Co-assembled Nanoparticles Towards Multi-target Combinational Therapy of Alzheimer's Disease by Making Full Use of Molecular Recognition and Self-assembly.

The complex pathologies in Alzheimer's disease (AD) severely limits the effectiveness of single-target pharmic interventions, thus necessitating multi-pronged therapeutic strategies. While flexibility is essentially demanded in constructing such multi-target systems, for achieving optimal synergies and also accommodating the inherent heterogeneity within AD. Utilizing the dynamic reversibility of supramolecular strategy for conferring sufficient tunability in component substitution and proportion adjustment, amphiphilic calixarenes are poised to be a privileged molecular tool for facilely achieving function integration. Herein, taking ß-amyloid (Aß) fibrillation and oxidative stress as model combination pattern, we proposed a supramolecular multifunctional integration by co-assembling guanidinium-modified calixarene with ascorbyl palmitate and loading dipotassium phytate within calixarene cavity. Serial pivotal events can be simultaneously addressed by this versatile system, including (1) inhibition of Aß production and aggregation, (2) disintegration of Aß fibrils, (3) acceleration of Aß metabolic clearance, and (4) regulation of oxidative stress, which is verified to significantly ameliorate the cognitive impairment of 5×FAD mice, with reduced Aß plaque content, neuroinflammation and neuronal apoptosis. Confronted with the extremely intricate clinical realities of AD, the strategy presented here exhibits ample adaptability for necessary alterations on combinations, thereby may immensely expedite the advancement of AD combinational therapy through providing an exceptionally convenient platform. This article is protected by copyright. All rights reserved.

Boosting Osmotic Energy Harvesting from Organic Solutions by Ultrathin Covalent Organic Framework Membranes.

Extracting osmotic energy from waste organic solutions via reverse electrodialysis represents a promising approach to reuse such industrial wastes and helps to mitigate the ever-growing energy needs. Herein, a molecularly thin membrane of covalent organic frameworks is engineered via interfacial polymerization to investigate its ion transport behavior in organic solutions. Interestingly, a significant deviation from linearity between ion conductance and reciprocal viscosity is observed, attributed to the nanoscale confinement effect on intermolecular interactions. This finding suggests a potential strategy to modulate the influence of apprarent viscosity on transmembrane transport. The osmotic energy harvesting of the ultrathin membrane in organic systems was studied, achieving an unprecedented output power density of over 84.5 W m-2 at a 1000-fold salinity gradient with a benign conversion efficiency and excellent stability. These findings provide a meaningful stepping stone for future studies seeking to fully leverage the potentials of organic systems in energy harvesting applications.

Whole-genome sequencing of Escherichia coli from retail meat in China reveals the dissemination of clinically important antimicrobial resistance genes.

Escherichia coli is one of the important reservoirs of antimicrobial resistance genes (ARG), which often causes food-borne diseases and clinical infections. Contamination with E. coli carrying clinically important antimicrobial resistance genes in retail meat products can be transmitted to humans through the food chain, posing a serious threat to public health. In this study, a total of 330 E. coli strains were isolated from 464 fresh meat samples from 17 food markets in China, two of which were identified as enterotoxigenic and enteropathogenic E. coli. Whole genome sequencing revealed the presence of 146 different sequence types (STs) including 20 new STs, and 315 different clones based on the phylogenetic analysis, indicating the high genetic diversity of E. coli from retail meat products. Antimicrobial resistance profiles showed that 82.42 % E. coli were multidrug-resistant strains. A total of 89 antimicrobial resistance genes were detected and 12 E. coli strains carried clinically important antimicrobial resistance genes blaNDM-1, blaNDM-5, mcr-1, mcr-10 and tet(X4), respectively. Nanopore sequencing revealed that these resistance genes are located on different plasmids with the ability of horizontal transfer, and their genetic structure and environment are closely related to plasmids isolated from humans. Importantly, we reported for the first time the presence of plasmid-mediated mcr-10 in E. coli from retail meat. This study revealed the high genetic diversity of food-borne E. coli in retail meat and emphasized their risk of spreading clinically important antimicrobial resistance genes.

