Hydroxy Acids Research Articles

(S)-2-Hydroxyisovalerate Production from d-Xylose with CO-Converting Clostridium ragsdalei

Clostridium ragsdalei was found to produce (S)-2-hydroxyisovalerate (2-HIV) as a novel product in addition to acetate, ethanol, and d-2,3-butanediol in heterotrophic (d-xylose), autotrophic (CO), and mixotrophic (d-xylose + CO) conditions. Mixotrophic batch processes in stirred-tank bioreactors with continuous gassing resulted in improved production of this alpha-hydroxy acid compared to batch processes solely with either d-xylose or CO. The maximal CO uptake rate was considerably reduced in mixotrophic compared to autotrophic processes, resulting in a concomitant decreased total CO2 production. Simultaneous conversion of 9.5 g L−1 d-xylose and 320 mmol CO enabled the production of 1.8 g L−1 2-HIV in addition to 1.1 g L−1 d-2,3-butanediol, 2.0 g L−1 ethanol, and 1.8 g L−1 acetate. With reduced initial d-xylose (3.1 g L−1), l-valine production started when d-xylose was depleted, reaching a maximum of 0.4 g L−1 l-valine. Using l-arabinose or d-glucose instead of d-xylose in mixotrophic batch processes reduced the 2-HIV production by C. ragsdalei. Considerable amounts of meso-2,3-butanediol (0.9–1.3 g L−1) were produced instead, which was not observed with d-xylose. The monomer 2-HIV can form polyesters that make the molecule attractive for application as bioplastic (polyhydroxyalkanoates) or new composite material.

Ring Opening Reduction of Cyclic Anhydrides Catalyzed by Tris(pentafluorophenyl)borane Using Hydrosilanes as a Hydride Source.

Hydrosilanes are widely used as reducing agents in the reduction of carbonyl groups, and various catalysts have been developed for the activation of hydrosilanes, the majority of them being transition metal-based. A main-group-based Lewis acid tris(pentafluorophenyl)borane (BCF) has gained increasing attention due to its Lewis acidity and versatility, along with being nonmetal. Herein, we describe the BCF-catalyzed ring opening reduction of cyclic anhydrides using hydrosilanes as a source of hydrides. The reduction affords unsymmetrical bis(silyl) protected hydroxy acids, leading to an efficient way for the synthesis of silyl ester functionalities. The capability of forming protected hydroxy acids under mild conditions with high yields in one step is also advantageous. A range of hydrosilanes and cyclic anhydrides can be employed with quantitative conversion, high yields, relatively fast reaction time, and mild reaction conditions. NMR spectroscopy is used in the characterization of the products, along with gaining insight into the potential mechanism.

Total Synthesis and Anticancer Evaluation of BZR-cotoxin IV

Anticancer peptides (ACPs) is a potential alternative for future cancer therapy. ACPs specifically inhibit cancer cells through a non-enzymatic membranolysis mechanism. One potential anticancer peptide worthy of investigation is BZR-cotoxin IV. Currently, research on BZR-cotoxin IV is limited to isolation, making it an interesting area for further development. One approach to developing BZR-cotoxin IV is through chemical synthesis techniques. This compound belongs to the group of cyclodepsipeptides that are naturally produced by the fungus Bipolaris zeicola Race 3. The synthesis of BZR cotoxin IV involves 3 steps: (1) Synthesis of the hydroxy acid precursor by conversion of L-valine amino acid to (2R)-hydroxyisovaleric acid, (2) synthesis of the linear depsipeptide using solid-phase peptide synthesis on 2-chlorotrityl chloride resin and (3) cyclization of the linear depsipeptide using solution phase synthesis to produce the BZR cotoxin IV compound with a purity of 11.7 %. BZR-cotoxin IV was characterized using HR-TOF-MS and 1H and 13C-NMR to validate the desired product. Anticancer activity testing was performed using the Resazurin assay on the HeLa cancer cell line, resulting in an IC50 of 187.50 μg/mL (214.014 μM) categorized as moderate. HIGHLIGHTS The chemical synthesis of BZR-cotoxin IV compounds has not been firstly reported. The synthesis of BZR-cotoxin IV was accomplished through a combination of solid-phase and solution-phase peptide synthesis. The objective was to synthesize and evaluate BZR-cotoxin IV for its cancer properties. GRAPHICAL ABSTRACT

From Catalysis of Evolution to Evolution of Catalysis.

