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Preclinical studies indicate that diverse muscarinic receptor antagonists, acting via the M1 sub-type, promote neuritogenesis from sensory neurons in vitro and prevent and/or reverse both structural and functional indices of neuropathy in rodent models of diabetes. We sought to translate this as a potential therapeutic approach against structural and functional indices of diabetic neuropathy using oxybutynin, a muscarinic antagonist approved for clinical use against overactive bladder. Studies were performed using sensory neurons maintained in vitro, rodent models of type 1 or type 2 diabetes and human subjects with type 2 diabetes and confirmed neuropathy. Oxybutynin promoted significant neurite outgrowth in sensory neuron cultures derived from adult normal rats and STZ-diabetic mice, with maximal efficacy in the 1-100 nmol/l range. This was accompanied by a significantly enhanced mitochondrial energetic profile as reflected by increased basal and maximal respiration and spare respiratory capacity. Systemic (3-10 mg/kg/day s.c.) and topical (3% gel daily) oxybutynin reversed paw heat hypoalgesia in the STZ and db/db mouse models of diabetes and reversed paw tactile allodynia in STZ-diabetic rats. Loss of nerve profiles in the skin and cornea of db/db mice was also prevented by daily topical delivery of 3% oxybutynin for 8 weeks. A randomized, double-blind, placebo-controlled interventional trial was performed in subjects with type 2 diabetes and established peripheral neuropathy. Subjects received daily topical treatment with 3% oxybutynin gel or placebo for 6 months. The a priori designated primary endpoint, significant change in intra-epidermal nerve fibre density (IENFD) in skin biopsies taken before and after 20 weeks of treatments, was met by oxybutynin but not placebo. Secondary endpoints showing significant improvement with oxybutynin treatment included scores on clinical neuropathy, pain and quality of life scales. This proof-of-concept study indicates that muscarinic antagonists suitable for long-term use may offer a novel therapeutic opportunity for treatment of diabetic neuropathy. Trial registry number: NCT03050827.

Keywords: ruthenium catalysis; mandelic acids; alkynes; annulation; isocoumarins EN ruthenium catalysis mandelic acids alkynes annulation isocoumarins 2005 2010 6 10/09/23 20231024 NES 231024 Graph Isocoumarins are an important class of natural lactones, and their skeletal structure is an important part of many active pharmaceutical ingredients. At present, the major methods for synthesizing isocoumarins include (1) the cyclization reaction of I ortho i -halogen-substituted benzoic acids or their esters or amides with 1,3-diketones or internal alkynes; [10][11][12] and (2) the internal cyclization reaction of I ortho i -alkenyl- or alkynyl-substituted benzoic acids or their esters. The reactions of benzaldehydes B 5 b and benzoic acids B 6 b with B 2a b proceeded when the amount of Cu(OAc) SB 2 sb -H SB 2 sb O was increased to 1.5 equivalents and the reaction time was shortened to ten hours. Ruthenium(II)-Catalyzed C-H Annulation of Mandelic Acids with Internal Alkynes to Construct Isocoumarins. [Extracted from the article]

The development of mild, efficient, and enantioselective methods for preparing chiral building blocks from simple, renewable carbon units has been a long‐term goal of the sustainable chemical industry. Mandelate derivatives are valuable pharmaceutical intermediates and chiral resolving agents, but their manufacture relies heavily on highly toxic cyanide. Herein, we report (S)‐4‐hydroxymandelate synthase (HmaS)‐centered biocatalytic cascades for the synthesis of mandelates from benzaldehydes and glycine. We show that HmaS can be engineered to perform R‐selective hydroxylation by single‐point mutation, empowering the stereodivergent synthesis of both (S)‐ and (R)‐mandelate derivatives. These biocatalytic cascades enabled the production of various mandelate derivatives with high atom economy as well as excellent yields (up to 98 %) and ee values (up to >99 %). This methodology offers an effective cyanide‐free technology for greener and sustainable production of mandelate derivatives. [ABSTRACT FROM AUTHOR]

p-Hydroxymandelate oxidase (Hmo) is a flavin mononucleotide (FMN)-dependent enzyme that oxidizes mandelate to benzoylformate. How the FMN-dependent oxidation is executed by Hmo remains unclear at the molecular level. A continuum of snapshots from crystal structures of Hmo and its mutants in complex with physiological/nonphysiological substrates, products and inhibitors provides a rationale for its substrate enantioselectivity/promiscuity, its active-site geometry/reactivity and its direct hydride-transfer mechanism. A single mutant, Y128F, that extends the two-electron oxidation reaction to a four-electron oxidative decarboxylation reaction was unexpectedly observed. Biochemical and structural approaches, including biochemistry, kinetics, stable isotope labeling and X-ray crystallography, were exploited to reach these conclusions and provide additional insights.

