Iridium-Catalysed Transfer Hydrogenation of 1,8-Naphthyridine with Indoline: Access to Functionalized N-Heteroarenes.

An iridium-catalysed hydrogen transfer strategy, enabling straightforward access to tetrahydro pyridine derivatives from aryl-1,8-naphthyridines and indolines, was developed. This method proceeds with unprecedented synthetic effectiveness including high step-economic fashion together with the advantages of having no by-product and no need for external high-pressure H2 gas, offering an important basis for the transformation of 1,8-naphthyridines and indolines into functionalized products.

A base substitution in OsphyC disturbs its Interaction with OsphyB and affects flowering time and chlorophyll synthesis in rice.

BACKGROUND: Phytochromes are important photoreceptors in plants, and play essential roles in photomorphogenesis. The functions of PhyA and PhyB in plants have been fully analyzed, while those of PhyC in plant are not well understood. RESULTS: A rice mutant, late heading date 3 (lhd3), was characterized, and the gene LHD3 was identified with a map-based cloning strategy. LHD3 encodes phytochrome C in rice. Animo acid substitution in OsphyC disrupted its interaction with OsphyB or itself, restraining functional forms of homodimer or heterodimer formation. Compared with wild-type plants, the lhd3 mutant exhibited delayed flowering under both LD (long-day) and SD (short-day) conditions, and delayed flowering time was positively associated with the day length via the Ehd1 pathway. In addition, lhd3 showed a pale-green-leaf phenotype and a slower chlorophyll synthesis rate during the greening process. The transcription patterns of many key genes involved in photoperiod-mediated flowering and chlorophyll synthesis were altered in lhd3. CONCLUSION: The dimerization of OsPhyC is important for its functions in the regulation of chlorophyll synthesis and heading. Our findings will facilitate efforts to further elucidate the function and mechanism of OsphyC and during light signal transduction in rice.

Hydrogen-Transfer-Mediated α-Functionalization of 1,8-Naphthyridines by a Strategy Overcoming the Over-Hydrogenation Barrier.

A general catalytic hydrogen transfer-mediated α-functionalization of 1,8-naphthyridines is reported for the first time that benefits from a hydrogen transfer-mediated activation mode for non-activated pyridyl cores. The pyridyl α-site selectively couples with the C8-site of various tetrahydroquinolines (THQs) to afford novel α-functionalized tetrahydro 1,8-naphthyridines, a class of synthetically useful building blocks and potential candidates for the discovery of therapeutic and bio-active products. The utilization of THQs as inactive hydrogen donors (HDs) appears to be a key strategy to overcome the over-hydrogenation barrier and address the chemoselectivity issue. The developed chemistry features operational simplicity, readily available catalyst and good functional group tolerance, and offers a significant basis for further development of new protocols to directly transform or functionalize inert N-heterocycles.

The brain in chronic insomnia and anxiety disorder: a combined structural and functional fMRI study.

Background: Chronic insomnia disorder (CID) is usually associated with Generalized Anxiety Disorder (GAD), which may change brain structure and function. However, the possible brain markers, imaging characteristics, and pathophysiology are unknown. Objective: To look at the probable brain markers, imaging characteristics, and pathogenesis of CID in combination with GAD. Methods: A total of 57 patients with CID concomitant GAD and 57 healthy controls (HC) were enrolled. Voxel-based morphometry (VBM) and functional connectivity (FC) were utilized to measure gray matter volume (GMV) and functional changes. Correlation analysis was utilized to identify relationships between brain changes and clinical characteristics. Results: Patients had decreased GMV in the left cerebellum, right cerebellar peduncle, and left insula; increased FC between the left cerebellum and right angular gyrus, as well as between the left insula and anterior left cingulate gyrus; and decreased FC in several areas, including the left cerebellum with the middle left cingulate gyrus and the left insula with the left superior postcentral gyrus. These brain changes related to CID and GAD. These data could be used to identify relevant brain markers, imaging features, and to better understand the etiology. Conclusion: The intensity of insomnia in patients was strongly related to the severity of anxiety. The lower GMV in the cerebellum could be interpreted as an imaging characteristic of CID. Reduced GMV in the insula, as well as aberrant function in the cingulate gyrus and prefrontal lobe, may contribute to the pathophysiology of CID and GAD. Abnormal function in the postcentral gyrus and angular gyrus may be associated with patients' clinical complaints.