ConspectusThe mystery of the origins of life is one of the most difficult yet intriguing challenges to which humanity has grappled. How did biopolymers emerge in the absence of enzymes (evolved biocatalysts), and how did long-lasting chemical evolution find a path to the highly selective complex biology that we observe today? In this paper, we discuss a chemical framework that explores the very roots of catalysis, demonstrating how standard catalytic activity based on chemical and physical principles can evolve into complex machineries. We provide several examples of how prebiotic catalysis by small molecules can be exploited to facilitate polymerization, which in biology has transformed the nature of catalysis. Thus, catalysis evolved, and evolution was catalyzed, during the transformation of prebiotic chemistry to biochemistry. Traditionally, a catalyst is defined as a substance that (i) speeds up a chemical reaction by lowering activation energy through different chemical mechanisms and (ii) is not consumed during the course of the reaction. However, considering prebiotic chemistry, which involved a highly diverse chemical space (i.e., high number of potential reactants and products) and constantly changing environment that lacked highly sophisticated catalytic machinery, we stress here that a more primitive, broader definition should be considered. Here, we consider a catalyst as any chemical species that lowers activation energy. We further discuss various demonstrations of how simple prebiotic molecules such as hydroxy acids and mercaptoacids promote the formation of peptide bonds via energetically favored exchange reactions. Even though the small molecules are partially regenerated and partially retained within the resulting oligomers, these prebiotic catalysts fulfill their primary role. Catalysis by metal ions and in complex chemical mixtures is also highlighted. We underline how chemical evolution is primarily dictated by kinetics rather than thermodynamics and demonstrate a novel concept to support this notion. Moreover, we propose a new perspective on the role of water in prebiotic catalysis. The role of water as simply a "medium" obscures its importance as an active participant in the chemistry of life, specifically as a very efficient catalyst and as a participant in many chemical transformations. Here we highlight the unusual contribution of water to increasing complexification over the course of chemical evolution. We discuss possible pathways by which prebiotic catalysis promoted chemical selection and complexification. Taken together, this Account draws a connection line between prebiotic catalysis and contemporary biocatalysis and demonstrates that the fundamental elements of chemical catalysis are embedded within today's biocatalysts. This Account illustrates how the evolution of catalysis was intertwined with chemical evolution from the very beginning.

Comprehensive stable-isotope tracing of glucose and amino acids identifies metabolic by-products and their sources in CHO cell culture

Mammalian cell culture processes are widely utilized for biotherapeutics production, disease diagnostics, and biosensors, and hence, should be optimized to support robust cell growth and viability. However, toxic by-products accumulate in cultures due to inefficiencies in metabolic activities and nutrient utilization. In this study, we applied comprehensive 13C stable-isotope tracing of amino acids and glucose to two Immunoglobulin G (IgG) producing Chinese Hamster Ovary (CHO) cell lines to identify secreted by-products and trace their origins. CHO cells were cultured in media formulations missing a single amino acid or glucose supplemented with a 13C-tracer of the missing substrate, followed by gas chromatography-mass spectrometry (GC-MS) analysis to track labeled carbon flows and identify by-products. We tracked the sources of all secreted by-products and verified the identity of 45 by-products, majority of which were derived from glucose, leucine, isoleucine, valine, tyrosine, tryptophan, methionine, and phenylalanine. In addition to by-products identified previously, we identified several metabolites including 2-hydroxyisovaleric acid, 2-aminobutyric acid, L-alloisoleucine, ketoisoleucine, 2-hydroxy-3-methylvaleric acid, desmeninol, and 2-aminobutyric acid. When added to CHO cell cultures at different concentrations, certain metabolites inhibited cell growth while others including 2-hydroxy acids, surprisingly, reduced lactate accumulation. In vitro enzymatic analysis indicated that 2-hydroxy acids were metabolized by lactate dehydrogenase suggesting a possible mechanism for lowered lactate accumulation, e.g., competitive substrate inhibition. The 13C-labeling assisted metabolomics pipeline developed and the metabolites identified will serve as a springboard to reduce undesirable by-products accumulation and alleviate inefficient substrate utilization in mammalian cultures used for biomanufacturing and other applications through altered media formulations and pathway engineering strategies.