Mitochondria: An Emerging Unavoidable Link in the Pathogenesis of Periodontitis Caused by Porphyromonas gingivalis.

Porphyromonas gingivalis (P. gingivalis) is a key pathogen of periodontitis. Increasing evidence shows that P. gingivalis signals to mitochondria in periodontal cells, including gingival epithelial cells, gingival fibroblast cells, immune cells, etc. Mitochondrial dysfunction affects the cellular state and participates in periodontal inflammatory response through the aberrant release of mitochondrial contents. In the current review, it was summarized that P. gingivalis induced mitochondrial dysfunction by altering the mitochondrial metabolic state, unbalancing mitochondrial quality control, prompting mitochondrial reactive oxygen species (ROS) production, and regulating mitochondria-mediated apoptosis. This review outlines the impacts of P. gingivalis and its virulence factors on the mitochondrial function of periodontal cells and their role in periodontitis.

Elevated proton motive force is a tetracycline resistance mechanism that leads to the sensitivity to gentamicin in Edwardsiella tarda.

Tetracycline is a commonly used human and veterinary antibiotic that is mostly discharged into environment and thereby tetracycline-resistant bacteria are widely isolated. To combat these resistant bacteria, further understanding for tetracycline resistance mechanisms is needed. Here, GC-MS based untargeted metabolomics with biochemistry and molecular biology techniques was used to explore tetracycline resistance mechanisms of Edwardsiella tarda. Tetracycline-resistant E. tarda (LTB4-RTET ) exhibited a globally repressed metabolism against elevated proton motive force (PMF) as the most characteristic feature. The elevated PMF contributed to the resistance, which was supported by the three results: (i) viability was decreased with increasing PMF inhibitor carbonylcyanide-3-chlorophenylhydrazone; (ii) survival is related to PMF regulated by pH; (iii) LTB4-RTET were sensitive to gentamicin, an antibiotic that is dependent upon PMF to kill bacteria. Meanwhile, gentamicin-resistant E. tarda with low PMF are sensitive to tetracycline is also demonstrated. These results together indicate that the combination of tetracycline with gentamycin will effectively kill both gentamycin and tetracycline resistant bacteria. Therefore, the present study reveals a PMF-enhanced tetracycline resistance mechanism in LTB4-RTET and provides an effective approach to combat resistant bacteria.

Observation of a Photonic Orbital Gauge Field.

Gauge field is widely studied in natural and artificial materials. With an effective magnetic field for uncharged particles, many intriguing phenomena are observed in several systems like photonic Floquet topological insulator. However, previous researches about the gauge field mostly focus on limited dimensions such as the Dirac spinor in graphene materials. Here, an orbital gauge field based on photonic triangular lattices is first proposed and experimentally observed. Disclination defects with Frank angle Ω created on such lattices breaks the original lattice symmetry and generates purely geometric gauge field operating on orbital basis functions. Interestingly, it is found that bound states near zero energy with the orbital angular momentum (OAM) l = 2 are intensively confined at the disclination as gradually expanding Ω. Moreover, the introduction of a vector potential field breaks the time-reversal symmetry of the orbital gauge field, experimentally manifested by the chiral transmission of light on helical waveguides. The orbital gauge field further suggests fantastic applications of manipulating the vortex light in photonic integrated devices.

Steroid-Dependency in Posner-Schlossman Syndrome: A Suggested Topical 2% Ganciclovir and Gradual Decrement of Topical Steroid Combination Therapy from Shanghai PSS Study.

