NMN synbiotics intervention modulates gut microbiota and metabolism in APP/PS1 Alzheimer's disease mouse models.

Alzheimer's disease (AD) is a complex neurodegenerative condition with growing evidence implicating the gut microbiota in its pathogenesis. This study aimed to investigate the effects of NMN synbiotics, a combination of ß-nicotinamide mononucleotide (NMN), Lactobacillus plantarum, and lactulose, on the gut microbiota composition and metabolic profiles in APP/PS1 transgenic mice. Results demonstrated that NMN synbiotics led to a notable restructuring of the gut microbiota, with a decreased Firmicutes/Bacteroidetes ratio in the AD mice, suggesting a potential amelioration of gut dysbiosis. Alpha diversity indices indicated a reduction in microbial diversity following NMN synbiotics supplementation, while beta diversity analyses revealed a shift towards a more balanced microbial community structure. Functional predictions based on the 16S rRNA data highlighted alterations in metabolic pathways, particularly those related to amino acid and energy metabolism, which are crucial for neuronal health. The metabolomic analysis uncovered a significant impact of NMN synbiotics on the gut metabolome, with normalization of metabolic composition in AD mice. Differential metabolite functions were enriched in pathways associated with neurotransmitter synthesis and energy metabolism, pointing to the potential therapeutic effects of NMN synbiotics in modulating the gut-brain axis and synaptic function in AD. Immunohistochemical staining observed a significant reduction of amyloid plaques formed by Aß deposition in the brain of AD mice after NMN synbiotics intervention. The findings underscore the potential of using synbiotics to ameliorate the neurodegenerative processes associated with Alzheimer's disease, opening new avenues for therapeutic interventions.

Characterization of the UDP-glycosyltransferase UGT33D1 in silkworm Bombyx mori.

Uridine diphosphate (UDP)-glycosyltransferases (UGTs) are important metabolizing enzymes functioning by adding a sugar moiety to a small lipophilic substrate molecule and play critical roles in drug/toxin metabolism for all realms of life. In this study, the silkworm Bombyx mori UGT33D1 gene was characterized in detail. UGT33D1 was found localized in the endoplasmic reticulum (ER) compartment just like other animal UGTs and was mainly expressed in the silkworm midgut. We first reported that UGT33D1 was important to BmNPV infection, as silencing UGT33D1 inhibited the BmNPV infection in silkworm BmN cells, while overexpressing the gene promoted viral infection. The molecular pathways regulated by UGT33D1 were analysed via transcriptome sequencing upon UGT33D1 knockdown, highlighting the important role of the gene in maintaining a balanced oxidoreductive state of the organism. In addition, proteins that physically interact with UGT33D1 were identified through immunoprecipitation and mass spectrometry analysis, which includes tubulin, elongation factor, certain ribosomal proteins, histone proteins and zinc finger proteins that had been previously reported for human UGT-interacting proteins. This study provided preliminary but important functional information on UGT33D1 and is hoped to trigger deeper investigations into silkworm UGTs and their functional mechanisms.

NMN Synbiotics: A Multifaceted Therapeutic Approach for Alzheimer's Disease.

With the aging global population, Alzheimer's disease (AD) has become a significant social and economic burden, necessitating the development of novel therapeutic strategies. This study investigates the therapeutic potential of nicotinamide mononucleotide (NMN) synbiotics, a combination of NMN, Lactiplantibacillus plantarum CGMCC 1.16089, and lactulose, in mitigating AD pathology. APP/PS1 mice were supplemented with NMN synbiotics and compared against control groups. The effects on amyloid-ß (Aß) deposition, intestinal histopathology, tight junction proteins, inflammatory cytokines, and reactive oxygen species (ROS) levels were assessed. NMN synbiotics intervention significantly reduced Aß deposition in the cerebral cortex and hippocampus by 67% and 60%, respectively. It also ameliorated histopathological changes in the colon, reducing crypt depth and restoring goblet cell numbers. The expression of tight junction proteins Claudin-1 and ZO-1 was significantly upregulated, enhancing intestinal barrier integrity. Furthermore, NMN synbiotics decreased the expression of proinflammatory cytokines IL-1ß, IL-6, and TNF-α, and reduced ROS levels, indicative of attenuated oxidative stress. The reduction in Aß deposition, enhancement of intestinal barrier function, decrease in neuroinflammation, and alleviation of oxidative stress suggest that NMN synbiotics present a promising therapeutic intervention for AD by modulating multiple pathological pathways. Further research is required to elucidate the precise mechanisms, particularly the role of the NLRP3 inflammasome pathway, which may offer a novel target for AD treatment.