The Essential Role of Herbal-based Therapies in Combatting Acne Vulgaris

Inflammation, follicular epidermal hyperproliferation, and Propionibacterium acnes (P. acnes) are the primary causes of acne vulgaris, a prevalent skin condition that affects millions of young adults and adolescents. This intricate pathophysiology leads to various acne symptoms, such as whiteheads and blackheads, inflammatory nodules, and scarring. Among the many traditional allopathic acne therapies that often have serious side effects include hormone therapy, hydroxy acids, oral and topical antibiotics, retinoic acid derivatives, and acne medications. Herbal extracts are becoming more and more well-liked as more holistic, kinder substitutes with fewer side effects. Herbal extracts with antibacterial, anti-inflammatory, and antioxidant qualities include Eucalyptus Globulus, Thymus vulgaris (thyme), Melaleuca alternifolia (tea tree), Lavandula angustifolia (lavender), Origanum vulgare (oregano), and Curcuma longa (turmeric). Because of these qualities, they are considered to be viable candidates for treating different elements of acne etiology, including wound healing, inflammation reduction, and P. acnes growth inhibition. Developing herbal remedies is a viable approach to developing efficient and minimally invasive acne treatments. Medicinal plants and essential oils have a long history of traditional use and the potential to attenuate harmful exposures and lessen drug-induced side effects. Their use in dermatological treatments demonstrates their ability to offer comprehensive and natural solutions for the treatment of acne vulgaris, a common and frequently upsetting skin condition.

Current trends and requirements in sensors for hydroxy acid-based skincare treatments: A mini-review

Hydroxy acids (HAs) play a pivotal role in skincare formulations that address dry skin, acne, and signs of aging by modulating skin keratinization. The effectiveness of HAs depends on precise application, concentration, and adaptability to individual skin types. The effect of HAs on the skin must be monitored to ensure safe, effective, and personalized skincare. This review highlights current sensor technologies for HA treatment of the skin, including measurements of pH, skin hydration, pigmentation, and transepidermal water loss. In addition, we explored key sensing elements related to HA application, such as Ca2+ concentration in the epidermis, hyaluronic acid levels, and glucose in the interstitial fluid, as well as the HA concentration in biofluids. We also highlighted the role of advanced sensor technologies in improving HA treatment and provided guidance to dermatologists and researchers regarding the use of cutting-edge methods. Finally, we discussed the emerging trends and prospects of sensor technologies, highlighting the synergy between artificial intelligence and multimodal sensing for the realization of smart, personalized at-home skincare solutions.

Design and Synthesis of Six‐Armed Antimicrobial Polymer to Battle Against Nosocomial Pathogens

