Discovery of salicyl benzoate UDP-glycosyltransferase, a central enzyme in poplar salicinoid phenolic glycoside biosynthesis

The salicinoids are anti-herbivore phenolic glycosides unique to the Salicaceae (Populus and Salix). They consist of a salicyl alcohol glucoside core, which is usually further acylated with benzoic, cinnamic or phenolic acids. While salicinoid structures are well known, their biosynthesis remains enigmatic. Recently, two enzymes from poplar, salicyl alcohol benzoyl transferase and benzyl alcohol benzoyl transferase, were shown to catalyze the production of salicyl benzoate, a predicted potential intermediate in salicinoid biosynthesis. Here, we used transcriptomics and co-expression analysis with these two genes to identify two UDP-glucose-dependent glycosyltransferases (UGT71L1 and UGT78M1) as candidate enzymes in this pathway. Both recombinant enzymes accepted only salicyl benzoate, salicylaldehyde and 2-hydroxycinnamic acid as glucose acceptors. Knocking out the UGT71L1 gene by CRISPR/Cas9 in poplar hairy root cultures led to the complete loss of salicortin, tremulacin and tremuloidin, and a partial reduction of salicin content. This demonstrated that UGT71L1 is required for synthesis of the major salicinoids, and suggested that an additional route can lead to salicin. CRISPR/Cas9 knockouts for UGT78M1 were not successful, and its in vivo role thus remains to be determined. Although it has a similar substrate preference and predicted structure as UGT71L1, it appears not to contribute to the synthesis of salicortin, tremulacin and tremuloidin, at least in roots. The demonstration of UGT71L1 as an enzyme of salicinoid biosynthesis will open up new avenues for the elucidation of this pathway

Biomimetic approach to manadomanzamines and preparation of derivatives of pelletierine for biomimetic synthesis of Lycopodium alkaloids.

Au cours de ce travail, nous nous sommes intéressés dans une première partie à la synthèse biomimétique d’alcaloïdes de type manzamines et plus particulièrement, aux manadomanzamines. Une étude de la réactivité des deux intermédiaires clés de leur biogenèse, les glutaconaldéhydes et les aminopentadiènals, a été entreprise. Ces mêmes molécules ont ensuite été utilisées comme équivalents synthétiques dans une synthèse biomimétique du squelette pentacyclique de la manadomanzamine A. Une seconde partie est consacrée à la préparation d’analogues stables de la pelletiérine en vue d’une synthèse biomimétique d’alcaloïdes du genre Lycopodium.This work is dedicated to the biomimetic synthesis of complex polycyclic alkaloids namely the manzamine alkaloids and especially to manadomanzamine. The biogenetic hypotheses postulated for these alkaloids are reported in a first introductory chapter. A few examples of manzamine alkaloids biogenesis are described and compared. The second chapter is focused on the reactivity of reactive units (considered as simplified models of two key biosynthetic intermediates, namely glutaconaldehydes and aminopentadienals) resulting from the ring-opening of pyridinium salts, and their implication in natural products synthesis. Particularly detailed are the investigations conducted on 5-dimethylamino-2-methylpenta-2,4-dienal and the condensation of potassium glutaconaldehyde onto a pyridinium salt. The chemistry of these reactive units has been exploited to design several model studies towards the synthesis of pentacyclic indole nucleus of manadomanzamine A, isolated from an Indonesian sponge Acanthostrongylophora sp.. These biomimetic models, elaborated from a biosynthetic intermediate postulated in our biosynthesis hypothesis have culminated in the synthesis of the central pentacyclic indole nucleus. The last chapter reports the preparation of more or less oxidized analogs of pelletierine, the well known alkaloid isolated from Punica granatum. Compounds such as phenyloxazolopelletierine have been prepared and their reactivity investigated in view of the biomimetic synthesis of Lycopodium alkaloids

Approche biomimétique des manadomanzamines et préparation d’analogues de la pelletiérine pour la synthèse biomimétique d’alcaloïdes de lycopodes

This work is dedicated to the biomimetic synthesis of complex polycyclic alkaloids namely the manzamine alkaloids and especially to manadomanzamine. The biogenetic hypotheses postulated for these alkaloids are reported in a first introductory chapter. A few examples of manzamine alkaloids biogenesis are described and compared.The second chapter is focused on the reactivity of reactive units (considered as simplified models of two key biosynthetic intermediates, namely glutaconaldehydes and aminopentadienals) resulting from the ring-opening of pyridinium salts, and their implication in natural products synthesis. Particularly detailed are the investigations conducted on 5-dimethylamino-2-methylpenta-2,4-dienal and the condensation of potassium glutaconaldehyde onto a pyridinium salt.The chemistry of these reactive units has been exploited to design several model studies towards the synthesis of pentacyclic indole nucleus of manadomanzamine A, isolated from an Indonesian sponge Acanthostrongylophora sp.. These biomimetic models, elaborated from a biosynthetic intermediate postulated in our biosynthesis hypothesis have culminated in the synthesis of the central pentacyclic indole nucleus.The last chapter reports the preparation of more or less oxidized analogs of pelletierine, the well known alkaloid isolated from Punica granatum. Compounds such as phenyloxazolopelletierine have been prepared and their reactivity investigated in view of the biomimetic synthesis of Lycopodium alkaloids.Au cours de ce travail, nous nous sommes intéressés dans une première partie à la synthèse biomimétique d’alcaloïdes de type manzamines et plus particulièrement, aux manadomanzamines. Une étude de la réactivité des deux intermédiaires clés de leur biogenèse, les glutaconaldéhydes et les aminopentadiènals, a été entreprise. Ces mêmes molécules ont ensuite été utilisées comme équivalents synthétiques dans une synthèse biomimétique du squelette pentacyclique de la manadomanzamine A. Une seconde partie est consacrée à la préparation d’analogues stables de la pelletiérine en vue d’une synthèse biomimétique d’alcaloïdes du genre Lycopodium