Improving the activity of an inulosucrase by rational engineering for the efficient biosynthesis of low-molecular-weight inulin.

Inulin, a widely recognized prebiotic, has diverse applications across various industrial sectors. Although inulin is primarily produced through plant extraction, there is growing interest in enzymatic synthesis as an alternative. The enzymatic production of inulin from sucrose, which yields polymers with degrees of polymerization similar to those of plant-derived inulin, shows potential as a viable replacement for traditional extraction methods. In this study, an inulosucrase from Neobacillus bataviensis was identified, demonstrating a non-processive mechanism specifically tailored for synthesizing inulin with polymerization degrees ranging from 3 to approximately 40. The enzyme exhibited optimal activity at pH 6.5 and 55 °C, efficiently producing inulin with a yield of 50.6%. Ca2+ can improve the activity and thermostability of this enzyme. To enhance catalytic total activity, site-directed and truncated mutagenesis techniques were applied, resulting in the identification of a mutant, T149S, displaying a significant 57% increase in catalytic total activity. Molecular dynamics simulations unveiled that the heightened flexibility observed in three surface regions positively influenced enzymatic activity. This study not only contributes to the theoretical foundation for inulosucrase engineering but also presents a potential avenue for the production of inulin.

Time trends and regional variation in utilization of antidiabetic medicines in China, 2015-2022.

AIM: To assess the use of non-insulin antidiabetic medicines in China. MATERIALS AND METHODS: We analysed the national procurement data for 29 non-insulin antidiabetic medicines from nine subgroups in China from 2015 to 2022. We estimated the number of defined daily doses (DDDs) procured per year in seven regions of China for nine subgroups and adjusted the data by the number of patients with diabetes. For each subgroup, the regional ratio was calculated by comparing the procurement per patient in each region with the procurement nationwide. The regional disparity was the difference between the highest and lowest regional ratios. We compared the medication patterns across regions. RESULTS: Nationally, between 2015 and 2022, the number of DDDs per patient increased from 14.45 to 47.37. The two most commonly used categories were sulphonylurea and biguanides, which increased from 7.04 to 15.39 (119%) and 3.28 to 11.11 (239%) DDDs per patient, respectively. The procurement of new drugs (dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter type 2 inhibitors and glucagon-like peptide-1 receptor agonists) increased quickly and had >5000% relative changes. Particularly for sodium-glucose cotransporter type 2 inhibitors, it increased from 0.08 to 5.03 DDDs (6662%). The southwest region had the highest relative change (319%), while the southern region had the lowest (118%). Biguanide and thiazolidinediones had the lowest (1.19) and highest level (2.21) of regional disparity in 2022, respectively. CONCLUSION: The procurement of non-insulin antidiabetic medicines in China has increased a lot from 2015 to 2022. In terms of DDDs per patient, sulphonylurea ranked first, followed by metformin. The procurement of new drugs increased greatly. A large regional disparity existed in medicine usage and patterns.

Changes in insulin utilization in China from 2020 to 2022.