ABSTRACTThe world is under threat from microorganisms that have evolved resistance to currently available medicinal drugs and multidrug resistance among bacterial pathogens is becoming to be a serious public health issue worldwide. It is imperative to find or develop new antibiotics against Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species (ESKAPE) pathogens because they exhibit multidrug resistance and virulence through a variety of mechanisms. ESKAPE infections are often associated with increased global healthcare costs, morbidity, and illnesses. As a result, the utilization of naturally occurring bioactive agents offers a solution since these molecules are widely available and safe to employ during their use. Ricinoleic acid, an extract of seed oil that contains an unsaturated omega‐9 fatty acid and hydroxy acid, has garnered increasing interest due to its wide‐range antibacterial properties. Herein, we report the synthesis of polyethyleneimine‐ricinoleic acid‐based polymer (PEIRA) to battle against Methicillin‐resistant Staphylococcus aureus (MRSA), Acinetobacter baumannii (one among ESKAPE) and Staphylococcus aureus. The synthesized polymer showed efficient activity against MRSA, Acinetobacter baumannii, and Staphylococcus aureus. A noticeable percentage inhibition against MRSA (74%), A. baumannii (73%), and S. aureus (81%) was achieved at 2.5 mg/mL. The time‐kill assay revealed that the PEIRA polymer exhibited a bacteriostatic effect against all the tested pathogens. Cytotoxicity assay on human dermal fibroblast (HDF) cell lines revealed the PEIRA has an IC 50 of 31.7 μg/mL and exhibited above 75% cell viability at the concentration 5 and 10 μg/mL were deemed nontoxic on HDF. Based on the investigation, the synthesized PEIRA polymer may have promising applications in the biomedical sector and hospital‐acquired infections (HAIs).

Comparing Tretinoin to Other Topical Therapies in the Treatment of Skin Photoaging: A Systematic Review.

Many morphological and histological changes take place in aging skin. Topical tretinoin is the gold standard anti-aging agent used to reduce signs of aging through stimulation of epidermal growth and differentiation and inhibition of collagenase. The aim of this systematic review is to summarize studies evaluating the efficacy of tretinoin compared with other topical medications and cosmeceuticals in reducing the appearance of skin aging. A systematic review was conducted following the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines. The literature search was conducted using the PubMed and Embase databases from conception to December 2023. Studies were included if they compared anti-aging outcomes of topical medications with those of topical tretinoin (also called all-trans retinoic acid and retinoic acid). Studies were excluded if they compared non-topical anti-aging treatments with tretinoin or were conducted on animal models. The literature search resulted in 25 studies that met all inclusion and exclusion criteria. The most common study comparators to tretinoin included other forms of vitamin A. Outcomes were reported on the basis of visual reduction of aging signs, histological assessment of the epidermis and dermis, and protein expression. Although comparators to tretinoin had variable efficacy (greater in 7 studies, equivalent in 13 studies, and less in 3 studies), most studies found the comparator to be less irritating and better tolerated by patients than tretinoin. Tretinoin is currently the gold standard therapy for the treatment of photoaging, but its poor tolerability often limits its use. Unfortunately, given that most studies comparing topical therapies with tretinoin are of poor quality and/or demonstrate bias, there is a lack of substantial evidence to support an alternative first-line therapy. However, given there are some data to support the efficacy of retinoid precursors, namely retinaldehyde, pro-retinal nanoparticles, and conjugated alpha-hydroxy acid and retinoid (AHA-ret), these agents can be considered a second-line option for anti-aging treatment in patients who cannot tolerate tretinoin.

α-Substituted 3-hydroxy acid production from glucose in Escherichia coli

Polyhydroxyalkanoates (PHAs) are renewably-derived, microbial polyesters composed of hydroxy acids (HAs). Demand for sustainable plastics alternatives, combined with the unfavorable thermal properties exhibited by some PHAs, motivates the discovery of novel PHA-based materials. Incorporation of α-substituted HAs yields thermostable PHAs; however, the reverse β-oxidation (rBOX) pathway, the canonical pathway for HA production, is unable to produce these monomers because it utilizes thiolases with narrow substrate specificity. Here, we present a thiolase-independent pathway to two α-substituted HAs, 3-hydroxyisobutyric acid (3HIB) and 3-hydroxy-2-methylbutyric acid (3H2MB). This pathway involves the conversion of glucose to various branched acyl-CoAs and ultimately to 3HIB or 3H2MB. As proof of concept, we engineered Escherichia coli for the specific production of 3HIB and 3H2MB from glucose at titers as high as 66 ± 5 mg/L and 290 ± 40 mg/L, respectively. Optimizing this pathway for 3H2MB production via a novel byproduct recycle increased titer by 60%. This work illustrates the utility of novel pathway design HA production leading to PHAs with industrially relevant properties.