Chimie du malonaldéhyde et implication biogénétique

CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

Salivary Gland Scintigraphy in Patients with Sjogren’s Syndrome: A local Experience with Dual-tracer

Objective(s): To review the findings of the patients with Sjögren’s syndrome (SS) having technetium-99m-pertechnetate (99mTc-pertechnetate) and gallium-67 citrate (Ga-67) salivary gland scintigraphy in the past eight years.Methods: The patients with SS, who were referred to our department for salivary gland scintigraphy during January 2008-December 2015 were studied using both 99mTc-pertechnetate and Ga-67 citrate scintigraphy.Results: Eighteen patients were included in the study, 17 of whom had positive findings on 99mTc- pertechnetate salivary gland scintigraphy. One patient had negative parotid glands findings on 99mTc-pertechnetate, but positive findings in Ga-67 study. Four patients had asymmetric involvement of the parotid glands, and one patient had asymmetric involvement of the submandibular glands in 99mTc-pertechnetate salivary gland scintigraphy. On the other hand, one patient had only submandibular gland involvement in the 99mTc-pertechnetate scan.Nine patients (9/18) had positive parotid gland findings on Ga-67 study. The involvements of the parotid glands were all symmetrical, except for one patient. No abnormal gallium uptake in the submandibular glands in our patients was noted.Conclusion: 99mTc-pertechnetate salivary gland scintigraphy is sufficient for the assessment in the majority of patients with SS. Ga-67 scintigraphy may be a useful supplementary test, especially if the result of 99mTc-pertechnetate scintigraphy is not conclusive

Serum bicarbonate is a marker of peri-operative mortality but is not associated with long term survival in colorectal cancer.

AimsInflammation is a hallmark of cancer whose activity is modulated within the tumor microenvironment by low tumoral pH. Recent evidence in the literature has suggested a link between low serum bicarbonate, low tumoral pH and cancer related inflammation. There is however little clinical evidence in human patients regarding the prognostic role of serum bicarbonate. Therefore, the primary aim of this study was to investigate the short and long-term prognostic utility of serum bicarbonate in colorectal cancer (CRC) patients undergoing resection of their primary tumor. The study also aimed to investigate the association of serum bicarbonate with known markers of systemic inflammation.MethodsA total of 3281 consecutive patients who underwent surgical resection of their primary CRC from January 1998 to December 2012. Of these, 2223 stage I-IV patients had available data for analysis. The association of serum bicarbonate with overall survival was assessed using univariate and multivariate cox regression analyses. The association of bicarbonate with other clinicopathological variables was assessed by chi squared and Fisher's exact tests.ResultsSerum bicarbonate was associated with peri-operative mortality in multivariate analysis (pConclusionsIn peri-operative colorectal cancer patients, serum bicarbonate was associated with 30-day survival but not 5-year survival

Tumor sidedness is not an independent prognostic marker of colorectal cancer patients undergoing curative resection: A retrospective cohort study.

BackgroundRecent literature has suggested that tumor sidedness in colorectal cancer (CRC) is an independent prognostic and potentially predictive marker of survival. The aims of the study were to determine the prognostic significance of tumor sidedness in colorectal cancer patients undergoing primary tumor resection and to assess associated tumor biology.MethodsA total of 3281 consecutive patients who underwent surgical resection of their primary CRC from January 1998 to December 2012 were analyzed for association with tumor biologic factors and with overall survival. Metastatic patients were excluded from analysis.ResultsLeft sided CRCs were associated with a number of additional key prognostic markers including BRAFV600E wildtype status (PConclusionsTumor sidedness was not an independent prognostic marker of CRC. However, right sided CRCs were associated with several key independent prognostic markers supporting a hypothesis that tumor sidedness is a surrogate for other biomarkers

A randomized clinical trial of mindfulness meditation versus exercise in Parkinson’s disease during social unrest

Abstract Clinical practice guidelines support resilience training and exercise for patients with Parkinson’s disease (PD). This assessor-blinded, randomized clinical trial aimed to compare the effects of a modified mindfulness meditation program versus stretching and resistance training exercise (SRTE) in patients with mild-to-moderate PD. A total of 126 potential participants were enrolled via convenience sampling, of which 68 eligible participants were randomized 1:1 to receive eight weekly 90-min sessions of mindfulness meditation or SRTE. Compared to the SRTE group, generalized estimating equation analyses revealed that the mindfulness group had significantly better improvement in outcomes, particularly for improving depressive symptoms (d, −1.66; 95% CI, −3.31 to −0.02) at week 8 and maintaining emotional non-reactivity at week 20 (d, 2.08; 95% CI, 0.59 to 3.56). Both groups demonstrated significant immediate, small-moderate effects on cognition (effect size [d] = 0.36–0.37, p = 0.006–0.011). Compared with the SRTE, mindfulness meditation appeared to be a feasible and promising strategy for managing depressive symptoms and maintaining emotional stability, with comparable benefits on cognitive performance. To combat the psychospiritual and cognitive sequelae of social unrest and COVID-19 pandemic, the integration of mindfulness training into motor-oriented PD rehabilitation protocols is recommended to strengthen the resilience and minimize the psycho-cognitive comorbidities among patients with mild-to-moderate PD. Trial Registration: HKU Clinical Trials Registry identifier: HKUCTR-2681