We report a Rh-catalyzed hydroamination of 1,3-dienes to generate homoallylic amines. Our work showcases the first case of anti-Markovnikov selectivity in the intermolecular coupling of amines and 1,3-dienes. By tuning the ligand properties and Brønsted acid additive, we find that a combination of rac-BINAP and mandelic acid is critical for achieving anti-Markovnikov selectivity.

[Display omitted] • Thirty-one novel skeletons of mandelic acid were designed and synthesized. • Compound Z 31 exhibited obvious in vitro antifungal activity against M. fructicola. • Compound Z 31 exhibited better in vivo protective effect for the postharvest pears. • A 3D-QSAR model was constructed for the deep SAR analysis of these target compounds. • Compound Z 31 can inhibit the growth of the mycelia by disrupting the cell membrane. Brown rot of stone fruit, a disease caused by the ascomycete fungus Monilinia fructicola , has caused significant losses to the agricultural industry. In order to explore and discover potential fungicides against M. fructicola , thirty-one novel mandelic acid derivatives containing piperazine moieties were designed and synthesized based on the amide skeleton. Among them, target compound Z 31 exhibited obvious in vitro antifungal activity with the EC 50 value of 11.8 mg/L, and significant effects for the postharvest pears (79.4 % protective activity and 70.5 % curative activity) at a concentration of 200 mg/L. Antifungal activity for the target compounds was found to be significantly improved by the large steric hindrance of the R 1 groups and the electronegative of the piperazines in the molecular structure, according to a three-dimensional quantitative structure–activity relationship (3D-QSAR) analysis. Further mechanism studies have demonstrated that the compound Z 31 can disrupt cell membrane integrity, resulting in increased membrane permeability, release of intracellular electrolytes, and affect the normal growth of hyphae. Additional, morphological study also indicated that Z 31 may disrupt the integrity of the membrane by inducing generate excess endogenous reactive oxygen species (ROS) and resulting in the peroxidation of cellular lipids, which was further verified by the detection of malondialdehyde (MDA) content. These studies have provided the basis for the creation of novel fungicides to prevent brown rot in stone fruits. [ABSTRACT FROM AUTHOR]

A novel teicoplanin functionalized organic-silica hybrid chiral monolithic column was prepared by a facile single-step approach. The conditions for the preparation of the organic-silica hybrid chiral monolithic column were systematically optimized, including the amount of poly (ethylene glycol) (PEG) and urea, the tetramethyl orthosilicate (TMOS)/3-(trimethoxysilyl)-propylmethacrylate (γ-MAPS) ratio (v/v), the content of teicoplanin-2-isocyanatoethyl methacrylate (Tei-ICNEML) monomer, and the reaction temperature and time. The optimum column exhibited satisfactory efficiency, permeability and stability. In order to obtain satisfactory enantioseparation performance, reversed phase (RPM) and polar organic phase (POM) modes were employed, and different experimental conditions were optimized, such as buffer concentration and pH, amount of the organic solvent, concentration and ratio of TEA/HAc, and MeOH/ACN ratio. The stability of the Tei-ICNEML organic-silica hybrid monolithic column was also investigated in both POM and RPM separation modes. Then, this novel monolithic column was successfully applied to achieve the enantioseparation of amino alcohols, N-derivatized amino acids and mandelic acids. 15 out of 20 amino alcohols were baseline separated with good column efficiency in the POM mode, and 3 out of 5 mandelic acids and 5 out of 6 N-derivatized amino acids were baseline separated in the RPM mode.