Pathway and Production Differences in Branched-Chain Hydroxy Acids as Bioactive Metabolites in Limosilactobacillus fermentum, Ligilactobacillus salivarius, and Latilactobacillus sakei.

Branched-chain hydroxy acids (BCHAs) as bioactive metabolites of Lactobacillaceae include 2-hydroxy isovaleric acid (HIVA), 2-hydroxy isocaproic acid (HICA), and 2-hydroxy-3-methyl isovaleric acid (HMVA). Combining targeted and untargeted metabolomics, this study elucidates differences in extracellular BCHA production in Limosilactobacillus fermentum, Ligilactobacillus salivarius, and Latilactobacillus sakei alongside comparing comprehensive metabolic changes. Through targeted metabolomics, BCHA production among 38 strains exhibited strain specificity, except for L. sakei, which showed significantly lower BCHA production. Explaining the lower production in L. sakei, which lacks the branched-chain amino acid (BCAA)-utilizing pathway, comparison of BCHA production by precursor reaction revealed that the pathway utilizing BCAAs is more dominant than the pathway utilizing pyruvate. Expanding upon the targeted approach, untargeted metabolomics revealed the effects of the reaction compound on other metabolic pathways besides BCHAs. Metabolism alterations induced by BCAA reactions varied among species. Significant differences were observed in glycine, serine, and threonine metabolism, pyruvate metabolism, butanoate metabolism, and galactose metabolism (p < 0.05). These results emphasize the importance of the synergy between fermentation strains and substrates in influencing nutritional components of fermented foods. By uncovering novel aspects of BCAA metabolism pathways, this study could inform the selection of fermentation strains and support the targeted production of BCHAs.

Effect of Alpha Hydroxy Acids as Dentin Conditioning Agents on Growth Factor Release: An In Vitro Study.

The study aimed to evaluate the effects of alpha hydroxy acids and chelating agents on dentin conditioning for the release of growth factors. The agents used for dentin conditioning included 17% ethylenediaminetetraacetic acid (EDTA), 10% glycolic acid (GA), 10% citric acid (CA), and 5% maleic acid (MA). Forty horizontally sectioned (SV1) human dentine slices were conditioned for 5 and 10 minutes so that the growth factor liberation reached quantifiable levels. Transforming growth factor beta-1 (TGF-β1) release and surface exposure were quantified by enzyme-linked immunosorbent assay (ELISA). Growth factor measurement required immediately removing the solutions from each of the 48-well plates (with consistent dentine surface area and weight) and freezing at -20°C so that ELISA measured the growth factors. After 5-min conditioning of dentine slices, CA was the most effective agent for growth factor release into the aqueous environment as measured by ELISA (post hoc Tukey's test p<0.05). Furthermore, dentine slices subjected to GA treatment for the same duration of time showed noticeably lower surface levels of TGF-β1 in comparison to the other agents employed. Based on the findings of this in vitro study, a desirable biological growth factor-mediated effect may be gained when conditioning dentin with milder acidic or chelating agents such as CA, MA, and EDTA.

Efficacy, Tolerability, and Face Lipidomic Modification of New Regimen with Cleanser and Corrective Serum in Women with Acne-Prone Skin

