Periodontal disease increases the severity of chronic obstructive pulmonary disease: a Mendelian randomization study.

BACKGROUND: Recent research suggests that periodontitis can increase the risk of chronic obstructive pulmonary disease (COPD). In this study, we performed two-sample Mendelian randomization (MR) and investigated the causal effect of periodontitis (PD) on the genetic prediction of COPD. The study aimed to estimate how exposures affected outcomes. METHODS: Published data from the Gene-Lifestyle Interaction in the Dental Endpoints (GLIDE) Consortium's genome-wide association studies (GWAS) for periodontitis (17,353 cases and 28,210 controls) and COPD (16,488 cases and 169,688 controls) from European ancestry were utilized. This study employed a two-sample MR analysis approach and applied several complementary methods, including weighted median, inverse variance weighted (IVW), and MR-Egger regression. Multivariable Mendelian randomization (MVMR) analysis was further conducted to mitigate the influence of smoking on COPD. RESULTS: We chose five single-nucleotide polymorphisms (SNPs) as instrumental variables for periodontitis. A strong genetically predicted causal link between periodontitis and COPD, that is, periodontitis as an independent risk factor for COPD was detected. PD (OR = 1.102951, 95% CI: 1.005-1.211, p = 0.039) MR-Egger regression and weighted median analysis results were coincident with those of the IVW method. According to the sensitivity analysis, horizontal pleiotropy's effect on causal estimations seemed unlikely. However, reverse MR analysis revealed no significant genetic causal association between COPD and periodontitis. IVW (OR = 1.048 > 1, 95%CI: 0.973-1.128, p = 0.2082) MR Egger (OR = 0.826, 95%CI:0.658-1.037, p = 0.1104) and weighted median (OR = 1.043, 95%CI: 0.941-1.156, p = 0.4239). The results of multivariable Mendelian randomization (MVMR) analysis, after adjusting for the confounding effect of smoking, suggest a potential causal relationship between periodontitis and COPD (P = 0.035). CONCLUSION: In this study, periodontitis was found to be independent of COPD and a significant risk factor, providing new insights into periodontitis-mediated mechanisms underlying COPD development.

Genetic Predisposition to Periodontitis and Risk of Migraine: A Two-Sample Mendelian Randomization Study.

INTRODUCTION: Previous observational studies have associated periodontitis (PD) with migraine; however, the results are inconclusive and the causality of the association between PD and migraine remains unclear. This two-sample Mendelian randomization (MR) study was performed to explore the bi-directional causal relationship between PD and migraine. METHODS: To investigate the relationship between PD (17,353 cases; 28,210 controls) and migraine (1072 cases; 360,122 controls), we used genetic tools from the largest available genome-wide association study of European descent. Inverse variance-weighted (IVW) and a series of sensitivity analyses were used to explore the association between migraine and PD. We performed an MR study using seven SNPs (single nucleotide polymorphisms) as instrumental variables for PD to investigate the causal relationship between migraine and PD. RESULTS: We found no significant causal relationship between PD and migraine (odds ratio, OR = 1.000; 95% confidence interval, CI = 0.99-1.00; p = 0.65). Similarly, no evidence supported a causal relationship between migraine and PD (OR = 0.07; CI = 2.04 × 10-9-2.65 × 106; p = 0.77). A sensitivity analysis revealed that no potential polymorphic effect (p = 0.356) and heterogeneity (p = 0.652) exists for the variants used in constructing the genetic instrument. CONCLUSIONS: Based on the results of our MR study, there is no causal relationship between PD and migraines or migraines and PD.

Phosphine-Catalyzed Annulations Based on [3+3] and [3+2] Trapping of Ketene Intermediates with Thioamides.

With the aim of developing novel annulations via ketene intermediates, allenyl imide and alkynoates bearing good leaving groups are used for their function in a tandem conjugate addition-elimination reaction (SN2' type) promoted by nucleophilic phosphine catalysts. By utilizing thioamides as 1S,3N-bis-nucleophiles, [3+3] and [3+2] annulations have been established to allow rapid access to 1,3-thiazin-4-ones and 5-alkenyl thiazolones in high yields, respectively. Furthermore, the possible reaction mechanisms are proposed on the basis of deuterium labeling experiments and density functional theory calculations.

Coinheritance of OLFM2 and SIX6 variants in a Chinese family with juvenile-onset primary open-angle glaucoma: A case report.