Epidemiological evidence concerning effects of simultaneous exposure to noise and benzene, toluene, ethylbenzene, xylene, and styrene (BTEXS) on renal function remains uncertain. In 2020, a cross-sectional study was conducted among 1160 petrochemical workers in southern China to investigate effects of their co-exposure on estimated glomerular filtration rate (eGFR) and mild renal impairment (MRI). Noise levels were assessed using cumulative noise exposure (CNE). Urinary biomarkers for BTEXS were quantified. We found the majority of workers had exposure levels to noise and BTEXS below China's occupational exposure limits. CNE, trans, trans-muconic acid (tt-MA), and the sum of mandelic acid and phenylglyoxylic acid (PGMA) were linearly associated with decreased eGFR and increased MRI risk. We observed U-shaped associations for both N-acetyl-S-phenyl-L-cysteine (SPMA) and o-methylhippuric acid (2-MHA) with MRI. In further assessing the joint effect of BTEXS (β, -0.164 [95% CI, -0.296 to -0.033]) per quartile increase in all BTEXS metabolites on eGFR using quantile g-computation models, we found SPMA, tt-MA, 2-MHA, and PGMA played pivotal roles. Additionally, the risk of MRI associated with tt-MA was more pronounced in workers with lower CNE levels (P = 0.004). Multiplicative interaction analysis revealed antagonisms of CNE and PGMA on MRI risk (P = 0.034). Thus, our findings reveal negative dose-effect associations between noise and BTEXS mixture exposure and renal function in petrochemical workers. With the exception of toluene, benzene, xylene, ethylbenzene, and styrene are all concerning pollutants for renal dysfunction. Effects of benzene, ethylbenzene, and styrene exposure on renal dysfunction were more pronounced in workers with lower CNE., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

This study aimed to elucidate the clinical diagnostic value of plasma catecholamines and their metabolites for pheochromocytoma and paraganglioma (PPGL)-induced secondary hypertension using ultraperformance liquid chromatography-mass spectrometry (UPLC-MS/MS). The study population included 155 patients with PPGL that were divided into the PPGL with hypertension (n = 79) and a PPGL without hypertension (n = 76) groups, and 90 healthy volunteers and 90 patients with primary hypertension as the control groups. UPLC-MS/MS was performed to detect plasma levels of catecholamines and their metabolites, including dopamine, vanillylmandelic acid (VMA), norepinephrine, metanephrine, and normetanephrine. Receiver operating characteristic curves were generated to analyze the diagnostic value of the plasma levels of catecholamines and their metabolites in PPGL-induced secondary hypertension. Patients in the primary hypertension and PPGL without hypertension groups had higher levels of dopamine, VMA, norepinephrine, metanephrine, and normetanephrine than patients in the normal group (all p < .05). On the other hand, patients in the PPGL with hypertension group had higher levels of dopamine, VMA, norepinephrine, metanephrine, and normetanephrine than patients in the normal, primary hypertension, and PPGL without hypertension groups (all p < .05). Collectively, our findings showed that dopamine, VMA, norepinephrine, metanephrine, and normetanephrine are all effective biomarkers for the diagnosis of PPGL and PPGL-induced secondary hypertension., (© 2024 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Importance: There is strong evidence for long-term cognitive effects with anticholinergic use. Differences in insurance coverage of anticholinergics and beta-3 agonists hinder individualization of overactive bladder (OAB) treatment., Objectives: The aims of the study were to assess individual and family health insurance plan coverage for select OAB medications and to compare coverage of preferred medications to those with a greater risk of cognitive dysfunction., Study Design: This cross-sectional study analyzed formularies for the top 7 U.S. medical insurers. Coverage tiers were assessed for the following 7 OAB medications: (1) oxybutynin instant-release 5 mg, (2) oxybutynin extended-release 5 mg, (3) solifenacin 5 mg, (4) trospium instant-release 20 mg, (5) trospium extended-release 60 mg, (6) mirabegron 25 mg, and (7) vibegron 75 mg. Coverage was compared between nonpreferred (oxybutynin, solifenacin) and preferred medications (trospium, mirabegron, vibegron). Coverage scores, representing a weighted average based on coverage tier frequency relative to the number of plans investigated for each state or insurer, were generated with a lower coverage score indicating better coverage (range, 0.2-1.0)., Results: A total of 2,780 insurance plans from 41 states representing a 47% market share for the individual and family marketplace were evaluated. Oxybutynin IR had the best coverage score across insurers (0.2) while vibegron had the worst (0.92). Preferred medications were more often designated to higher tiers with worse coverage compared with nonpreferred medications (P < 0.001). Less concordance in coverage between insurers was noted for anticholinergics with greater bladder specificity and for extended-release formulations., Conclusions: Despite risks with anticholinergics, beta-3 agonists were more expensive across all insurers highlighting the need for expanded coverage of preferred medications to avoid cognitive dysfunction when undergoing treatment for OAB., Competing Interests: The authors have declared they have no conflicts of interest., (Copyright © 2024 American Urogynecologic Society. All rights reserved.)