Acne-prone skin is a common condition in adult women, and skin imperfections could affect quality of life and self-esteem. This study aimed to investigate the efficacy of a cosmetic combination regimen for face care (a cleanser gel and a serum containing niacinamide, retinol, and alpha hydroxy acids). A total of 20 women with acne-prone mixed or oily skin were enrolled in a prospective 42-day trial. Sebum content, skin radiance, skin profilometry, and evaluation of face area occupied by pores were evaluated at baseline and after 14, 28, and 42 days. In addition, a face lipidomic evaluation was performed at baseline and after 42 days. Finally, self-assessment questionnaires at each visit checkpoint were performed to evaluate efficacy and tolerability of the tested products. All the subjects but one concluded the study. Both products were very well tolerated and 84% of the subjects reported a global clinical improvement. Skin sebum content was significantly (p &lt; 0.05) reduced at each of the evaluation time points (−9.9% at day 14, −19.4% at day 28, and −23.7% at day 42). The tested regimen significantly decreased the gloss parameter (mattifying effect) at day 14, 28, and 42, with a maximum reduction of 7.2% at the end of the study period. The pores area demonstrated a significant reduction at each of the checkpoint evaluations in comparison with baseline. Inflammatory and non-inflammatory lesions were significantly reduced by 16% at day 28 and day 42 (p &lt; 0.01). Lipidomic analysis demonstrated that this cosmetic face care regimen induced significant and positive effects in face sebum lipids composition, characterized by a significant increase in ceramides and triacylglycerols and a decrease in fatty acids and oxidized fatty acids.

Trifarotene alleviates skin photoaging injury by inhibition of JNK/c-Jun/MMPs.

Long-term exposure to ultraviolet (UV) radiation induces skin photoaging, which manifests as oxidative stress, inflammation, and collagen degradation. Multiple approaches (topical or systemic retinoids, antioxidants, alpha-hydroxy acids, laser, surgery) are used in the treatment of photoaged skin, and the use of topical retinoids is currently a primary clinical treatment. Previous studies revealed that retinoic acid promotes keratinocyte proliferation and reduces melanin deposition and matrix metalloproteinase (MMP) secretion; it also causes potential allergic and inflammatory damage to the skin. This study aimed to investigate the therapeutic effects and mechanisms of trifarotene, a functional retinoic acid analog, on UV-irradiated photoaging ICR and BALB/c nude mice and UVB photodamaged human epidermal keratinocyte (HaCaT) cells by examining indicators such as collagen, oxidoreductase, and inflammatory factor presence through histochemical staining, Western blot, and ELISA. Results suggested that trifarotene significantly reduced UV-induced photoaging in mouse skin tissue, potentially by reducing oxidative stress damage and inflammatory factor release, and inhibiting melanin deposition and collagen degradation by downregulating MMP expression. Concentrations of malondialdehyde, tyrosinase, interleukin-6, interleukin- 12, and tumor necrosis factor-alpha in photoaged skin decreased, while SOD content in photodamaged HaCaT cells significantly increased. Trifarotene (3.3 μmol L-1) inhibited phosphorylated JNK and c-Jun expression both independently and collaboratively with the JNK activator anisomycin, demonstrating that trifarotene mitigates UV-induced collagen degradation and apoptosis through inhibition of the JNK/c-Jun/MMPs signaling pathway.

γ-Lactones in Canadian high arctic aerosols: Tracers for the oxidation of unsaturated fatty acids and intramolecular esterification of γ-hydroxyacids during polar sunrise

In this study, we detected for the first time a series of γ-lactones (C7-C16) isolated from Canadian high arctic aerosols collected from late February to June as the sun rises from below the horizon to the maximum. γ-Lactones were identified and quantified by GC-MS utilizing the fragment ion (m/z 85) of [C4H5O2]+. Their molecular distributions showed the predominance of C9 species (on average, 25 pg/m3) followed by C10, C8, C11, C12, C16, C15, and C7. The odd-carbon numbered γ-lactones such as C9 and C11 are produced by the oxidation of oleic (Δ9C18:1) and eicosanoic (Δ9C20:1) acids, respectively, to monocarboxylic acids in the atmosphere, followed by the subsequent oxidation to positional isomers of hydroxy acids and intramolecular esterification of γ-hydroxy acids. Unsaturated fatty acids, plausible sources of the γ-lactones, can originate from marine phytoplankton and terrestrial vegetation via long-range atmospheric transport to the Arctic. Series of ω-oxoacids were also detected with the predominance of C9 species, supporting the photochemical oxidation of biogenic unsaturated fatty acids in the Arctic atmosphere after polar sunrise and/or during the long-range transport to the Arctic.