BACKGROUND: Juvenile-onset primary open-angle glaucoma (JOAG), characterized by severe elevation of intraocular pressure and optic neuropathy prior to the age of 40, is a rare subtype of primary open-angle glaucoma. Several genetic mutations have been associated with JOAG. CASE SUMMARY: The proband patient was a young male, diagnosed with primary open-angle glaucoma at the age of 27. The patient and his unaffected parents who have been excluded from classic genetic mutations for primary open-angle glaucoma were included to explore for other possible genetic variants through whole genome sequencing and bioinformatics analysis. In this trio, we found two heterozygous variants inherited from the parents in the proband: c.281G>A, p.Arg94His in OLFM2 and c.177C>G, p.Ile59Met in SIX6. Both genetic mutations are predicted through bioinformatics analysis to replace evolutionary conserved amino acids, therefore rendering a pathogenic effect on proteins. In contrast, very low frequencies for these genetic mutations were recorded in most common control databases. CONCLUSION: This is the first report on coinherited mutations of OLFM2 and SIX6 in a JOAG family, which shows the complexity of JOAG inheritance. Large-scale clinical screening and molecular functional investigations on these coinherited mutations are imperative to improve our understanding of the development of JOAG.

Asymmetric Petasis reaction for the synthesis of chiral α- and ß-butadienyl amines.

The Petasis reaction using (1S,2R)-1-amino-2-indanol as the substrate and an activator to construct α- and ß-butadienyl amines in optically pure forms was realized, which are otherwise difficult to prepare. The reactions feature a metal-free nature, broad substrate scope, complete regioselectivities (γ-selectivity of pinacol homoallenyl- and isoprenylboronates), and high to excellent chirality induction (up to >20 : 1 dr). The favored nucleophilic addition across the Si-face of the imine intermediate was explained using DFT calculations of the six-membered chair-like transition state.

Catalytic asymmetric aldehyde prenylation and application in the total synthesis of (-)-rosiridol and (-)-bifurcadiol.

Chiral phosphoric acid-catalyzed asymmetric aldehyde prenylation has been established using an α,α-dimethyl allyl boronic ester. The transformation provides expedient access to a wide array of aryl, heteroaryl, aryl-substituted alkenyl and primary and secondary aliphatic homoprenyl alcohols with excellent asymmetric induction. The utility of this asymmetric catalysis strategy has been demonstrated through a short and efficient total synthesis of the two natural products (-)-rosiridol and (-)-bifurcadiol.

Brønsted Acid-Catalyzed General Petasis Allylation and Isoprenylation of Unactivated Ketones.

Brønsted acid-catalyzed general Petasis allylation and isoprenylation of unactivated ketones were developed by using o-hydroxyaniline and the corresponding pinacolyl boronic esters. This robust methodology provided access to a broad variety of quaternary homoallylic amines and dienyl amines in high yields, proved to be applicable to a gram-scale synthesis, and allowed the synthesis of a potentially bioactive quaternary homoallylic aminodiol.

Gypenosides Prevent H2O2-Induced Retinal Ganglion Cell Apoptosis by Concurrently Suppressing the Neuronal Oxidative Stress and Inflammatory Response.

Our previous study demonstrated that gypenosides (Gp) exert protective effects on retinal nerve fibers and axons in a mouse model of experimental autoimmune optic neuritis. However, the therapeutic mechanisms remain unclear. Thus, in this study, a model of oxidative damage in retinal ganglion cells (RGCs) was established to investigate the protective effect of Gp, and its possible influence on oxidative stress in RGCs. Treatment of cells with H2O2 induced RGC injury owing to the generation of intracellular reactive oxygen species (ROS). In addition, the activities of antioxidative enzymes decreased and the expression of inflammatory factors increased, resulting in an increase in cellular apoptosis. Gp helped RGCs to become resistant to oxidation damage by directly reducing the amount of ROS in cells and exerting protective effects against H2O2-induced apoptosis. Treatment with Gp also reduced the generation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and increased nuclear respiratory factor 2 (Nrf-2) levels so as to increase the levels of heme oxygenase-1 (HO-1) and glutathione peroxidase 1/2 (Gpx1/2), which can enhance antioxidation in RGCs. In conclusion, our data indicate that neuroprotection by Gp involves its antioxidation and anti-inflammation effects. Gp prevents apoptosis through a mitochondrial apoptotic pathway. This finding might provide novel insights into understanding the mechanism of the neuroprotective effects of gypenosides in the treatment of optic neuritis.

Diastereodivergent Asymmetric 1,3-Dipolar Cycloaddition of Azomethine Ylides and ß-Fluoroalkyl Vinylsulfones: Low Copper(II) Catalyst Loading and Theoretical Studies.