Objective: Adrenocorticotropic hormone (ACTH) is the first-line treatment of infantile epileptic spasm syndrome (IESS). Its reported effectiveness varies, and our current understanding regarding the role of gut microbiota composition in IESS treatment response is limited. This study assessed the microbiome-metabolome association to understand the role and mechanism of gut microbiota composition in IESS treatment outcomes., Methods: Children with IESS undergoing ACTH treatment were enrolled. Pre-treatment stool and serum samples were collected for 16S rRNA gene sequencing and liquid chromatography-tandem mass spectrometry, respectively. The children were divided into "responsive" and "non-responsive" groups, and gut microbiota and serum metabolome differences were analyzed., Results: Of the 30 patients with IESS, 14 responded to ACTH and 16 did not. The "non-responsive" group had larger maleficent Clostridioides and Peptoclostridium&#95;phage&#95;p630P populations (linear discriminant analysis >2; false discovery rate q < 0.05). Ten metabolites were upregulated (e.g., xanthurenic acid) and 15 were downregulated (e.g., vanillylmandelic acid) (p < 0.05). Association analysis of the gut microbiome and serum metabolome revealed that Clostridioides and Peptoclostridium&#95;phage&#95;p630P2 were positively correlated with linoleic and xanthurenic acids, while Clostridioides was negatively correlated with vanillylmandelic acid (p < 0.05). A classifier using differential gut bacteria and metabolites achieved an area under the receiver operating characteristic curve of 0.906 to distinguish responders from non-responders., Conclusion: This study found significant differences in pre-treatment gut microbiota and serum metabolome between children with IESS who responded to ACTH and those who did not. Additional exploration may provide valuable information for treatment selection and potential interventions. Our results suggest that varying ACTH responses in patients with IESS may be associated with increased gut Clostridioides bacteria and kynurenine pathway alteration, but additional experiments are needed to verify this association., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Urinary tract infection (UTI) mainly results from bacterial infections in the urinary tract and markedly impacts the normal lives of millions of patients worldwide. The infection and damage to urethral epithelial cells is the first and key step of UTI development and is a critical target for treating clinical UTI. Oxybutynin, an agent for treating urinary incontinence, is recently claimed with protective effects on bladder ultrastructure. Our study will assess the impact of Oxybutynin on inflammation in lipopolysaccharide (LPS)-stimulated bladder epithelial cells. Bladder epithelial T24 cells were treated with 1 μg/mL LPS with or without 10 and 20 μM Oxybutynin for 24 h. Increased levels of oxidative stress (OS) biomarkers, such as reactive oxygen species, 8-hydroxy-2'-deoxyguanosine, malondialdehyde, as well as upregulated inducible nitric oxide synthase and promoted release of nitric oxide, were observed in LPS-managed T24 cells, all of which were signally suppressed by Oxybutynin. Furthermore, severe inflammatory responses, including enhanced release of cytokines, upregulated matrix metallopeptidase-2 (MMP-2) and MMP-9, and raised monocyte chemoattractant protein-1 level, were found in LPS-challenged T24 cells, which were markedly reversed by Oxybutynin. Moreover, the activated toll-1ike receptor 4/nuclear factor-κB pathway observed in LPS-managed T24 cells was repressed by Oxybutynin. Collectively, Oxybutynin mitigated LPS-induced inflammatory response in human bladder epithelial cells., (© 2023 Wiley Periodicals LLC.)