Ameliorative Effect of Ellagic Acid on Aging in Rats with the Potential Mechanism Relying on the Gut Microbiota and Urolithin A-Producing Ability.

Ellagic acid (EA) exhibits potential antiaging activity. Differences in individual ability to produce urolithins may result in large interindividual variability in the health effects of EA. Therefore, the effects and mechanism of EA on d-galactose-induced aging, considering urolithin A-producing ability, were investigated. Our results showed that EA improved cognitive impairment and hippocampal damage, increased the GABA (by 107.84-117.86%) and 5-HT (by 72.56-100.85%) levels, and suppressed the inflammatory and oxidative stress in aging rats. Thirteen plasma metabolites and 12 brain metabolites were improved by EA administration in aging rats. In particular, EA showed a better anti-aging effect in high-UroA-producing rats than in the low counterparts, while antibiotic intervention almost offset EA-alleviated aging induced by d-gal. Furthermore, the lower ratio of Firmicutes and Bacteroidota as well as the greater abundances of Akkermansia (by 139.21%), Bifidobacterium (by 88.04%), Clostridium_sensu_stricto_1 (by 183.47%), Lactobacillus (by 97.23%), and Turicibacter (by 83.06%) were observed in the high-UroA-producing group compared with the model group (p < 0.05). These findings provide novel insights into the anti-aging effects of EA and suggest that the ability of the gut microbiota responding to EA largely determines EA's anti-aging performance.

Cerebellum and hippocampus abnormalities in patients with insomnia comorbid depression: a study on cerebral blood perfusion and functional connectivity.

Chronic insomnia disorder and major depressive disorder are highly-occurred mental diseases with extensive social harm. The comorbidity of these two diseases is commonly seen in clinical practice, but the mechanism remains unclear. To observe the characteristics of cerebral blood perfusion and functional connectivity in patients, so as to explore the potential pathogenesis and biological imaging markers, thereby improving the understanding of their comorbidity mechanism. 44 patients with chronic insomnia disorder comorbid major depressive disorder and 43 healthy controls were recruited in this study. The severity of insomnia and depression were assessed by questionnaire. The cerebral blood perfusion and functional connectivity values of participants were obtained to, analyze their correlation with questionnaire scores. The cerebral blood flow in cerebellum, vermis, right hippocampus, left parahippocampal gyrus of patients were reduced, which was negatively related to the severity of insomnia or depression. The connectivities of left cerebellum-right putamen and right hippocampus-left inferior frontal gyrus were increased, showing positive correlations with the severity of insomnia and depression. Decreased connectivities of left cerebellum-left fusiform gyrus, left cerebellum-left occipital lobe, right hippocampus-right paracentral lobule, right hippocampus-right precentral gyrus were partially associated with insomnia or depression. The connectivity of right hippocampus-left inferior frontal gyrus may mediate between insomnia and depression. Insomnia and depression can cause changes in cerebral blood flow and brain function. Changes in the cerebellar and hippocampal regions are the result of insomnia and depression. They reflect abnormalities in sleep and emotion regulation. That may be involved in the pathogenesis of comorbidity.

Aberrant structural and functional alterations in postpartum depression: a combined voxel-based morphometry and resting-state functional connectivity study.

