3-(4-Hydroxy-3-methoxyphenyl) propionic acid contributes to improved hepatic lipid metabolism via GPR41.

3-(4-hydroxy-3-methoxyphenyl) propionic acid (HMPA) is a metabolite produced by the gut microbiota through the conversion of 4-hydroxy-3-methoxycinnamic acid (HMCA), which is a widely distributed hydroxycinnamic acid-derived metabolite found abundantly in plants. Several beneficial effects of HMPA have been suggested, such as antidiabetic properties, anticancer activities, and cognitive function improvement, in animal models and human studies. However, the intricate molecular mechanisms underlying the bioaccessibility and bioavailability profile following HMPA intake and the substantial modulation of metabolic homeostasis by HMPA require further elucidation. In this study, we effectively identified and characterized HMPA-specific GPR41 receptor, with greater affinity than HMCA. The activation of this receptor plays a crucial role in the anti-obesity effects and improvement of hepatic steatosis by stimulating the lipid catabolism pathway. For the improvement of metabolic disorders, our results provide insights into the development of functional foods, including HMPA, and preventive pharmaceuticals targeting GPR41.

Cationic Materials for Gene Therapy: A Look Back to the Birth and Development of 2,2-Bis-(hydroxymethyl)Propanoic Acid-Based Dendrimer Scaffolds.

Gene therapy is extensively studied as a realistic and promising therapeutic approach for treating inherited and acquired diseases by repairing defective genes through introducing (transfection) the "healthy" genetic material in the diseased cells. To succeed, the proper DNA or RNA fragments need efficient vectors, and viruses are endowed with excellent transfection efficiency and have been extensively exploited. Due to several drawbacks related to their use, nonviral cationic materials, including lipidic, polymeric, and dendrimer vectors capable of electrostatically interacting with anionic phosphate groups of genetic material, represent appealing alternative options to viral carriers. Particularly, dendrimers are highly branched, nanosized synthetic polymers characterized by a globular structure, low polydispersity index, presence of internal cavities, and a large number of peripheral functional groups exploitable to bind cationic moieties. Dendrimers are successful in several biomedical applications and are currently extensively studied for nonviral gene delivery. Among dendrimers, those derived by 2,2-bis(hydroxymethyl)propanoic acid (b-HMPA), having, unlike PAMAMs, a neutral polyester-based scaffold, could be particularly good-looking due to their degradability in vivo. Here, an overview of gene therapy, its objectives and challenges, and the main cationic materials studied for transporting and delivering genetic materials have been reported. Subsequently, due to their high potential for application in vivo, we have focused on the biodegradable dendrimer scaffolds, telling the history of the birth and development of b-HMPA-derived dendrimers. Finally, thanks to a personal experience in the synthesis of b-HMPA-based dendrimers, our contribution to this field has been described. In particular, we have enriched this work by reporting about the b-HMPA-based derivatives peripherally functionalized with amino acids prepared by us in recent years, thus rendering this paper original and different from the existing reviews.

The digestion and absorption characteristics of human milk phospholipid analogs: a combination study between in vitro and in vivo.

Phospholipids play a crucial role in the growth and neurodevelopment of infants. Currently, soybean phospholipids (SPLs) are the common phospholipid component in most infant formulas (IFs), which, however, shows an obvious difference with the phospholipid (PL) composition of human milk fat. Therefore, in the present study, human milk phospholipid analogs (HMPAs) were prepared by mimicking the composition of PE, PC, PI, PS, and SM in breast milk phospholipids and the composition of the major fatty acids (C16:0, C18:0, C18:1, and C18:2), and their digestion and absorption characteristics were explored using in vitro and mice models. The prepared HMPA contained 26.48% PE, 24.64% PC, 36.19% SM, 6.35% PI, and 6.32% PS, with 40.51% C16:0, 17.02% C18:0, 29.19% C18:1, and 13.26% C18:2, showing different digestive properties relative to SPL. There was little effect on the physical and chemical properties of HMPA under in vitro gastric conditions. The hydrolysis degree, fatty acids release rate, and average particle size decreasing rate of HMPA was significantly higher than that of SPL during digestion in vitro intestine (P < 0.05), showing better digestive process relative to SPL. In terms of the mice model, HMPA had a higher hydrolysis degree in the intestinal tract. Based on the area under curve (AUC) analysis of serum fatty acids, it was found that despite HMPA being absorbed at a slower rate than SPL, it was absorbed more than SPL. In summary, the digestion and absorption of HMPA were preferred to SPL, and these obtained results might provide a theoretical basis for the development and utilization of HMPA in IF.

