemotherapy can provide certain basis for efficacy evaluation.

PdII -Catalyzed Enantioselective C(sp3 )-H Arylation of Cyclobutyl Ketones Using a Chiral Transient Directing Group.

The use of chiral transient directing groups (TDGs) is a promising approach for developing PdII -catalyzed enantioselective C(sp3 )-H activation reactions. However, this strategy is challenging because the stereogenic center on the TDG is often far from the C-H bond, and both TDG covalently attached to the substrate and free TDG are capable of coordinating to PdII centers, which can result in a mixture of reactive complexes. We report a PdII -catalyzed enantioselective ß-C(sp3 )-H arylation reaction of aliphatic ketones using a chiral TDG. A chiral trisubstituted cyclobutane was efficiently synthesized from a mono-substituted cyclobutane through sequential C-H arylation reactions, thus demonstrating the utility of this method for accessing structurally complex products from simple starting materials. The use of an electron-deficient pyridone ligand is crucial for the observed enantioselectivity. Interestingly, employing different silver salts can reverse the enantioselectivity.

Alkenyl Exchange of Allylamines via Nickel(0)-Catalyzed C-C Bond Cleavage.

A functional group exchange reaction between allylamines and alkenes via nickel-catalyzed C-C bond cleavage and formation was developed. This reaction provides a novel protocol, which does not require the use of unstable imine substrates, for the synthesis of allylamines, which are widely used in the production of fine chemicals, pharmaceuticals, and agrochemicals.

Transferrin Receptor Targeted Cellular Delivery of Doxorubicin Via a Reduction-Responsive Peptide-Drug Conjugate.

PURPOSE: Transferrin receptors (TfRs) are overexpressed in tumor cells but are scarce in normal tissues, which makes TfR an attractive target for drug treatment of cancer. The objective of this study was to evaluate the potential of BP9a (CAHLHNRS) as a peptide vector for constructing TfR targeted peptide-drug conjugates and selective drug delivery. METHODS: Doxorubicin (DOX) was connected to BP9a via a disulfide-intercalating linker to afford a reduction-responsive BP9a-SS-DOX conjugate. By using HepG2 human liver cancer cells and L-O2 normal hepatic cells as TfR over-expressing and low-expressing in vitro models, respectively, TfR mediated cellular uptake of this conjugate was studied by using flow cytometry and confocal laser scanning microscopy. The in vitro cytotoxicities of the conjugate against HepG2 and L-O2 cells were examined by cell counting kit-8 (CCK-8) assay to evaluate its tumorous specificity. RESULTS: Cellular uptake and TfR blockage test results showed that the BP9a-SS-DOX conjugate gained entry into HepG2 cells via endocytosis mediated by TfR and mainly accumulated in cytoplasm. The in vitro antiproliferative activity of this conjugate against HepG2 cells (IC50 6.21 ± 1.12 µM) was approximately one-sixth of that of free DOX (IC50 1.03 ± 0.13 µM). However, its cytotoxic effect on L-O2 cells was obviously reduced compared with that of free DOX. CONCLUSIONS: The BP9a-SS-DOX conjugate showed specific antiproliferative activity against HepG2 liver cancer cells. Our study suggests that BP9a has the potential to target chemotherapeutic agents to tumor cells over-expressing TfR and facilitate selective drug delivery.

Function of low back muscle exercise : Preventive effect of refracture analysis of postoperative vertebral fractures.

BACKGROUND: Low back muscles exercise reportedly influence the risk of osteoporotic vertebral fractures. The exact relationship between the low back muscles exercise and the incidence of vertebral refractures remain unclear. OBJECTIVE: To investigate the ability of exercise to strengthen the low back muscles to prevent vertebral refracture after surgery, through clinical analysis of the vertebral fracture risk reduction program. METHODS: In total 152 patients with vertebral fractures who had undergone percutaneous vertebroplasty (PVP) and anti-osteoporosis treatment were randomly divided into observation and control groups. The observation group performed exercises to strengthen the back muscles after surgery. The clinical efficacy and incidence of re-fractures were compared between groups. RESULTS: The observation group had reduced physical dysfunction and pain following surgery. After 3 months, the vertebral body height had significantly decreased (P < 0.05) in the control group but not in the observation group (P > 0.05). In the observation and control groups, the incidence of vertebral refractures was 9.2% (7/76) and 17.1% (13/76), respectively (P < 0.05). CONCLUSION: Postoperative exercise to strengthen the back muscles can improve physical function, relieve pain and promote the recovery of vertebral height; it can also assist in maintaining bone density, thereby significantly reducing the risk of refracture. This approach is safe and effective and can help improve the quality of life in patients with vertebral fractures.

Nickel(0)-Catalyzed Hydroalkylation of 1,3-Dienes with Simple Ketones.

We developed a highly regioselective addition of 1,3-dienes with simple ketones by nickel-hydride catalyst bearing DTBM-SegPhos ligand. A wide range of aromatic and aliphatic ketones directly coupled with 1,3-dienes, providing synthetically useful γ,δ-unsaturated ketones in high yield and regioselectivity. The asymmetric version of the reaction was also realized in high enantioselectivity by using novel chiral ligand DTBM-HO-BIPHEP. The utility of this hydroalkylation was demonstrated by facile product modification and enantioselective synthesis of ( R)-flobufen.