Green and Enantioselective Synthesis via Cascade Biotransformations: From Simple Racemic Substrates to High-Value Chiral Chemicals.

Asymmetric synthesis of chiral chemicals in high enantiomeric excess (ee) is pivotal to the pharmaceutical industry, but classic chemistry usually requires multi-step reactions, harsh conditions, and expensive chiral ligands, and sometimes suffers from unsatisfactory enantioselectivity. Enzymatic catalysis is a much greener and more enantioselective alternative, and cascade biotransformations with multi-step reactions can be performed in one pot to avoid costly intermediate isolation and minimise waste generation. One of the most attractive applications of enzymatic cascade transformations is to convert easily available simple racemic substrates into valuable functionalised chiral chemicals in high yields and ee. Here, we review the three general strategies to build up such cascade biotransformations, including enantioconvergent reaction, dynamic kinetic resolution, and destruction-and-reinstallation of chirality. Examples of cascade transformations using racemic substrates such as racemic epoxides, alcohols, hydroxy acids, etc. to produce the chiral amino alcohols, hydroxy acids, amines, and amino acids are given. The product concentration, ee, and yield, scalability, and substrate scope of these enzymatic cascades are critically reviewed. To further improve the efficiency and practical applicability of the cascades, enzyme engineering to enhance catalytic activities of the key enzymes using the latest microfluidics-based ultrahigh-throughput screening and artificial intelligence-guided directed evolution could be a useful approach.

Design of Experiments and Optimization of Monacolin K Green Extraction from Red Yeast Rice by Ultra-High-Performance Liquid Chromatography.

Monacolin K (MK), in red yeast rice (RYR) in the forms of lactone (LMK) and hydroxy acid (AMK), is known for its anti-hypercholesterolemic activity. Under the rising demand for natural bioactive molecules, we present a green ultrasound-assisted extraction (UAE) optimization study for MK in RYR. The development and validation of a fast, sensitive, selective, reproducible, and accurate ultra-high-performance liquid chromatography (UHPLC) method coupled to diode array detection for LMK and AMK allowed us to evaluate the MK recovery in different extract media. Firstly, the ethanol comparability to acetonitrile was assessed (recovery of 80.7 ± 0.1% for ethanol and 85.5 ± 0.2% for acetonitrile). Then, water/ethanol mixtures, with decreasing percentages of organic solvent, were tested by modulating temperature and extraction times. Water extractions at 80 °C for 10 min produced MK yield > 85%. Thus, UAE conditions were optimized by a DOE study using a water-based formulation (mouthwash). The optimal total MK extraction yield (86.6 ± 0.4%) was found under the following conditions: 80 °C, 45 min, 5 mg mL-1 (RYR powder/solvent). Therefore, the new single-process green approach allowed the simultaneous direct extraction of MK and mouthwash enrichment (MK concentration = 130.0 ± 0.6 µg mL-1), which might be tested for the prevention and treatment of periodontitis or oral candidiasis.

Redefining Statin Dosage Post-Gastric Bypass: Insights from a Population Pharmacokinetics-Pharmacodynamics Link Approach.