Objectives: Postpartum depression (PPD) is a severe postpartum psychiatric disorder with unclear pathogenesis. Previous neuroimaging studies have reported structural or functional alterations in areas associated with emotion regulation, cognitive disorder, and parenting behaviors of PPD. The primary goal of this investigation was to explore the presence of brain structural alterations and relevant functional changes in PPD patients. Methods: A total of 28 patients and 30 matched healthy postnatal women (HPW) underwent both three-dimensional T1-weighted magnetic resonance imaging (MRI) and resting-state functional MRI. Structural analysis was performed by voxel-based morphometry (VBM), followed by resting-state functional analysis using a seed-based whole-brain functional connectivity (FC) approach with abnormal gray matter volume (GMV) regions as seed. Results: Compared with HPW, the PPD patients showed increased GMV in the left dorsolateral prefrontal cortex (DLPFC.L), the right precentral gyrus (PrCG.R), and the orbitofrontal cortex (OFC). In the PPD group, the DLPFC.L showed increased FC with the right anterior cingulate and paracingulate gyri (ACG.R) and the right middle frontal gyrus (MFG.R); the FC between the PrCG.R and the right median cingulate and paracingulate gyri (DCG.R) exhibited enhanced; the OFC showed increased FC with MFG.R and the left inferior occipital gyrus (IOG.L). In PPD, GMV of DLPFC.L was positively correlated with EDPS scores (r = 0.409 p = 0.031), and FC of PrCG.R-DCG.R was positively correlated with EDPS scores (r = 0.483 p = 0.020). Conclusion: Structural and functional damage of the DLPFC.L and OFC is associated with cognitive disorders and parenting behaviors in PPD, while structural abnormalities of the DLPFC.L and PrCG.R are involved in impaired executive function. The increased GMV of DLPFC.L may be a unique structural pathological mechanism of PPD related to the inability of PPD patients to withstand long-term parenting stress. These findings have important implications for understanding neural mechanisms in PPD.

A myocardium tropic adeno-associated virus (AAV) evolved by DNA shuffling and in vivo selection.

To engineer gene vectors that target striated muscles after systemic delivery, we constructed a random library of adeno-associated virus (AAV) by shuffling the capsid genes of AAV serotypes 1 to 9, and screened for muscle-targeting capsids by direct in vivo panning after tail vein injection in mice. After 2 rounds of in vivo selection, a capsid gene named M41 was retrieved mainly based on its high frequency in the muscle and low frequency in the liver. Structural analyses revealed that the AAVM41 capsid is a recombinant of AAV1, 6, 7, and 8 with a mosaic capsid surface and a conserved capsid interior. AAVM41 was then subjected to a side-by-side comparison to AAV9, the most robust AAV for systemic heart and muscle gene delivery; to AAV6, a parental AAV with strong muscle tropism. After i.v. delivery of reporter genes, AAVM41 was found more efficient than AAV6 in the heart and muscle, and was similar to AAV9 in the heart but weaker in the muscle. In fact, the myocardium showed the highest gene expression among all tissues tested in mice and hamsters after systemic AAVM41 delivery. However, gene transfer in non-muscle tissues, mainly the liver, was dramatically reduced. AAVM41 was further tested in a genetic cardiomyopathy hamster model and achieved efficient long-term delta-sarcoglycan gene expression and rescue of cardiac functions. Thus, direct in vivo panning of capsid libraries is a simple tool for the de-targeting and retargeting of viral vector tissue tropisms facilitated by acquisition of desirable sequences and properties.

Widespread muscle expression of an AAV9 human mini-dystrophin vector after intravenous injection in neonatal dystrophin-deficient dogs.

Duchenne (DMD) and golden retriever (GRMD) muscular dystrophy are caused by genetic mutations in the dystrophin gene and afflict striated muscles. We investigated systemic gene delivery in 4-day-old GRMD dogs given a single intravenous injection of an AAV9 vector (1.5 x 10(14) vector genomes/kg) carrying a human codon-optimized human mini-dystrophin gene under control of the cytomegalovirus (CMV) promoter. One of the three treated dogs was euthanized 9 days later due to pre-existing conditions. Scattered mini-dystrophin-positive myofibers were seen by immunofluorescent (IF) staining in numerous muscles. At the end of the 16-week study, the other two dogs showed generalized muscle expression of mini-dystrophin in ~15% to nearly 100% of myofibers. Western blot and vector DNA quantitative PCR results agreed with the IF data. Delayed growth and pelvic limb muscle atrophy and contractures were seen several weeks after vector delivery. T-2 weighted magnetic resonance imaging (MRI) at 8 weeks showed increased signal intensity compatible with inflammation in several pelvic limb muscles. This marked early inflammatory response raised concerns regarding methodology. Use of the ubiquitous CMV promoter, extra-high vector dose, and marked expression of a human protein in canine muscles may have contributed to the pathologic changes seen in the pelvic limbs.