AIM: To assess the variation in patterns of use of insulin and other antidiabetic medicines across China, both geographically and over time. MATERIALS AND METHODS: Nationally, we calculated the relative change in antidiabetic medicine purchases between the first and last quarters of 2020 through 2022 based on the number of defined daily doses procured per quarter. We used annual data to analyse differences in antidiabetic medicine use and patterns across seven regions of China. Considering large regional variations, we used multifactor linear regression to preliminarily explore the possible factors influencing this variation. RESULTS: Nationally, the procurement of antidiabetic medicines and insulin increased from 2020 to 2022, while the proportion of insulin among antidiabetic medicines remained stable at approximately 22%. Among all insulins, premixed insulin (human) was ranked first. Of the three subgroups of insulin, analogues were the most preferred and had the largest procurement, but different categories showed different trends in terms of purchases and proporation. Regionally, the growth rate of antidiabetic medicines, the proportion of insulin procurement and the preferred types of insulin across the seven regions were different. Regarding preliminary influencing factors, the level of education and owning a domestically funded producer had a positive effect on insulin procurement. CONCLUSIONS: From 2020 to 2022, the procurement of insulin increased, which may be due to the increased attention for diabetes from the country and residents.However, the proportion of insulin among all antidiabetic medicines was essentially unchanged, while the use of some non-insulin hypoglycemic drugs increased significantly, especially the SGLT2i and GLP-1 RA. Given the economic and cultural diversity, Insulin procurement and utilization patterns varied greatly across the regions. Owning domestic enterprises potentially influences the procurement of insulin. Enhancing education to further improve the self-management of patients with diabetes is essential.

Efficient synthesis of α-amino-vinylphosphine oxides from alkyl nitriles via manganese-catalyzed phosphinoenamination.

A protocol for the synthesis of α-amino-vinylphosphine oxides by phosphinoenamination reaction between alkyl nitriles and phosphine oxides was developed. The combination of Mn(OAc)2 as a Lewis acid and guanidine as a Lewis base was found to be an efficient catalytic system for this reaction. A series of alkyl nitriles and phosphine oxides are compatible with this conversion, furnishing the desired products in up to 95% yield under mild conditions. Furthermore, this method demonstrates the capability of gram-scale synthesis.

Cloning of suppressor of cytokine signaling 7 from silkworm (Bombyx mori) and its response to the infection of Bombyx mori nucleopolyhedrovirus.

Suppressors of cytokine signaling (SOCS) play important roles in the regulation of growth, development, and immunity of eukaryotic organisms. SOCS7 is an important member of the SOCS family, but its physiological and pathological functions remain largely unknown in invertebrates including insects. Here, we first report the cloning of a SOCS7 gene from a domesticated silkworm (Bombyx mori), named BmSOCS7. We have characterized BmSOCS7 expression profiles in silkworm varieties susceptible or resistant to the infection of Bombyx mori nucleopolyhedrovirus (BmNPV) using the real-time fluorescence quantitative PCR. BmSOCS7 expresses highly in embryogenesis and lowly in metamorphosis in resistant silkworms but does in opposite contrast in susceptible silkworms. Its expression is at very low level in the fat body of resistant silkworms but is relatively high in the fat body of susceptible ones. BmNPV inoculation induces a transient downregulation and then a general upregulation of BmSOCS7 expression in BmN cells, while it induces a general downregulation in silkworm midgut, fat body and hemolymph with more pronounced effect in resistant silkworms than susceptible ones and more prominent in the fat body and hemolymph than the midgut. Together, our work reveals that downregulation of BmSOCS7 expression may be an important strategy for silkworm anti-BmNPV immune response, and BmSOCS7 may mainly function in the fat body and hemolymph rather than the midgut to participate in BmNPV infection process.

Postoperative PFME versus PFME alone for moderate SUI in pre-menopause women and influencing factors: a comparative effectiveness study.