A CuII -catalyzed asymmetric 1,3-dipolar cycloaddition using ß-fluoroalkyl alkenyl arylsulfones as dipolarophiles and glycine/alanine iminoesters as azomethine ylide precursors has been developed. Remarkably, a catalyst loading as low as 0.5 mol % is highly efficient. Accordingly, a wide range of enantioenriched 3-fluoroalkyl pyrrolidines, as well as Δ2 -pyrroline and pyrrole derivatives, are generated in good to excellent yields with high asymmetric induction. This synthetic approach is diastereodivergent in that exo-adducts could be converted into the corresponding exo'-adducts by 1,8-diazabicyclo[5.4.0]undec-7-ene mediated epimerization at C2 of the pyrrolidine core. The free-energy profiles from DFT calculations suggest the Michael addition of the 1,3-dipole to be the rate- and enantiodetermining step, and the origin of stereoselectivity is studied by means of the noncovalent interaction (NCI) analysis.

Transitions of the Understanding and Definition of Primary Glaucoma.

OBJECTIVE: In previous decades, glaucoma has been primarily attributed to elevated intraocular pressure (IOP), but this has gradually been replaced by the development of optic neuropathy as the central concept of glaucoma in developed countries. However, there still remain strong controversies in the definition of glaucoma in China. In this current review, we are going to discuss these controversies and elaborate on the historical transitions of the definition of glaucoma both in China and developed countries. Furthermore, we will briefly describe the "ocular-cranial pressure gradient" theory and discuss the relationship between glaucoma and degenerative diseases of the central nervous system (CNS) in order to show the complex pathogenesis of glaucoma and the importance for the modification to the definition of glaucoma. DATA SOURCES: We performed a comprehensive search in both PubMed and SinoMed using the following keywords: (a) "primary glaucoma" and "guideline," (b) "ocular-cranial pressure gradient," and (c) "glaucoma," "Alzheimer's disease," and "Parkinson's disease." The literature search included the related articles with no restrictions on publication date. STUDY SELECTION: The primary references were Chinese and English articles including (a) original guidelines and expert consensuses of primary glaucoma, (b) reviews focusing on the differences between various versions of these guidelines and consensuses, and (c) papers about ocular-cranial pressure gradient theory and the relationship between glaucoma and CNS degenerative diseases. RESULTS: The definitions and classifications of both primary open-angle glaucoma and primary angle-closure glaucoma differ between Chinese glaucoma consensuses and international primary glaucoma guidelines. Chinese definitions and classifications put more emphasis on the IOP, while international guidelines put more emphasis on the presence of optic neuropathy. The ocular-cranial pressure gradient theory and the research on the relationship between glaucoma and CNS degenerative diseases have provided new directions for exploring the pathogenesis of glaucoma. CONCLUSIONS: As regards the definition and classification of primary glaucoma, we find that there are still some discrepancies between Chinese expert consensuses and international guidelines. Glaucoma is a disease with complex etiologies, while its common characteristic is a specific optic neuropathy. The current definition and understanding of glaucoma is an ongoing and evolving process, reflecting our latest available evidence on its pathogenesis. Chinese ophthalmology community may need to update our guidelines, accommodating these latest developments.

Neuroprotective effects of gypenosides in experimental autoimmune optic neuritis.

AIM: To determine whether gypenosides have protective effects in experimental autoimmune optic neuritis (EAON). METHODS: Mice were randomly divided into seven groups: control group, model group, three different density gypenosides monotherapy, methylprednisolone monotherapy, combination of gypenosides and methylprednisolone group. The control group was subcutaneously injected with oil emulsion adjuvant and all other groups were subcutaneously immunized with an emulsified mixture of myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide to induce EAON. Mice in the gypenosides groups were administered injections daily with three concentrations (15 mg/kg, 30 mg/kg, 45 mg/kg) of gypenosides respectively. Mice in the methylprednisolone group and the combination treatment group were injected daily with methylprednisolone (20 mg/kg) or methylprednisolone (20 mg/kg) + gypenosides (30 mg/kg), respectively. After MOG immunization, visual evoked potential (VEP), optical coherence tomography (OCT), and histopathologic examination were performed at 14, 20, 30, and 40d post-inoculation (p.i.). All results were expressed as mean±SEM. The data were evaluated by one-way ANOVA followed by Tukey or Games-Howell test. RESULTS: Compared with the control group, p2 latency was prolonged in the model group (P=0.041). Combination treatment can alleviated the change in VEP at 20d p.i. (P=0.012). Average peripapillary retinal nerve fiber layer (RNFL) thickness was reduced in the model group (P=0.000, 30d; P=0.000, 40d) and gypenosides treatment remarkably diminished the degree of RNFL degeneration at 30d and 40d p.i (P=0.000, 30d; P=0.000, 40d). The pathomorphological results showed a decrease in demye-lination (P=0.020) and inflammatory reactions in the combination group compared with the model group (20d p.i.). Gypenosides treatment also alleviated the degree of axonal loss (40d p.i.) (P=0.003). CONCLUSION: Treatment with gypenosides exerts protective effects on retinal nerve fibers and axons in EAON. When combined with gypenosides, methylprednisolone reduces demyelination in the acute stage of EAON.