Pharmacokinetic profiles of 3-(4-hydroxy-3-methoxyphenyl) propionic acid and its conjugates in Sprague-Dawley rats.

3-(4-hydroxy-3-methoxyphenyl)propionic acid (HMPA) is one of the end-products from gut microbiota from dietary polyphenols, which might contribute to their health benefits. This study aims to investigate the absorption, metabolism, and tissue accumulation of HMPA in Sprague-Dawley (SD) rats. After HMPA (10 mg/kg body weight) was orally administered, intact and conjugated HMPAs in the bloodstream were detected and reached the maximum concentration in 15 min (HMPA, 2.6 ± 0.4 nmol/mL; sulfated HMPA, 3.6 ± 0.9 nmol/mL; glucuronidated HMPA, 0.55 ± 0.09 nmol/mL). HMPA and its conjugates were also detected in the target organs 6 h postadministration, indicating that HMPA undergoes rapid conversion into conjugates, and they broadly distribute to organs with similar profiles (kidneys > liver > thoracic aorta > heart > soleus muscle > lungs). This study demonstrated that orally administered HMPA (10 mg/kg) in SD rats undergoes rapid metabolism and wide tissue distribution with ≥1.2% absorption ratio.

Luminescence, CPL and magnetic properties of 1D enantiopure Ln3+ complexes with (S-) and (R-) α-methoxyphenylacetate ligand.

The reaction of Ln(NO3)2·6H2O (Ln = Eu, Tb, Dy and Sm) with (R)-(-)-α-methoxyphenylacetic acid (R-HMPA) and 1,10-phenanthroline (phen) in EtOH/H2O allows the isolation of 1D chiral compounds of formula [Ln(µ-R-MPA)(R-MPA)2(phen)]n in which Ln = Eu (R-Eu), Tb (R-Tb), Dy (R-Dy) and Sm (R-Sm). The same synthesis by using (S)-(+)-α-methoxyphenylacetic acid (S-HMPA) instead of (R)-(-)-α-methoxyphenylacetic acid allows the isolation of the enantiomeric compounds with formula [Ln(µ-S-MPA)(S-MPA)2(phen)]n where Ln = Eu (S-Eu), Tb (S-Tb), Dy (S-Dy) and Sm (S-Sm). Single crystal X-Ray diffraction measurements were performed for compounds R/S-Eu, R/S-Tb, S-Dy and S-Sm. The luminescence and the circular dichroism measured in the solid state are reported. All compounds show sensitized luminescence, notably the Eu3+ and Tb3+ ones, whose emission color can be perceived by the naked eye. For the Eu3+ and Tb3+ derivatives the quantum yield and the circular polarized luminescence have been measured. For the magnetic allowed transition 5D0 → 7F1 of the Eu3+ compound, the anisotropy factor glum is ±0.013 (+for S-Eu). Also, magnetic properties of all compounds were studied with the Dy3+ analogue showing slow relaxation of the magnetization under a direct current magnetic field of 1000 Oe.

Samarium Diiodide Acting on Acetone-Modeling Single Electron Transfer Energetics in Solution.

Samarium diiodide is a versatile single electron transfer (SET) agent with various applications in organic chemistry. Lewis structures regularly insinuate the existence of a ketyl radical when samarium diiodide binds a carbonyl group. The study presented here investigates this electron transfer by the means of computational chemistry. All electron CASPT2 calculations with the inclusion of scalar relativistic effects predict an endotherm electron transfer from samarium diiodide to acetone. Energies calculated with the PBE0-D3(BJ) functional and a small core pseudopotential are in good agreement with CASPT2. The calculations confirm the experimentally measured increase of the samarium diiodide reduction potential through the addition of hexamethylphosphoramide also known as HMPA.