Distribution of Urolithins Metabotypes in Healthy Chinese Youth: Difference in Gut Microbiota and Predicted Metabolic Pathways.

This is the first study to report the distribution of urolithin metabotypes (UMs) in Asian people, specifically in the Chinese. As was reported for Europeans and Latin Americans, three UMs were observed, UM-A (54.3%), UM-B (31.4%), and UM-0 (14.3%), in 35 healthy Chinese youth. The richness and diversity of gut microbiota were lower in UM-0 than in UM-A and UM-B at the genus level. Gordonibacter in UM-A and UM-B was significantly higher than that in UM-0. The Akkermansia was not found in UM-0. The correlation analysis between the type and content of urolithins and the gut microbiota at the genus level showed that 27 genera were significantly positively correlated with urolithin A and 20 genera were significantly positively associated with isourolithin A and urolithin B. In addition, different KEGG pathways such as TCA cycle, energy metabolism, and some disease were found between the gut microbiome of the three UMs. Further research is needed to explore the mechanisms of metabotypes and the differential health benefits or illness predisposition of the three UMs.

Salted and Unsalted Zhàcài (Brassica juncea var. tumida) Alleviated High-Fat Diet-Induced Dyslipidemia by Regulating Gut Microbiota: A Multiomics Study.

SCOPE: Zhàcài (ZC), a salting-processed Brassica juncea var. tumida vegetable, is widely consumed as a pickle, but little is known about the health benefits of both salted and unsalted ZC as a whole food. METHODS AND RESULTS: The preventive effects of salted and unsalted ZC against dyslipidemia are assessed in high-fat (HF) diet-fed mice. HF intake for 12 continuous weeks cause dyslipidemia in mice, as evidenced by the elevations in serum total triglyceride, total cholesterol, and low-density lipoprotein cholesterol levels by 30%, 66%, and 117%, respectively. Metabolomics analysis and the 16S rRNA genes sequencing suggest that dietary administration of salted and unsalted ZC (2.5% w/w) alleviates HF-induced dyslipidemia, metabolic disorders of short-chain fatty acids, and disturbance of intestinal flora in mice. These positive effects of unsalted ZC are stronger than those of salted ZC. Moreover, fecal bacteria transplantation confirms the antidyslipidemia of ZC. CONCLUSION: These results suggest that consumption of ZC may prevent HF-induced dyslipidemia by regulating gut microbiota.

[Observation of the changes in ventral prostatic microcirculation in castrated rats].

OBJECTIVE: Castrated rats exhibit significant shrinkage of the ventral prostate and apoptosis of prostatic cells, which can be attributed to the reduced blood supply to the prostate. But what causes the blood decrease in the prostate remains unknown. This study aims to explore the molecular mechanism of the changes in the microcirculation of the ventral prostate of rats following castration. METHODS: We randomized 24 male adult rats into 6 groups of equal number, and collected their ventral prostates at 0, 1/2, 1, 2, 3 and 7 d, respectively, after castration. Then we observed the changes of the microvessels under the transmission electron microscope, detected the apoptosis of endothelial cells by TUNEL, and determined the expressions of VEGF, endostatin, angiostatin and angiopoietin-2 by Western blot. RESULTS: The castrated rats showed dramatic changes in the microvessels of the ventral prostate, obvious apoptosis of the endothelial cells, down-regulated expression of VEGF, and up-regulated expressions of endostatin and angiostatin, while angiopoietin-2 remained unchanged. CONCLUSION: The decreased level of VEGF and increased levels of endostatin and angiostatin might underlie the mechanism of the changes in the microcirculation of the ventral prostate of rats following castration.

Adeno-associated virus serotype 8 efficiently delivers genes to muscle and heart.

Systemic gene delivery into muscle has been a major challenge for muscular dystrophy gene therapy, with capillary blood vessels posing the principle barrier and limiting vector dissemination. Previous efforts to deliver genes into multiple muscles have relied on isolated vessel perfusion or pharmacological interventions to enforce broad vector distribution. We compared the efficiency of multiple adeno-associated virus (AAV) vectors after a single injection via intraperitoneal or intravenous routes without additional intervention. We show that AAV8 is the most efficient vector for crossing the blood vessel barrier to attain systemic gene transfer in both skeletal and cardiac muscles of mice and hamsters. Serotypes such as AAV1 and AAV6, which demonstrate robust infection in skeletal muscle cells, were less effective in crossing the blood vessel barrier. Gene expression persisted in muscle and heart, but diminished in tissues undergoing rapid cell division, such as neonatal liver. This technology should prove useful for muscle-directed systemic gene therapy.