PURPOSE: This study focused on the prevalence, unique features, and required treatment of steroid-dependent Posner-Schlossman syndrome (SD-PSS), and analyzed the outcome of 2% Ganciclovir and gradual decrement steroid combination therapy in SD-PSS patients. METHODS: Retrospective comparative and interventional study. SD-PSS was defined as PSS patients with continuous steroid use for over 3 months and relapsed within 2 weeks after steroid withdrawal or tapered dosage. Totally 74 SD-PSS eyes were compared with 78 randomly chosen non-steroid dependent PSS eyes. SD-PSS patients who underwent 2% GCV and gradual decrement steroid therapy with at least two follow-ups (n = 50) were analyzed for the treatment outcome. RESULTS: The prevalence of SD-PSS is 26.87% (97/361) in our PSS patients. SD-PSS patients demonstrated significantly younger onset age, longer disease course, higher intraocular pressure (IOP), and higher degree of iris depigmentation at the first visit. They required significantly more IOP-lowering medication and stronger steroid after the first visit. Our 2% GCV and gradual decrement steroid therapy helped 66% (33/50) SD-PSS patients with steroid withdrawal (median stable time: 13 weeks) and another 32% (16/50) SD-PSS managed to lower the dose or strength of topical steroid. Steroid-induced ocular hypertension happened in 5.26% (19/361) of the PSS patients. CONCLUSION: Young onset age, high IOP, and high iris depigmentation level during acute stage are indicators of steroid dependency in PSS patients. SD-PSS patients require more medical surveillance. Two percent ganciclovir and gradual decrement steroid combination therapy help with steroid withdrawal and minimize steroid use.

Research on the development methodology for clinical practice guidelines for organic integration of traditional Chinese and Western medicine.

Integrated traditional Chinese medicine (TCM) and Western medicine (WM) is a new medical science grounded in the knowledge bases of both TCM and WM, which then forms a unique modern medical system in China. Integrated TCM and WM has a long history in China, and has made important achievements in the process of clinical diagnosis and treatment. However, the methodological defects in currently published clinical practice guidelines limit its development. The organic integration of TCM and WM is a deeper integration of TCM and WM. To realize the progression of "integration" to "organic integration", a targeted and standardized guideline development methodology is needed. Therefore, the purpose of this study is to establish a standardized development procedure for clinical practice guidelines for the organic integration of TCM and WM to promote the systematic integration of TCM and WM research results into clinical practice guidelines in order to achieve optimal results as the whole is greater than the sum of the parts.

Duration and dosing of systemic corticosteroids for acute exacerbation of COPD, protocol for a systematic review with meta-analysis of randomized trials and cohort studies.

PURPOSE: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is a leading cause of deterioration in patients with otherwise stably controlled COPD. Treatments of AECOPD often require the use of corticosteroid therapy in conjunction with bronchodilators and antibiotics. However, the duration and dosage of corticosteroids still remain unclear. We propose to perform this systematic review and meta-analysis of all available randomized control trials (RCTs) and observational cohort studies to comprehensively assess the efficacy and safety of different corticosteroid duration and dosing regimen in the current body of evidence. METHODS: We will search MEDLINE, EMBASE, CENTRAL via Ovid as well as CINAHL and Web of Science for available literature comparing different corticosteroid duration and dosage in the treatment of AECOPD. We will perform title and full text screening in duplicate, then extract relevant data using a pre-piloted extraction form. We will define short duration as less than 14-day duration of treatment and long duration as greater than 14-day treatment. We will report mortality difference as our primary outcome, with additional comparisons in incidence of re-exacerbation, hospital length of stay, lung function, incidence of hyperglycemia and infection. We will perform risk of bias assessment using the ROB2.0 and ROBINS-I tool, as well as the GRADE assessment to assess the quality of evidence. RESULTS: We will publish the full results of our systematic review and meta-analysis in a peer-reviewed journal. DISCUSSIONS: To our knowledge, this represents an updated and most comprehensive review of the literature comparing different duration and dosing regimen of corticosteroid treatments in AECOPD, as we will include both RCTs and observational studies without date or language restrictions. We aim to validate prior meta-analyses and study findings on the efficacy of short duration corticosteroid therapy over longer treatments and to inform future research directions in dosing regimens.

The occurrence of acute primary angle closure triggered, aggravated, and accelerated by COVID-19 infection: retrospective observational study.