Roux-en-Y gastric bypass (RYGB) involves creating a small stomach pouch, bypassing part of the small intestine, and rerouting the digestive tract. These alterations can potentially change the drug exposure and response. Our primary aim was to assess the impact of RYGB on the pharmacokinetics of simvastatin lactone (SV) and its active metabolite, simvastatin hydroxy acid (SVA). Ultimately, we aimed to optimize dosing for this understudied population by employing a population pharmacokinetic-pharmacodynamic link approach. The study comprised patients who had undergone RYGB surgery and individuals without a previous history of RYGB. All participants received a single oral dose of simvastatin. Plasma concentration data were analyzed with a nonlinear mixed-effect modeling approach. A parent-metabolite model with first-order absorption, 2-compartments for SV and 1-compartment for SVA, linear elimination, and enterohepatic circulation best described the data. The model was linked to the turnover pharmacodynamic model to describe the SVA inhibition on LDL-cholesterol production. Our simulations indicated that following RYGB surgery, the exposure to SV and SVA decreased by 40%. Consequently, for low-intensity statin patients, we recommend increasing the dose from 10 to 20 mg in post-RYGB patients to maintain a comparable response to that of non-operated subjects. Moderate-intensity statin patients should require increasing doses to 40 or 60 mg or the addition of a non-statin medication to achieve similar therapeutic outcomes. In conclusion, individuals post-RYGB exhibit diminished exposure to SV and may benefit from increasing the dose or adjunctive therapy with non-statin drugs to attain equivalent responses and mitigate potential adverse events.

Iron-catalyzed non-directed arene C-H difluoromethylation

Practical, undirected and selective catalytic functionalization of unactivated arenes remains a challenging problem in organic synthesis. We herein report a bioinspired L-cystine-derived ligand BCPOM/Fe-enabled innate C-H difluoromethylation of unactivated arenes as limiting reagents with stable and inexpensive BrCF2CO2Et as the difluoromethylation source in high efficiency. Notably, this method uses environmentally benign H2O2 as the sole oxidant, and enables late-stage functionalization and exceptionally functional-group tolerance, even including oxidation-labile aldehyde, phenolic hydroxy, primary amine, and boronic acid groups, which is difficult to access by current means.

Reactions Driven by Primitive Nonbiological Polyesters.

ConspectusAll life on Earth is composed of cells, which are built from and run by biological reactions and structures. These reactions and structures are generally the result of action by cellular biomolecules, which are indispensable for the function and survival of all living organisms. Specifically, biological catalysis, namely by protein enzymes, but also by other biomolecules including nucleic acids, is an essential component of life. How the biomolecules themselves that perform biological catalysis came to exist in the first place is a major unanswered question that plagues researchers to this day, which is generally the focus of the origins of life (OoL) research field. Based on current knowledge, it is generally postulated that early Earth was full of a myriad of different chemicals, and that these chemicals reacted in specific ways that led to the emergence of biochemistry, cells, and later, life. In particular, a significant part of OoL research focuses on the synthesis, evolution, and function of biomolecules potentially present under early Earth conditions, as a way to understand their eventual transition into modern life. However, this narrative overlooks possibilities that other molecules contributed to the OoL, as while biomolecules that led to life were certainly present on early Earth, at the same time, other molecules that may not have strict, direct biological lineage were also widely and abundantly present. For example, hydroxy acids, although playing a role in metabolism or as parts of certain biological structures, are not generally considered to be as essential to modern biology as amino acids (a chemically similar monomer), and thus research in the OoL field tends to perhaps focus more on amino acids than hydroxy acids. However, their likely abundance on early Earth coupled with their ability to spontaneously condense into polymers (i.e., polyesters) make hydroxy acids, and their subsequent products, functions, and reactions, a reasonable target of investigation for prebiotic chemists. Whether "non-biological" hydroxy acids or polyesters can contribute to the emergence of life on early Earth is an inquiry that deserves attention within the OoL community, as this knowledge can also contribute to our understanding of the plausibility of extraterrestrial life that does not exactly use the biochemical set found in terrestrial organisms. While some demonstrations have been made with respect to compartment assembly, compartmentalization, and growth of primitive polyester-based systems, whether these "non-biological" polymers can contribute any catalytic function and/or drive primitive reactions is still an important step toward the development of early life. Here, we review research both from the OoL field as well as from industry and applied sciences regarding potential catalysis or reaction driven by "non-biological" polyesters in various forms: as linear polymers, as hyperbranched polyesters, and as membraneless microdroplets.