Iridium-Catalyzed Dehydrogenative α-Functionalization of (Hetero)aryl-Fused Cyclic Secondary Amines with Indoles.

Herein, by employing dehydrogenation as a substrate-activating strategy, a new iridium-catalyzed direct α-functionalization of (hetero)aryl-fused cyclic secondary amines with indoles has been demonstrated, which proceeds with merits that include high step- and atom-efficiency, readily available feedstocks, a simple catalyst system, good functional group tolerance, and operational simplicity.

Transfer hydrogenative para-selective aminoalkylation of aniline derivatives with N-heteroarenes via ruthenium/acid dual catalysis.

By ruthenium/acid dual catalysis, we present, for the first time, a transfer hydrogenative para-selective aminoalkylation of aniline derivatives with N-heteroarenes. Position-2 of the sterically less-hindered pyridine ring of the N-heteroarenes couples with various aniline derivatives at the site para to the amino group, affording a wide array of structurally modified anilines, a class of highly valuable compounds with the potential for discovery and further creation of functional molecules. The developed chemistry features operational simplicity, a readily available catalyst system, excellent functional group tolerance, and exclusive regioselectivity, which offers a significant basis to access novel aniline derivatives that are currently inaccessible or challenging to prepare with conventional approaches, and design new coupling reactions via a hydrogen transfer strategy.

Ultrasensitive electrochemical detection of methyl parathion pesticide based on cationic water-soluble pillar[5]arene and reduced graphene nanocomposite.

We report a rapid, sensitive and selective electrochemical sensor based on pillar[5]arene (CP5) reduced graphene (rGO) nanohybrid-modified glassy carbon electrode CP5-rGO/GCE for the trace detection of methyl parathion (MP) by differential pulse voltammetry (DPV) for the first time. Compared to beta-cyclodextrin (ß-CD)-functionalized reduced graphene (rGO)-modified GCE ß-CD-rGO/GCE, the proposed CP5-rGO/GCE sensor exhibits excellent electrochemical catalytic activity, rapid response, high sensitivity, good reproducibility and anti-interference ability towards MP. The recognition mechanism of ß-CD/MP and CP5/MP was studied by 1H NMR. The results indicate a higher supramolecular recognition capability between CP5 and MP compared to that between ß-CD and MP. The ß-CD-rGO and CP5-rGO nano-composites were prepared via a wet chemistry approach. The resulting nano-composites have been characterized by thermogravimetric analysis (TGA), fourier transform infrared spectrometry (FTIR), charge transfer resistance (R ct) and zeta potential. The CP5-rGO/GCE combines the merits of CP5 and rGO, and is used for quantitative detection of MP. It has a low detection limit of 0.0003 µM (S/N = 3) and a linear response range of 0.001-150 µM for MP. This method has been used to detect MP in soil and waste water samples with satisfactory results. This study provides a promising electrochemical sensing platform and is a promising tool for the rapid, facile and sensitive analysis of MP.

Widespread and stable pancreatic gene transfer by adeno-associated virus vectors via different routes.

Diabetes is a disease of epidemic proportions and is on the rise worldwide. Gene therapy has been actively pursued but limited by technical hurdles and profound inefficiency of direct gene transfer to the pancreas in vivo. Here, we show that, for the first time, appropriate serotypes of adeno-associated virus (AAV), coupled with a double-stranded vector DNA cassette, enable extensive and long-term in vivo gene transfer in the adult mouse pancreas by three different delivery methods. Intraperitoneal and intravenous delivery of AAV8 effectively transduced exocrine acinar cells as well as endocrine beta-cells, while local pancreatic intraductal delivery of AAV6 showed the best efficiency in the beta-cells among all AAV serotypes tested in this study. Nearly the entire islet population showed gene transfer but with distinct gene transfer efficiency and patterns when different delivery methods and vectors were used. Importantly, localized gene delivery coupled with an insulin promoter allowed extensive yet specific gene expression in the beta-cells. These effective new methods should provide useful tools to study diabetes pathogenesis and gene therapy.