Introduction: The aim of this study is to demonstrate the relevance of primary acute angle closure (APAC) and COVID-19 infection, compare the demographic features and manifestations between COVID-19 positive and negative patients with APAC, and infer the underlying mechanism. Methods: This study is based on all patients diagnosed with APAC at the glaucoma center of Eye, Ear, Nose and Throat Hospital of Fudan University (Fenyang road center) from 15th December 2022 to 11th January 2023. Totally 171 APAC cases were categorized into COVID-19 positive and negative group. Demographic features and final treatment level of the patients were compared between the two groups. Clinical manifestations, intraocular pressure, and anterior chamber configuration were also compared between the two groups. Results: In the COVID-19 positive group, the number of cases with APAC onset spiked in 22nd December 2022, which coincided with the spike of COVID-19 antigen positive people. Compared to the COVID-19 negative group, COVID-19 positive APAC patients were younger with a lower percentage of APAC history. Additionally, more eyes of COVID-19 positive APAC patients showed keratic precipitates. COVID-19 positive eyes had significantly larger anterior chamber depth with a more dilated pupil. Therefore, COVID-19 infection could probably act as a triggering factor of APAC. Discussion: The onset of APAC might be accelerated by COVID-19 infection for patients with younger age and milder anatomical configuration. Additionally, COVID-19 related APAC cases might have a more abrupt and fierce onset. Ophthalmic emergent services should not be neglected during the epidemic period.

Effects of dysregulated glucose metabolism on the occurrence and ART outcome of endometriosis.

BACKGROUND: Endometriosis is associated with systemic metabolic indicators, including body mass index (BMI), glucose metabolism and lipid metabolism, while the association between metabolic indexes and the occurrence and assisted reproductive technology (ART) outcome of endometriosis is unclear. We aimed to evaluate the characteristics of systemic metabolic indexes of endometriosis patients with infertility and their effects on pregnancy outcome after ART treatment. METHODS: A retrospective cohort study involve 412 endometriosis patients and 1551 controls was conducted. Primary outcome was metabolic indexes, and secondary measures consisted of the influence of metabolic indexes on the number of retrieved oocytes and ART outcomes. RESULTS: Endometriosis patients had higher insulin (INS) [6.90(5.10-9.50) vs 6.50(4.80-8.90) µU/mL, P = 0.005]. A prediction model for endometriosis combining the number of previous pregnancies, CA125, fasting blood glucose (Glu) and INS, had a sensitivity of 73.9%, specificity of 67.8% and area under curve (AUC) of 0.77. There were no significant differences in ART outcomes and complications during pregnancy. The serum levels of Glu before pregnancy were associated with GDM both in endometriosis group (aOR 12.95, 95% CI 1.69-99.42, P = 0.014) and in control group (aOR 4.15, 95% CI 1.50-11.53, P = 0.006). CONCLUSIONS: We found serum Glu is related to the number of retrieved oocytes in control group, serum INS is related to the number of retrieved oocytes in endometriosis group, while serum Glu and INS before pregnancy are related to the occurrence of GDM in two groups. A prediction model based on metabolic indexes was established, representing a promising non-invasive method to predict endometriosis patients with known pregnancy history.

Anomalous Mechanical and Electrical Interplay in a Covalent Organic Framework Monolayer Membrane.

Ion transport through nanoconfinement, driven by both electrical and mechanical forces, has drawn ever-increasing attention, due to its high similarity to stress-sensitive ion channels in biological systems. Previous studies have reported only pressure-induced enhancement in ion conductance in low-permeable systems such as nanotubes, nanoslits, or single nanopores. This enhancement is generally explained by the ion accumulation caused by the capacitive effect in low-permeable systems. Here, we fabricate a highly permeable COF monolayer membrane to investigate ion transport behavior driven by both electrical and mechanical forces. Our results show an anomalous conductance reduction activated by external mechanical force, which is contrary to the capacitive effect-dominated conductance enhancement observed in low-permeable nanopores or channels. Through simulations, we uncovered a distinct electrical-mechanical interplay mechanism that depends on the relative rate between the ion diffusion from the boundary layer to the membrane surface and the ion transport through the membrane. The high pore density of the COF monolayer membrane reduces the charge accumulation caused by the capacitive effect, resulting in fewer accumulated ions near the membrane surface. Additionally, the high membrane permeability greatly accelerates the dissipation of the accumulated ions under mechanical pressure, weakening the effect of the capacitive layer on the streaming current. As a result, the ions accumulated on the electrodes, rather than in the capacitive layer, dominating the streaming current and giving rise to a distinct electrical-mechanical interplay mechanism compared to that in low-permeable nanopores or channels. Our study provides new insights into the interplay between electrical and mechanical forces in ultra-permeable systems.

