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There is emerging evidence that human health and disease are modulated by the microbiota and their various metabolites, formed through intestinal and gut bacterial metabolism [...]

It has been well established that a vegetarian and polyphenol-rich diet, including fruits, vegetables, teas, juices, wine, indigestible fiber and whole grains, provide health-promoting phytochemicals and phytonutrients that are beneficial for the heart and brain. What is not well-characterized is the affect these foods have when co-metabolized within our dynamic gut and its colonizing flora. The concept of a heart shunt within the microbiota-gut-brain axis underscores the close association between brain and heart health and the so-called “French paradox” offers clues for understanding neurodegenerative and cerebrovascular diseases. Moreover, oxidation-redox reactions and redox properties of so-called brain and heart-protective foods are underappreciated as to their enhanced or deleterious mechanisms of action. Focusing on prodromal stages, and common mechanisms underlying heart, cerebrovascular and neurodegenerative diseases, we may unmask and understanding the means to better treat these related diseases.

Polyphenolic antioxidants, including dietary plant lignans, modulate the gut−brain axis, which involves transformation of these polyphenolic compounds into physiologically active and neuroprotector compounds (called human lignans) through gut bacterial metabolism. These gut bacterial metabolites exert their neuroprotective effects in various neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), and also have protective effects against other diseases, such as cardiovascular diseases, cancer, and diabetes. For example, enterolactone and enterodiol, the therapeutically relevant polyphenols, are formed as the secondary gut bacterial metabolites of lignans, the non-flavonoid polyphenolic compounds found in plant-based foods. These compounds are also acetylcholinesterase inhibitors, and thereby have potential applications as therapeutics in AD and other neurological diseases. Polyphenols are also advanced glycation end product (AGE) inhibitors (antiglycating agents), and thereby exert neuroprotective effects in cases of AD. Thus, gut bacterial metabolism of lignans and other dietary polyphenolic compounds results in the formation of neuroprotective polyphenols—some of which have enhanced blood−brain barrier permeability. It is hypothesized that gut bacterial metabolism-derived polyphenols, when combined with the nanoparticle-based blood−brain barrier (BBB)-targeted drug delivery, may prove to be effective therapeutics for various neurological disorders, including traumatic brain injury (TBI), AD, and PD. This mini-review addresses the role of polyphenolic compounds in the gut−brain axis, focusing on AD.

Ab initio calculations at the MP2/cc-pVTZ level of theory show that the classical 1-(trifluoromethyl)cyclopentyl cation (11) is substantially destabilized (by 9.8 kcal/mol) as compared to its isomeric μ-hydrido-bridged global minimum structure 16. However, the classical carbocation 11 is relatively more stable than the nonclassical cyclobutylmethyl cations 6 and 7, by 7.9 and 3.6 kcal/mol, respectively. We have also shown involvement of the noncovalent H⋯F bonding interactions in the μ-hydrido bridged structures, 13, 16, 19, and 20. The latter H⋯F bond distances are dependent on the number of fluorines in the fluoroalkyl group, and decrease in the order: 16 (CF3) > 20 (CHF2) > 19 (CH2F), in accordance with the decreased basicity of the fluorine atom across this series.

Nucleophilic trifluoromethylation of aromatic N-tosylaldimines has been achieved using trifluoromethyltrimethylsilane (TMSCF3) in the presence of the in situ generated N-heterocyclic carbene catalysts. Aromatic N-tosylaldimines with electron-withdrawing as well as electron-donating groups on the aryl ring afforded the corresponding trifluoromethylated sulfonamides in moderate to good yields.

A green approach for the synthesis of 2-amino azoles by the reaction of 2-chloro azoles with various types of amines using water as an environment friendly solvent at room temperature has been developed. The significant features of this methodology are short reaction time and easy product separation. This approach provides various biologically active compounds in good to excellent yields without adding any catalyst, ligand, or base.

We describe an efficient ruthenium-catalyzed C–H bond ortho-arylation of 9-(pyrimidin-2-yl)-9H-carbazole using boronic acids. This methodology exhibits excellent and high site-selectivity, functional group tolerance and gave the desired product in moderate to good yields.

Boron based fluoride anion receptors as electrolyte additives would significantly improve lithium ion battery performance. Fluorinated versions of triarylboranes, boronate esters, boroxines, and other boron based anion receptors have potential applications in the design of high specific energy lithium ion batteries. There is also an emerging interest in recent years in the design of colorimetric sensors for the fluoride anion, especially in aqueous systems, using boron based anion receptors. This mini review highlights the recent trends in the design and applications of the boron based fluoride anion receptors as electrolyte additives and as colorimetric sensors.