Cytochrome P450 2J2 promotes the neoplastic phenotype of carcinoma cells and is up-regulated in human tumors.

Cytochrome P450 (CYP) arachidonic acid epoxygenase 2J2 converts arachidonic acid to four regioisomeric epoxyeicosatrienoic acids, which exert diverse biological activities in cardiovascular system and endothelial cells. However, it is unknown whether this enzyme highly expresses and plays any role in cancer. In this study, we found that very strong and selective CYP2J2 expression was detected in human carcinoma tissues in 101 of 130 patients (77%) as well as eight human carcinoma cell lines but undetectable in adjacent normal tissues and nontumoric human cell lines by Western, reverse transcription-PCR, and immunohistochemical staining. In addition, forced overexpression of CYP2J2, and CYP BM3F87V or addition of epoxyeicosatrienoic acids (EET) in cultured carcinoma cell lines in vitro markedly accelerated proliferation by analyses of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, cell accounts, and cell cycle analysis, and protected carcinoma cells from apoptosis induced by tumor necrosis factor alpha (TNF-alpha) in cultures. In contrast, antisense 2J2 transfection or addition of epoxygenase inhibitors 17-ODYA inhibited proliferation and accelerated cell apoptosis induced by TNF-alpha. Examination of signaling pathways on the effects of CYP2J2 and EETs revealed activation of mitogen-activated protein kinases and PI3 kinase-AKT systems and elevation of epithelial growth factor receptor phosphorylation level. These results strongly suggest that CYP epoxygenase 2J2 plays a previously unknown role in promotion of the neoplastic cellular phenotype and in the pathogenesis of a variety of human cancers.

Direct Access to Nitrogen Bi-heteroarenes via Iridium-Catalyzed Hydrogen-Evolution Cross-Coupling Reaction.

Through cooperative actions of iridium catalyst and NaOTf additive we report a new direct access to nitrogen bi-heteroarenes via hydrogen-evolution cross-coupling of the ß-site of indoles/pyrrole with the α-site of N-heteroarenes. The reaction proceeds in an atom- and redox-economic fashion together with the merits of an easily available catalyst system, broad substrate scope, excellent functional tolerance, and no need for external oxidants, offering a practical way to create π-conjugated systems.

Sustained whole-body functional rescue in congestive heart failure and muscular dystrophy hamsters by systemic gene transfer.

BACKGROUND: The success of muscular dystrophy gene therapy requires widespread and stable gene delivery with minimal invasiveness. Here, we investigated the therapeutic effect of systemic delivery of adeno-associated virus (AAV) vectors carrying human delta-sarcoglycan (delta-SG) gene in TO-2 hamsters, a congestive heart failure and muscular dystrophy model with a delta-SG gene mutation. METHODS AND RESULTS: A single injection of double-stranded AAV serotype 8 vector carrying human delta-SG gene without the need of any physical or pharmaceutical interventions achieved nearly complete gene transfer and tissue-specific expression in the heart and skeletal muscles of the diseased hamsters. Broad and sustained (>12 months) restoration of the missing delta-SG gene in the TO-2 hamsters corrected muscle cell membrane leakiness throughout the body and normalized serum creatine kinase levels (a 50- to 100-fold drop). Histological examination revealed minimal or the absence of central nucleation, fibrosis, and calcification in the skeletal muscle and heart. Whole-body functional analysis such as treadmill running showed dramatic improvement, similar to the wild-type F1B hamsters. Furthermore, cardiac functional studies with echocardiography revealed significantly increased percent fractional shortening and decreased left ventricular end-diastolic and end-systolic dimensions in the treated TO-2 hamsters. The survival time of the animals was also dramatically extended. CONCLUSIONS: Systemic gene transfer of delta-SG by the AAV serotype 8 vector could effectively ameliorate cardiac and skeletal muscle pathology, profoundly improve cardiac and whole-body functions, and significantly prolong the lifespan of the treated TO-2 hamsters.