Predictive validation of existing bleeding and thromboembolic scores in elderly patients with comorbid atrial fibrillation and acute coronary syndrome.

BACKGROUND: The validation of various risk scores in elderly patients with comorbid atrial fibrillation (AF) and acute coronary syndrome (ACS) has not been reported. The present study compared the predictive performance of existing risk scores in these patients. METHODS: A total of 1252 elderly patients with AF and ACS comorbidities (≥ 65 years old) were consecutively enrolled from January 2015 to December 2019. All patients were followed up for one year. The predictive performance of risk scores in predicting bleeding and thromboembolic events was calculated and compared. RESULTS: During the 1-year follow-up, 183 (14.6%) patients had thromboembolic events, 198 (15.8%) patients had BARC class ≥ 2 bleeding events, and 61 (4.9%) patients had BARC class ≥ 3 bleeding events. For the BARC class ≥ 3 bleeding events, discrimination of the existing risk scores was low to moderate, PRECISE-DAPT (C-statistic: 0.638, 95% CI: 0.611-0.665), ATRIA (C-statistic: 0.615, 95% CI: 0.587-0.642), PARIS-MB (C-statistic: 0.612, 95% CI: 0.584-0.639), HAS-BLED (C-statistic: 0.597, 95% CI: 0.569-0.624) and CRUSADE (C-statistic: 0.595, 95% CI: 0.567-0.622). However, the calibration was good. PRECISE-DAPT showed a higher integrated discrimination improvement (IDI) than PARIS-MB, HAS-BLED, ATRIA, and CRUSADE (P < 0.05) and the best decision curve analysis (DCA). For thromboembolic events, the discrimination of GRACE (C-statistic: 0.636, 95% CI: 0.608-0.662) was higher than CHA2DS2-VASc (C-statistic: 0.612, 95% CI: 0.584-0.639), OPT-CAD (C-statistic: 0.602, 95% CI: 0.574-0.629) and PARIS-CTE (C-statistic: 0.595, 95% CI: 0.567-0.622). The calibration was good. Compared to OPT-CAD and PARIS-CTE, the IDI of the GRACE score slightly improved (P < 0.05). However, NRI analysis showed no significant difference. DCA showed that the clinical practicability of thromboembolic risk scores was similar. CONCLUSIONS: The discrimination and calibration of existing risk scores in predicting 1-year thromboembolic and bleeding events were unsatisfactory in elderly patients with comorbid AF and ACS. PRECISE-DAPT showed higher IDI and DCA than other risk scores in predicting BARC class ≥ 3 bleeding events. The GRACE score showed a slight advantage in predicting thrombotic events.

2% Ganciclovir Controlled Posner-Schlossman Syndrome Relapse and Reduced the Chance of Corticosteroid Dependence: A Large Cohort in East China.

PURPOSE: To present the process from acute Posner-Schlossman syndrome (PSS) relapse to remission under 2% ganciclovir (GCV), corticosteroids and anti-glaucoma agents on 323 patients. METHODS: A retrospective study enrolling 323 PSS patients. Demographics and ophthalmic examination results were generated. Patients were treated with GCV, corticosteroids and anti-glaucoma agents andfollowed up every 2-6 weeks. RESULTS: Patients were divided into the GCV monotherapy (N = 65, 20.12%), GCV and corticosteroids (G+C, N = 106) and GCV, corticosteroid and IOP-lowering drugs (G+C+L, N = 152) group. The G+C+L group had the highest intraocular pressure (IOP, 26.33 ± 10.26 mmHg, P < 0.001) and largest cup-to-disc ratio (0.58 ± 0.19, P < 0.05). After treatment, IOP of three groups dropped to similar level. Ninety-nine (30.65%) patients were corticosteroid-dependent whose daily corticosteroid consumption decreased after using GCV (from 2.23 ± 1.02 to 0.97 ± 0.98 drops/day). CONCLUSION: 2% GCV solutions worked effectively on PSS relapse with corticosteroids and anti-glaucoma agents. In patients suspected of CMV infection, proper GCV could reduce the chance of corticosteroid dependence.