Insufficient and/or improper protein degradation is associated with the development of various human pathologies. Enzymatic therapy with proteolytic enzymes aimed to improve insufficient proteolytic activity was suggested as a treatment of protease deficiency-induced disorders. Since in many cases human degradome is incapable of degrading the entire target protein(s), other organisms can be used as a source of proteases exhibiting activities distinct from human enzymes, and plants are perspective candidates for this source. In this study recombinant wheat cysteine protease Triticain-α was shown to refold in vitro into an autocatalytically activated proteolytic enzyme possessing glutenase and collagenase activities at acidic (or close to neutral) pH levels at the temperature of human body. Mass-spectrometry analysis of the products of Triticain-α-catalyzed gluten hydrolysis revealed multiple cleavage sites within the sequences of gliadin toxic peptides, in particular, in the major toxic 33-mer α-gliadin-derived peptide initiating inflammatory responses to gluten in celiac disease (CD) patients. Triticain-α was found to be relatively stable in the conditions simulating stomach environment. We conclude that Triticain-α can be exploited as a basic compound for development of (i) pharmaceuticals for oral administration aimed at release of the active enzyme into the gastric lumen for CD treatment, and (ii) topically active pharmaceuticals for wound debridement applications.

Aβ exerts prooxidant or antioxidant effects based on the metal ion concentrations that it sequesters from the cytosol; at low metal ion concentrations, it is an antioxidant, whereas at relatively higher concentration it is a prooxidant. Thus Alzheimer disease (AD) treatment strategies based solely on the amyloid-β clearance should be re-examined in light of the vast accumulating evidence that increased oxidative stress in the human brains is the key causative factor for AD. Accumulating evidence indicates that the reduced brain glucose availability and brain hypoxia, due to the relatively lower concentration of ATP and 2,3-diphosphoglycerate, may be associated with increased concentration of endogenous ammonia, a potential neurotoxin in the AD brains. In this review, we summarize the progress in this area, and present some of our ongoing research activities with regard to brain Amyloid-β, systemic ammonia, erythrocyte energy metabolism and the role of 2,3-diphosphoglycerate in AD pathogenesis.

A ligand free Ru/C-catalyzed amination of 2-halo azoles with a broad scope of aminating reagents has been developed. A variety of 2-aminoazole derivatives were synthesized in moderate to good yields by utilizing this protocol. The methodology is operationally simple and not sensitive to air and moisture. It provides potentially useful products by using an inexpensive and recyclable catalytic system under ligand free conditions without significant loss of its catalytic activity up to four cycles.

The gut microbiota is extremely important for the health of the host across its lifespan. Recent studies have elucidated connections between the gut microbiota and neurological disease and disorders such as depression, anxiety, Alzheimer’s disease (AD), autism, and a host of other brain illnesses. Dysbiosis of the normal gut flora can have negative consequences for humans, especially throughout key periods during our lifespan as the gut microbes change with age in both phenotype and number of bacterial species. Neurologic diseases, mental disorders, and euthymic states are influenced by alterations in the metabolites produced by gut microbial milieu. We introduce a new concept, namely, the mycobiota and microbiota-gut-brain neuroendocrine axis and discuss co-metabolism with emphasis on means to influence or correct disruptions to normal gut flora throughout the lifespan from early development to old age. These changes involve inflammation and involve the permeability of barriers, such as the intestine blood barrier, the blood–brain barrier, and others. The mycobiota and microbiota–gut–brain axis offer new research horizons and represents a great potential target for new therapeutics, including approaches based around inflammatory disruptive process, genetically engineered drug delivery systems, diseased cell culling “kill switches„, phage-like therapies, medicinal chemistry, or microbial parabiosis to name a few.

This short review summarizes the recent progress in organofluorinations catalyzed by N-heterocyclic carbene (NHC)-transition metal ion complexes. NHC-metal ion complexes are increasingly used in a variety of organic transformations, and they have opened up new opportunities, especially in the synthesis of organofluorine compounds. New advances in olefin metathesis, trifluoromethylations, Heck and Suzuki coupling, selective hydrodefluorination, and enantioselective synthesis of organofluorine compounds have been achieved through catalysis by NHC and their metal ion complexes. In this review, synthetic methods for various NHC-metal ion complexes and their applications in the synthesis of organofluorine compounds are comprehensively outlined.