Lithiated Oppolzer Enolates: Solution Structures, Mechanism of Alkylation, and Origin of Stereoselectivity.

Camphorsultam-based lithium enolates referred to colloquially as Oppolzer enolates are examined spectroscopically, crystallographically, kinetically, and computationally to ascertain the mechanism of alkylation and the origin of the stereoselectivity. Solvent- and substrate-dependent structures include tetramers for alkyl-substituted enolates in toluene, unsymmetric dimers for aryl-substituted enolates in toluene, substrate-independent symmetric dimers in THF and THF/toluene mixtures, HMPA-bridged trisolvated dimers at low HMPA concentrations, and disolvated monomers for the aryl-substituted enolates at elevated HMPA concentrations. Extensive analyses of the stereochemistry of aggregation are included. Rate studies for reaction with allyl bromide implicate an HMPA-solvated ion pair with a +Li(HMPA)4 counterion. Dependencies on toluene and THF are attributed to exclusively secondary-shell (medium) effects. Aided by density functional theory (DFT) computations, a stereochemical model is presented in which neither chelates nor the lithium gegenion serves roles. The stereoselectivity stems from the chirality within the sultam ring and not the camphor skeletal core.

Effects of four chemosterilants on Bactrocera tau.

Bactrocera tau (Walker) is a fly pest species mainly distributed in Southeast Asia and the South Pacific; it causes substantial ecological and economic issues because of its destructiveness and rapid reproduction. Chemical sterilization technology can reduce the use of insecticides and is widely applied for insect pest control. In this study, the sterilization efficacy of varying concentrations of four chemosterilants, namely, hexamethylphosphoramide (HMPA), CSII Aqua, 5-fluorouracil (5-FU), and colchicine, on adult pumpkin flies was investigated. The results indicated that a solution of 0.03% HMPA had the highest sterilization efficacy. When the number of sterile males was equal to or exceeded 20 times that of untreated males, the hatching rate of offspring eggs was less than 10%. Chemosterilant treatment significantly altered the levels of acid phosphatase (ACP), alkaline phosphatase (AKP), and B. tau vitellogenin (BtVg); these substances have an important impact on reproductive development. The treatment also decreased the size of the reproductive organs (i.e., testes and ovaries). Our results suggest that 0.03% HMPA has unique sterilization properties and may represent a new chemical agent for the control of B. tau populations in agricultural settings.

S-Nitrosylation of the virulence regulator AphB promotes Vibrio cholerae pathogenesis.

Vibrio cholerae is the etiologic agent of the severe human diarrheal disease cholera. To colonize mammalian hosts, this pathogen must defend against host-derived toxic compounds, such as nitric oxide (NO) and NO-derived reactive nitrogen species (RNS). RNS can covalently add an NO group to a reactive cysteine thiol on target proteins, a process called protein S-nitrosylation, which may affect bacterial stress responses. To better understand how V. cholerae regulates nitrosative stress responses, we profiled V. cholerae protein S-nitrosylation during RNS exposure. We identified an S-nitrosylation of cysteine 235 of AphB, a LysR-family transcription regulator that activates the expression of tcpP, which activates downstream virulence genes. Previous studies show that AphB C235 is sensitive to O2 and reactive oxygen species (ROS). Under microaerobic conditions, AphB formed dimer and directly repressed transcription of hmpA, encoding a flavohemoglobin that is important for NO resistance of V. cholerae. We found that tight regulation of hmpA by AphB under low nitrosative stress was important for V. cholerae optimal growth. In the presence of NO, S-nitrosylation of AphB abolished AphB activity, therefore relieved hmpA expression. Indeed, non-modifiable aphBC235S mutants were sensitive to RNS in vitro and drastically reduced colonization of the RNS-rich mouse small intestine. Finally, AphB S-nitrosylation also decreased virulence gene expression via debilitation of tcpP activation, and this regulation was also important for V. cholerae RNS resistance in vitro and in the gut. These results suggest that the modulation of the activity of virulence gene activator AphB via NO-dependent protein S-nitrosylation is critical for V. cholerae RNS resistance and colonization.