Material design, development, and trend for surface-enhanced Raman scattering substrates.

Surface-enhanced Raman scattering (SERS) is a powerful and non-invasive spectroscopic technique that can provide rich and specific chemical fingerprint information for various target molecules through effective SERS substrates. In view of the strong dependence of the SERS signals on the properties of the SERS substrates, design, exploration, and construction of novel SERS-active nanomaterials with low cost and excellent performance as the SERS substrates have always been the foundation and the top priority for the development and application of the SERS technology. This review specifically focuses on the extensive progress made in the SERS-active nanomaterials and their enhancement mechanism since the first discovery of SERS on the nanostructured plasmonic metal substrates. The design principles, unique functions, and influencing factors on the SERS signals of different types of SERS-active nanomaterials are highlighted, and insight into their future challenge and development trends is also suggested. It is highly expected that this review could benefit a complete understanding of the research status of the SERS-active nanomaterials and arouse the research enthusiasm for them, leading to further development and wider application of the SERS technology.

Murine cytomegalovirus localization and uveitic cell infiltration might both contribute to trabecular meshwork impairment in Posner-Schlossman syndrome: Evidence from an open-angle rat model.

As a special type of glaucoma, Posner-Schlossman syndrome (PSS) is characterized by elevated intraocular pressure (IOP) and anterior uveitis. Cytomegalovirus (CMV) anterior chamber infection has now been considered the leading cause of PSS. We used murine CMV (MCMV) intracameral injection to establish a rat model manifested in IOP elevation and mild anterior uveitis, much like PSS; viral localization and gene expression at various time points and inflammatory cell infiltration derived from innate and adaptive immunity were investigated, as well as pathogenetic changes of the trabecular meshwork (TM). The IOP and uveitic manifestations peaked at 24 h post-infection (p.i.) and returned to normal after 96 h; the iridocorneal angle remained open consistently. At 24 h p.i., leucocytes gathered at the chamber angle. Maximum transcription of MCMV immediate early 1 (IE1) was reached at 24 h in the cornea and 48 h in the iris and ciliary body. MCMV localized in aqueous humor outflow facilities and the iris from 24 h to 28 d p.i. and was detected by in situ hybridization, though it did not transcribe after 7 d p.i. TM and iris pigment epithelial cells harboring viral inclusion bodies and autophagosomes were present at 28 d p.i. These findings shed light on how and where innate and adaptive immunity reacted after MCMV was found and transcribed in a highly ordered cascade, as well as pathogenetic changes in TM as a result of virus and uveitis behaviors.

Enhancement Mechanism of Minerals on Lignite-Water Molecule Interactions.

Five coal samples were prepared by deashing Shengli lignite in distinct phases, which consisted of residual ash from spontaneous combustion. The effects of removal and introduction of inherent minerals on the water reabsorption performance of coal samples were systematically investigated in three aspects: pore structure, oxygen-containing functional groups, and lignite materials. Low-field nuclear magnetic resonance spectroscopy was employed to investigate the changes in the water molecular adsorption tendency of coal samples with the variation in the mineral content. The study elucidates that the hygroscopic performance of the coal samples is significantly reduced due to the massive removal of inherent minerals. However, the pore structure of the coal samples after HCl/HF washing becomes more developed, and the oxygen-containing functional groups on the surface are more exposed, leading to an increase in the equilibrium adsorbed moisture content (EMC) of the coal samples. The binding force between coal samples and water molecules is reduced by the removal of the inherent minerals, which weakens the interaction forces between lignite and water molecules. The oxygen-containing functional groups on the surface of lignite interact with the residual ash from spontaneous combustion to enhance the binding force between lignite and surface water molecules, thus leading to the improved tendency of lignite to adsorb water molecules. The formation of intermediate complexes between minerals and oxygen-containing functional groups, in particular, carboxyl functional groups, on the surface of lignite enhances the acting force of polar sites, which improves the interaction of lignite-water molecules.