The electron-impact mass spectra of the tris(pentafluorophenyl)boroxine (1) and triphenylboroxine (2) were analyzed to probe the McLafferty type of rearrangements involving 1,3-fluorine or 1,3-hydrogen migrations to boron from the adjacent aromatic rings. 1,3-Sigmatropic fluorine migration leading to the McLafferty rearrangement of 1 results in the formation of the tetrafluorobenzyne radical cation (1c), whereas the similar rearrangement involving 1,3-hydrogen rearrangement is not observed for the nonfluorinated analog 2. The DFT calculations show that the activation barrier for the 1,3-fluorine migration in 1 is significantly lower than that for the 1,3-hydrogen migration in 2 (ΔΔG^‡ ∼33 kcal/mol), which is in accordance with the observed 1,3-fluorine migration for the fluorinated boroxine and the lack of such rearrangement for the nonfluorinated boroxine. The 1:1 stoichiometry of the fluoride anion with 1 has also been demonstrated by high resolution electrospray ionization time-of-flight mass spectrometry.

We have synthesized and determined the electrochemical and thermal stabilities of a series of 1-methyl-3-alkoxyalkyl and 1-methyl-3-fluoroalkyl imidazolium and the corresponding pyrrolidinium-based ionic liquids and estimated the cytotoxicities of representative ionic liquids. The pyrrolidinium-TFSI based ionic liquids have wide electrochemical stability (>5.7–6.2 V vs. Li/Li+) but show limited thermal stabilities and lithium cell discharge characteristics, as compared to those that are imidazolium-based (4.8–5.1 V vs. Li/Li+). The fluoroalkyl-derived ionic liquids typically have superior thermal stability (Td > 350 °C) as compared to the alkoxyalkyl-substituted analogues. In all these cases, TFSI− anion-based ionic liquids are thermally and electrochemically more stable than the BF4− anion-based analogues. We have also shown that the imidazolium-based ionic liquids are relatively nontoxic and their EC50 values are comparable to their corresponding lithium salts.

The ortho-arylation of the title compounds is carried out using aryl boronic acids to afford the target compounds in moderate to good yields and with good functional group tolerance.

This facile protocol allows the synthesis of 2-aminoazoles under catalyst-, ligand-, and base-free conditions at room temperature.

An efficient and conceptually new protocol for C–Se cross coupling of potassium selenocyanate with aryl halides via copper-catalyzed cascade reaction has been developed in water. Utilizing this protocol, a variety of aryl and heteroaryl halides were reacted with potassium selenocyanate to afford the corresponding diaryl selenides in moderate to good yields.

An unprecedented transfer of selenium ion from potassi- um selenocyanate was observed in C-Se cross-coupling reaction catalyzed by copper oxide nanoparticles under ligand-free condi- tions. Utilizing this protocol wide range of symmetrical diaryl se- lenides were obtained in excellent yields. Nano-CuO is recyclable up to four cycles without loss of catalytic activity.

Recyclable copper oxide nanoparticles catalyzed simple and highly efficient protocol for the synthesis of symmetrical aryl sulfides was developed by the cross-coupling of aromatic halides with inexpensive and commercially available thiourea which was used as an effective sulfur surrogate. The present cross-coupling protocol of thiourea, via cascade reaction with various substituted aryl halides, producing desired aryl sulfides, has an added advantage of avoiding foul-smelling thiols.

trans -4-Hydroxy- l -proline is used for the first time as an effective nucleophilic coupling partner with aryl halides mediated by copper iodide with Cs 2 CO 3 as the base and DMSO as the solvent. Utilizing this protocol cross-coupling of trans -4-hydroxy- l -proline with a wide variety of substituted aryl halides to produce N -aryl pyrroles in moderate to good yields.

A new and efficient protocol for the C-N cross-coupling of aryl halides with heteroaromatic amines in the presence of lanthanum(III) oxide (10 mol%) as a recyclable catalyst, N,N'-dimethylethylenediamine (DMEDA) (20 mol%) and potassium hydroxide (KOH) as a base in dimethyl sulfoxide (DMSO) at 110°C has been developed. This inexpensive catalytic system is highly effective towards the amination of aryl halides with various nitrogen nucleophiles and is significantly tolerant towards other functional groups in the substrates.

Polyphenolic antioxidants from dietary sources are frequently a topic of interest due to widespread scientific agreement that they may help lower the incidence of certain cancers, cardiovascular and neurodegenerative diseases, and DNA damage and even may have antiaging properties. On the other hand, questions still remain as to whether some antioxidants could be potentially harmful to health, because an increase in glycation-mediated protein damage (carbonyl stress) has been reported in some cases. Nevertheless, the quest for healthy aging has led to the extensive use of phytochemically derived antioxidants to disrupt age-associated deterioration in physiological function and to prevent many age-related diseases. Although a diet rich in the polyphenolic forms of antioxidants does seem to offer hope in delaying the onset of age-related disorders, it is still too early to define their exact clinical benefit for treating age-related disease. This review critically examines polyphenolic antioxidants, such as flavonoids, curcumene, and resveratrol in health, disease, and aging with the hope that a better understanding of the many mechanisms involved with these diverse compounds may lead to better health and novel treatment approaches for age-related diseases.