Exploring the Role of the NO-Detoxifying Enzyme HmpA in the Evolution of Domesticated Alfalfa Rhizobia.

We have previously shown the extensive loss of genes during the domestication of alfalfa rhizobia and the high nitrous oxide emission associated with the extreme genomic instability of commercial inoculants. In the present note, we describe the molecular mechanism involved in the evolution of alfalfa rhizobia. Genomic analysis showed that most of the gene losses in inoculants are due to large genomic deletions rather than to small deletions or point mutations, a fact consistent with recurrent DNA double-strand breaks (DSBs) at numerous locations throughout the microbial genome. Genetic analysis showed that the loss of the NO-detoxifying enzyme HmpA in inoculants results in growth inhibition and high DSB levels under nitrosative stress, and large genomic deletions in planta but not in the soil. Therefore, besides its known function in the effective establishment of the symbiosis, HmpA can play a critical role in the preservation of the genomic integrity of alfalfa rhizobia under host-derived nitrosative stress.

Potential type 2 diabetes mellitus drug HMPA promotes short-chain fatty acid production by improving carbon catabolite repression effect of gut microbiota.

BACKGROUND AND PURPOSE: Gut microbiota plays an important role in type 2 diabetes mellitus (T2DM) progression. From our previous work N-(4-Hydroxyphenethyl)-3-mercapto-2-methylpropanamide (HMPA) is a potential T2DM drug. We evaluated the effect of HMPA on gut microbiota and studied the molecular mechanism underlying HMPA's regulation of gut microbiota. EXPERIMENTAL APPROACH: The pseudo germ-free (PGF) T2DM model and faecal microbiota transplantation method were used to study whether gut microbiota mediates the actions of HMPA. The composition of gut microbiota was detected by using 16S rRNA sequence. Short-chain fatty acids (SCFAs) content was detected by gas chromatography. The HMPA probe was synthesised for finding and identifying the target protein of HMPA. The effect of HMPA on the utilisation of carbon sources in Bifidobacterium was evaluated. KEY RESULTS: HMPA has a slight effect on the PGF T2DM model. The gut microbiota changed by HMPA can also alleviate the symptoms of T2DM. HMPA can regulate gut microbiota structure, increase SCFAs production and reduce nitrate content in the intestinal tissues. The thickness of the mucus on colon tissues increases after HMPA treatment. The target protein of HMPA in gut microbiota is the nitrogen metabolism global transcriptional regulator (GlnR). HMPA promotes the utilisation of less preferred carbon source in the gut microbiota and increases the fermentation product of SCFAs. CONCLUSION AND IMPLICATIONS: HMPA plays a hypoglycaemic role through the gut microbiota. HMPA improves the carbon catabolite repression effect of gut microbiota and increases SCFAs production by targeting GlnR. GlnR may be a target for gut microbiota regulation.

HMPA-Catalyzed Transfer Hydrogenation of 3-Carbonyl Pyridines and Other N-Heteroarenes with Trichlorosilane.

A method for the HMPA (hexamethylphosphoric triamide)-catalyzed metal-free transfer hydrogenation of pyridines has been developed. The functional group tolerance of the existing reaction conditions provides easy access to various piperidines with ester or ketone groups at the C-3 site. The suitability of this method for the reduction of other N-heteroarenes has also been demonstrated. Thirty-three examples of different substrates have been reduced to designed products with 45⁻96% yields.

Total Synthesis of the Marine Alkaloid Discoipyrrole C via the MoOPH-Mediated Oxidation of a 2,3,5-Trisubstituted Pyrrole.

A total synthesis of the marine alkaloid discoipyrrole C (3) is described. In the pivotal step, the 2,3,5-trisubstituted pyrrole 19 was treated with MoOPH in the presence of MeOH, and the resulting methoxylated 1,2-dihydro-3H-pyrrol-3-one 20 subjected to reaction with potassium carbonate in MeOH then trifluoroacetic acid and H2O. This gave a mixture of target 3 and its dehydration product, and the structure of the former compound was confirmed by single-crystal X-ray analysis.