PURPOSE: To explore the effectiveness of sling surgery followed by pelvic floor muscle exercises (PFME) or PFME alone for moderate stress urinary incontinence (SUI) in women and its influencing factors. METHODS: This is a prospective observational cohort study investigating whether sling surgery or PFME is preferred for pre-menopause women with moderate uncomplicated SUI. Those who received PFME alone or sling surgery were divided to PT or TVT group, respectively. The primary outcome was objective cure at 12 months. The secondary outcomes included Incontinence Impact Questionnaire-Short Form (IIQ-7) scores and PFME adherence. RESULTS: The study sample comprised 130 and 74 patients in the PT and TVT groups, respectively. There was 38.2% of patients adhered to PFME twice weekly or more often, and the compliance varied by education level. At 12 months, the objective cure rate was significantly higher in the TVT versus PT group (75.7% vs 47.7%; adjusted OR = 4.27; 95% CI, 2.05-8.87; P < 0.001). In addition, the mean reduction in IIQ-7 scores was greater in the TVT group (16.2 vs 10.0; adjusted OR = 3.38; 95% CI, 1.93-4.82; P < 0.001). However, among patients with lower education or those without adherence to PFME at 12 months, the TVT was also favorized, and the discrepancy in cure rates was greater between the two groups. CONCLUSION: Sling procedures followed by PFME demonstrate greater efficacy versus physiotherapy alone for moderate female SUI management. Continued adherence to PFME was important, even for patients undergoing sling procedures. Educational factors influenced patient PFME adherence and the advantage conferred by sling procedures.

Changes in the Objective Vision Quality of Adolescents in a Mesopic Visual Environment After Wearing Orthokeratology Lenses: A Prospective Study.

PURPOSE: This study aimed to investigate changes in objective vision quality in mesopic environments in teenagers with myopia after wearing orthokeratology (OK) lenses. METHODS: This prospective clinical study included 45 patients (80 eyes) who received OK lenses at the First Affiliated Hospital of Jinan University from March 2021 to September 2021. An Optical Path Difference-Scan III refractive power/corneal analyzer was used to determine the corneal topographic parameters (corneal e, corneal Q, surface asymmetry index (SAI), and surface regularity index (SRI)), higher-order aberrations (HOAs), axial length (AL) change, lens decentration, induced astigmatism, target power, and Strehl ratio (SR) in a mesopic visual environment after wearing OK lenses for 6 months. In addition, corneal morphological parameters, HOAs, and SR were analyzed in a mesopic visual environment. Finally, we investigated the correlations among corneal morphology, HOAs, AL change, lens decentration, induced astigmatism, and SR. RESULTS: The SAI value was significantly higher ( P <0.01), and the corneal e was significantly lower ( P <0.01), in a mesopic visual environment after wearing OK lenses for 1 week than baseline. A significant increase was observed in total HOAs and spherical aberrations, compared with before the OK lenses were worn ( P <0.01). In addition, SR in the mesopic visual environment decreased significantly after wearing the lenses ( P <0.01). No significant differences were observed ( P >0.05) among the 1-week, 1-month, 3-month, and 6-month follow-up findings. After 6 months, AL and lens decentration did not differ significantly compared with before ( P >0.05), whereas induced astigmatism significantly increased ( P <0.05). Negative correlations were observed between corneal Q, SAI, SRI, HOAs, induced astigmatism, and SR, and positive correlations were found between corneal e, AL change, lens decentration, and SR, after wearing OK lenses. KEY POINTS: • Wearing orthokeratology lenses significantly altered corneal morphology and HOAs in myopic teenagers within 1 week. • The changes that we observed in the eyes of adolescents with myopia after wearing orthokeratology lenses decreased vision quality in mesopic environments. • Strehl ratio is significantly correlated with multiple parameters, including HOAs, AL change, and lens decentration. CONCLUSIONS: In teenagers with myopia wearing OK lenses, significant changes in vision quality and corneal morphology were observed, leading to increased aberrations and affecting optical imaging quality. Furthermore, SR is significantly correlated with multiple parameters, including HOAs, AL change, and lens decentration. REGISTRATION NUMBER: This study is registered with the United States Clinical Trials Registry under registration number NCT04929119.