Amino-functional silica-coated N-doped carbon dots (NH 2 -SiO 2 -CDs) were covalently modified by l-tryptophan (chiral selector) by producing an amide bond between carboxyl groups of L-try and amino groups of NH 2 -SiO 2 -CDs to develop a novel high throughput chiral nanoprobes (L-try-CONH-SiO 2 -CDs) for highly sensitive and enantioselective quantification of S-/R-mandelic acid (S-/R-Man). The method showed a great difference between S- and R-isomers (enantioselectivity coefficient = 4.17) due to the ultra-stability of the Meisenheimer complex that was formed between S-isomer and nanoprobe (K S-Man /K R-man  = 2122.7, where K is the binding-constant). At optimal experimental conditions, two linear ranges of 0.5-25.0 (LOD of 0.05 μM) and 0.5-22.0 μM (LOD of 0.27 μM) for S- and R-Man, respectively, along with an enhanced sensitivity toward S-isomer (about 5.7-fold higher than R-isomer) were attained. High selectivity for the determination of mandelic acid was achieved compared to metal ions, amino acids, and sugars that commonly coexist with it. Intra-day as well as inter-day assays, respectively, showed RSD values of about 3.2 and 3.9%. The mechanistic studies were performed for proving the enantioselective behavior of the developed nanoprobe. The method was then used for S-/R-mandelic acid determination in bio-samples. The figures of merit for the method were found to be better than those already reported for enantioselective detection of R-/S-Man., Competing Interests: Declaration of competing interest The Authors declare that there are no known conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Frequently, a good chiral separation is the result of long trial and error processes. The three-point interaction mechanisms require the fair geometrical fitting and functional group compatibility of the interacting groups. Structure-chiral selectivity correlations are guidelines that can be established via trough systematic studies using model compounds. The enantiorecognition of the test compounds was studied on an octakis 2,3-Di-O-acetyl-6-O-tert-butyldimethylsilyl-gamma-cyclodextrin (TBDMSDAGCD) chiral selector. In our work, mandelic acid and its variously substituted compounds were used as model compounds to establish adaptable rules for other enantiomeric pairs. The mandelic acid and its modified compounds were altered at both their carboxyl and hydroxyl positions to test the key interaction forces of the chiral recognition processes. Ring- and alkyl-substituted mandelic acid derivatives were also used in our experiments. The chiral selectivity values of 20 test compounds were measured and extrapolated to 100 °C. The hydrogen donor abilities of test compounds improved their chiral selectivities. The inclusion phenomenon also played a role in chiral recognition processes in several cases. Enantiomer elution reversals were observed for different derivatives of hydroxyl groups, providing evidence for the multimodal character of the selector. The results of our research can serve as guidelines to achieve appropriate chiral separation for other enantiomeric pairs.

Objective: To prospectively compare the results of intradetrusor onabotulinumtoxinA injections and oral oxybutynin for urinary continence, urodynamic parameters and quality of life in patients with neurogenic detrusor overactivity due to spinal cord injury. Methods: Adult patients under intermittent catheterization were randomized 1:1 to receive one injection of onabotulinumtoxinA 300U or oxybutynin 5mg, per oris, three times/day. Primary study endpoint was change in urinary incontinence episodes/24 hours and secondary study endpoints were maximum cystometric capacity, maximum detrusor pressure, bladder compliance and quality of life before randomization and at week 24. Results: Sixty-eight patients participated in the trial. Significant improvements in urinary incontinence per 24 hours, all investigated urodynamic parameters and quality of life were observed in both groups. Compared with oral oxybutynin, onabotulinumtoxinA was significantly more efficacious for all parameters investigated. Non-response to treatment was higher for oral oxybutynin (23.5%) than onabotulinumtoxinA (11.8%). Dry mouth was the most common adverse in patients with oral oxybutynin (72%) and transient macroscopic hematuria in patients with onabotulinumtoxinA (28%). Only one patient with oral oxybutynin dropped out the study because of adverse effects. Conclusion: The comparison of the two study drugs showed that onabotulinumtoxinA was significantly more efficacious than oral oxybutynin with regard to continence, urodynamic parameters and quality of life. [ABSTRACT FROM AUTHOR]