Juvenile Idiopathic Arthritis.

Juvenile idiopathic arthritis is the most common chronic rheumatic disease of unknown aetiology in childhood and predominantly presents with peripheral arthritis. The disease is divided into several subgroups, according to demographic characteristics, clinical features, treatment modalities and disease prognosis. Systemic juvenile idiopathic arthritis, which is one of the most frequent disease subtypes, is characterized by recurrent fever and rash. Oligoarticular juvenile idiopathic arthritis, common among young female patients, is usually accompanied by anti-nuclear antibodie positivity and anterior uveitis. Seropositive polyarticular juvenile idiopathic arthritis, an analogue of adult rheumatoid arthritis, is seen in less than 10% of paediatric patients. Seronegative polyarticular juvenile idiopathic arthritis, an entity more specific for childhood, appears with widespread large- and small-joint involvement. Enthesitis-related arthritis is a separate disease subtype, characterized by enthesitis and asymmetric lower-extremity arthritis. This disease subtype represents the childhood form of adult spondyloarthropathies, with human leukocyte antigen-B27 positivity and uveitis but commonly without axial skeleton involvement. Juvenile psoriatic arthritis is characterized by a psoriatic rash, accompanied by arthritis, nail pitting and dactylitis. Disease complications can vary from growth retardation and osteoporosis secondary to treatment and disease activity, to life-threatening macrophage activation syndrome with multi-organ insufficiency. With the advent of new therapeutics over the past 15 years, there has been a marked improvement in juvenile idiopathic arthritis treatment and long-term outcome, without any sequelae. The treatment of juvenile idiopathic arthritis patients involves teamwork, including an experienced paediatric rheumatologist, an ophthalmologist, an orthopaedist, a paediatric psychiatrist and a physiotherapist. The primary goals of treatment are to eliminate active disease, to normalize joint function, to preserve normal growth and to prevent long-term joint damage. Timely and aggressive treatment is important to provide early disease control. The first-line treatment includes disease-modifying anti-rheumatic drugs (methotrexate, sulphasalazine, leflunomide) in combination with corticosteroids, used in different dosages and routes (oral, intravenous, intra-articular). Intra-articular application of steroids seems to be an effective treatment modality, especially in monoarthritis. Biological agents should be added in the treatment of unresponsive patients. Anti-tumour necrosis factor agents (etanercept, infliximab, adalimumab), anti-interleukin-1 agents (anakinra, canakinumab), anti- interleukin-6 agents (tocilizumab) and T-cell regulatory agents (abatacept) have been shown to be safe and effective in childhood patients. Recent studies reported sustained reduction in joint damage with even complete clinical improvement in paediatric patients, compared to previous data.

Elucidating Structural Characteristics of Biomass using Solution-State 2 D NMR with a Mixture of Deuterated Dimethylsulfoxide and Hexamethylphosphoramide.

Recent developments of NMR methods for characterization of lignocellulosic biomass allow improved understanding of plant cell-wall structures with minimal deconstruction and modification of biomass. This study introduces a new NMR solvent system composed of dimethylsulfoxide (DMSO-d6 ) and hexamethylphosphoramide (HMPA-d18 ). HMPA as a co-solvent enhanced swelling and mobility of the biomass samples; thereby it allowed enhancing signals of NMR spectra. The structural information of biomass was successfully analyzed by the proposed NMR solvent system (DMSO-d6 /HMPA-d18 ; 4:1, v/v) with different biomass. The proposed bi-solvent system does not require derivatization or isolation of biomass, facilitating a facile sample preparation and involving with no signals overlapping with biomass peaks. It also allows analyzing biomass with a room-temperature NMR probe instead of cryo-probes, which are traditionally used for enhancing signal intensities.

Modified in vivo comet assay detects the genotoxic potential of 14-hydroxycodeinone, an α,ß-unsaturated ketone in oxycodone.