Nickel-Catalyzed Radical Ring-Opening Phosphorylation of Cycloalkyl Hydroperoxides Leading to Distal Acylphosphine Oxides.

A facile and efficient nickel-catalyzed C-C bond cleavage/phosphorylation of various cycloalkyl hydroperoxides was developed. This radical ring-opening strategy provided practical access to structurally diverse distal ketophosphine oxides in one pot through concurrent C═O/C-P bond formation with high atom economy under mild room temperature and base-free conditions.

Gut microbial characteristical comparison reveals potential anti-aging function of Dubosiella newyorkensis in mice.

Introduction: Previous study has indicated Dubosiella newyorkensis may act as a potential probiotic in age-related diseases. However, its detailed role in aging has not yet been promulgated. This study aimed to explore the potential anti-aging role of Dubosiella newyorkensis by comparing the anti-aging effect of resveratrol in young and old mice. Method: Measurement of intestinal aging-related factors in colon and serum, and vascular endothelial function-related factors in serum were performed by enzyme-linked immunosorbent assay (ELISA). Gut microbial analysis of intestinal contents were identified by 16S rRNA gene sequencing. Results: The effect of Dubosiella newyorkensis on reducing malondialdehyde (MDA) and increasing superoxide dismutase (SOD) in aged mice were greater than that of resveratrol. While the effect of Dubosiella newyorkensis on nitric oxide (NO) level was less than that of resveratrol, the reduction of vascular endothelial growth factor (VEGF) and pentosidine (PTD) was better than that of resveratrol in young mice. In young mice, Dubosiella newyorkensis promoted an increase in the beneficial genus Lactobacillus, Bifidobacterium and Ileibacterium less effectively as compared with resveratrol treatment. In aged mice, Dubosiella newyorkensis promoted the increase of Bifidobacterium, Ileibacterium less effectively than resveratrol, and promoted the increase of Akkermansia, Staphylococcus, Verrucomicrobiota expression better as compared with resveratrol treatment. Both young and old mice showed the same results for the remaining markers, including changes in gut microbial composition and predictions of function. Conclusion: Dubosiella newyorkensis has similar anti-aging functions with resveratrol. Dubosiella newyorkensis may even be more effective than resveratrol in reducing oxidative stress, improving vascular endothelial function, and redistributing gut microbiota. The research provides an innovative strategy of Dubosiella newyorkensis to improve aging.

Follicular fluid progesterone downregulated HPGD and COX2 in granulosa cells via suppressing NF-ĸB in endometriosis†.

Increasing evidences showed that ovulatory dysfunction, possibly caused by luteinized unruptured follicular follicle syndrome (LUFS), is one of the reasons for endometriosis-related infertility. The present study was conducted to explore the potential effect of elevated progesterone in follicular fluid (FF) on ovulation in endometriosis. A prospective study including 50 ovarian endometriosis patients and 50 control patients with matched pairs design was conducted with alterations in FF and peritoneal fluid (PF) components identified by metabolomics analyses and differentially expressed genes in granulosa cells (GCs) identified by transcriptome analysis. Patients with endometriosis exhibited a significantly higher progesterone level in serum, FF, and PF. Granulosa cells from endometriosis patients revealed decreased expression of HPGD, COX-2, and suppressed NF-ĸB signaling. Similarly, progesterone treatment in vitro downregulated HPGD and COX2 expression and suppressed NF-ĸB signaling in granulosa tumor-like cell line KGN (Bena Culture Collection, China) and primarily cultured GCs, as manifested by decreased expressions of IL1R1, IRAK3, reduced pIĸBα/IĸBα ratio, and nucleus translocation of p65. On the contrary, TNF-α treatment increased expression of IL1R1, IRAK3, pIĸBα, p65, and HPGD in GCs. One potential p65 binding site was identified in the promoter region of HPGD by chromatin immunoprecipitation. In conclusion, we found that intrafollicular progesterone might downregulate HPGD and COX-2 in GCs via suppressing the NF-ĸB signaling pathway, shedding light on the mechanism underlying the endometriosis-related ovulatory dysfunction.