14-Hydroxycodeinone (14-HC) is an α,ß-unsaturated ketone impurity found in oxycodone drug substance and has a structural alert for genotoxicity. 14-HC was tested in a combined Modified and Standard Comet Assay to determine if the slight decrease in % Tail DNA noted in a previously conducted Standard Comet Assay with 14-HC could be magnified to clarify if the response was due to cross-linking activity. One limitation of the Standard Comet Assay is that DNA cross-links cannot be reliably detected. However, under certain modified testing conditions, DNA cross-links and chemical moieties that elicit such cross-links can be elucidated. One such modification involves the induction of additional breakages of DNA strands by gamma or X-ray irradiation. To determine if 14-HC is a DNA crosslinker in vivo, a Modified Comet Assay was conducted using X-ray irradiation as the modification to visualize crosslinking activity. In this assay, 14-HC was administered orally to mice up to 320 mg/kg/day. Results showed a statistically significant reduction in percent tail DNA in duodenal cells at 320 mg/kg/day, with a nonstatistically significant but dose-related reduction in percent tail DNA also observed at the mid dose of 160 mg/kg/day. Similar decreases were not observed in cells from the liver or stomach, and no increases in percent tail DNA were noted for any tissue in the concomitantly conducted Standard Comet Assay. Taken together, 14-HC was identified as a cross-linking agent in the duodenum in the Modified Comet Assay.

Indole synthesis from N-allenyl-2-iodoanilines under mild conditions mediated by samarium(II) diiodide.

A novel method for indole skeleton synthesis under mild conditions mediated by samarium(ii) diiodide has been developed. The reaction of N-allenyl-2-iodoaniline derivatives with SmI2 in the presence of HMPA and i-PrOH at 0 °C afforded indole derivatives in high yields.

Phycocyanobilin in solution--a solvent triggered molecular switch.

We present a computational investigation of the conformational response of phycocyanobilin (PCB) to the ability of solvents to form hydrogen bonds. PCB is the chromophore of several proteins in light harvesting complexes. We determine the conformational distributions in different solvents (methanol and hexamethylphosphoramide HMPT) by means of ab initio molecular dynamics simulations and characterize them via ab initio calculations of NMR chemical shift patterns. The computed trajectories and spectroscopic fingerprints illustrate that the energy landscape is very complex and exhibits various conformations of similar energy. We elucidate the strong influence of the solvent characteristics on the structural and spectroscopic parameters. Specifically, we predict a cis-trans isomerization of phycocyanobilin upon switching from the aprotic to the protic solvent, which explains an experimentally observed change in the NMR patterns. In the context of technological molecular recognition, solvent induced conformational switching can be considered a precursor mechanism to the recognition of single molecules.

Unprecedented biomimetic homodimerization of oroidin and clathrodin marine metabolites in the presence of HMPA or phosphonate salt tweezers.

The first biomimetic homodimerization of oroidin and clathrodin was effected in the presence HMPA and diphosphonate salts, strong guanidinium and amide chelating agents. The intermolecular associations probably interfere with the entropically and kinetically favored intramolecular cyclizations. Use of oroidin·(1)/2HCl salt or clathrodin·(1)/2HCl was indicative in the presence of the ambident nucleophilic and electrophilic tautomers of the 2-aminoimidazolic oroidin and clathrodin precursors. Surprisingly, the homodimerization of oroidin led to the nagelamide D skeleton, while the homodimerization of clathrodin gave the benzene para-symmetrical structure 19. The common process was rationalized from tautomeric precursors I and III.

1,4-Chirality transfer via the ester enolate Claisen rearrangements in the preparation of (25R)- and (25S)-cholestenoic acids.

Two variants of the Claisen rearrangement were evaluated for a stereoselective construction of a C-25 stereogenic center in cholestenoic acids based on 1,4-chirality transfer. Johnson orthoester Claisen rearrangement of (22R)- and (22S)-propargyl enol ethers proceeded in a highly stereoselective manner to give (25R)- and (25S)-isomeric allenes. The stereochemical outcome of the Ireland-Claisen rearrangement of 22-allylic alcohols was dependent on the configuration of the C-22 hydroxyl group and the geometry of the enol ether. The latter could be controlled by the solvent (THF or a mixture of THF/HMPA) chosen for the generation of silyl enolate.