Lowering mortality risk in CR-HvKP infection in intestinal immunohistological and microbiota restoration.

Gut damage during carbapenem-resistant and hypervirulent Klebsiella pneumoniae (CR-HvKP) infection is associated with a death risk. Understanding the mechanisms by which CR-HvKP causes intestinal damage and gut microbiota alteration, and the impact on immunity, is crucial for developing therapeutic strategies. This study investigated if gastrointestinal tract damage and disruption of gut microbiota induced by CR-HvKP infection undermined host immunity and facilitated multi-organ invasion of CR-HvKP; whether the therapeutic value of the rifampicin (RIF) and zidovudine (ZDV) combination was attributed to their ability to repair damages and restore host immunity was determined. A sepsis model was utilized to assess the intestinal pathological changes. Metagenomic analysis was performed to characterize the alteration of gut microbiota. The effects of the RIF and ZDV on suppressing inflammatory responses and improving immune functions and gut microbiota were evaluated by immunopathological and transcriptomic analyses. Rapid colonic damage occurred upon activation of the inflammation signaling pathways during lethal infections. Gut inflammation compromised host innate immunity and led to a significant decrease in probiotics abundance, including Bifidobacterium and Lactobacillus. Treatment with combination drugs significantly attenuated the inflammatory response, up-regulated immune cell differentiation signaling pathways, and promoted the abundance of Bifidobacterium (33.40 %). Consistently, supplementation of Bifidobacterium alone delayed the death in sepsis model. Gut inflammation and disrupted microbiota are key disease features of CR-HvKP infection but can be reversed by the RIF and ZDV drug combination. The finding that these drugs can restore host immunity through multiple mechanisms is novel and deserves further investigation of their clinical application potential.

The effect of Par3 on the cellular junctions and biological functions of odontoblast-lineage cells.

Perfect intercellular junctions are key for odontoblast barrier function. However, whether Partitioning defective-3 (Par3) is expressed in odontoblasts and its potential effects on odontoblast junctions are unknown. Herein, we investigated the effect of Par3 on cellular junctions and the biological behavior of odontoblast-lineage cells (OLCs). Whole-transcriptome sequencing was used to analyze the effects of Par3 on OLCs and the underlying molecular mechanism. Par3 was detected under physiological and inflammatory conditions in OLCs. To investigate the regulatory effect of Par3 on junctions between mouse OLCs, the effects of Par3 downregulation on the proliferation, migration, cycle and apoptosis of OLCs were detected by 5-ethyl-2'-deoxyuridine (EdU) and Transwell assays and flow cytometry. Western blotting and alizarin red S and alkaline phosphatase (ALP) staining were used to observe the effect of Par3 downregulation on OLC mineralization. Whole-transcriptome sequencing was used to investigate the biological role of Par3 in OLCs and potential molecular mechanisms. Par3 was located along the odontoblast layer in the rat pulp tissue and in the cytoplasm of OLCs. Par3 expression was downregulated under inflammatory conditions. The OLC junctions were discontinuous, and total Zona occluden-1 (ZO-1) expression and expression of ZO-1 at the membrane in OLCs were reduced after Par3 silencing (P < 0.05). Expression of a junction-related protein (ZO-1) was downregulated after the downregulation of Par3 (P < 0.05), and ZO-1 moved from the cell membrane to the cytoplasm. OLC proliferation and migration were enhanced, but apoptosis and mineralization were inhibited in shPar3-transfected cells (P < 0.05). Sequencing identified 2996 differentially expressed genes (DEGs), which were mainly enriched in the response to stimuli and binding. Downregulation of Par3 could overactivate the PI3k-AKT pathway by promoting AKT phosphorylation (P < 0.05). Downregulation of Par3 may disrupt junctions between OLCs by affecting ZO-1 expression and distribution and promote OLC proliferation and migration but inhibit OLC mineralization. Par3 may interact with 14-3-3 proteins for PI3K-AKT pathway activation to affect OLC junctions and function.

OONO-/MMP2/MMP9 pathway-mediated apoptosis of porcine granulosa cells is associated with DNA damage.

In brief: The apoptosis of granulosa cells (GCs) is the main reason for porcine follicular atresia. This study provides a novel mechanism for peroxynitrite anion-mediated GC apoptosis and follicular atresia in porcine ovary. Abstract: Granulosa cells play a crucial role in the development of follicles, and their cell apoptosis in the porcine ovary is a major contributor to follicular atresia. Here, we provide a new mechanism for follicular atresia by describing a crucial mechanism by which peroxynitrite anion (OONO-) may cause GC death. We discovered that nitric oxide, oxidative stress level, and OONO- were positively correlated with porcine follicular atresia, which was accompanied by high expression of matrix metalloproteinase 2 (MMP2) and MMP9. We created a model of OONO--induced apoptosis in GCs and discovered that OONO- could boost the expression of MMP2 and MMP9 and increase the expression of pro-apoptotic proteins and DNA damage. Furthermore, by inhibiting the activities of MMP2 and MMP9, we found that SB-3CT (a specific inhibitor for MMP2 and MMP9) alleviated the decrease in cell survival rates and DNA damage caused by OONO-, which may have been impacted by reducing the cleavage of PARP1 by MMP2 and MMP9. Therefore, our findings imply that OONO- can cause DNA damage to GCs, participating in mediating the expression of pro-apoptotic proteins and inhibiting DNA repair by preventing the activity of PARP1 through MMP2 and MMP9. These results help explain how OONO-/MMP2/MMP9 affects porcine follicular atresia and GC apoptosis.

Novel bioactive nanospheres show effective antibacterial effect against multiple endodontic pathogens.

Aim: The current study evaluated the antibacterial activity of a newly developed quaternary ammonium polymethacrylate (QAPM)-containing bioactive glasses (BGs) via a two-step method by our group, namely BGs-HAEMB, and explored its cytotoxicity and biocompatibility. Methods: The antibacterial effects of the BGs-HAEMB against planktonic bacteria, bacterial biofilm formation, and experimental root canal biofilms of persistent pathogens (Enterococcus faecalis, Streptococcus sanguis and Porphyromonas endodontalis) associated with endodontic infection were evaluated in vitro by agar diffusion tests, direct contact tests and live/dead staining. The cytotoxicity and biocompatibility of BGs-HAEMB were evaluated by CCK-8 assays in vitro and a skin implantation model in vivo. Results: Compared to three clinically used endodontic sealers (Endofill, AH Plus, and iRoot SP), BGs-HAEMB exhibited the relatively strongest antibacterial effect against E. faecalis, S. sanguis and P. endodontalis after sitting for 14 and 28 days (P < 0.01). SEM images and CLSM images also showed that for each tested bacteria, BGs-HAEMB killed the most microorganism among all the experimental groups, regardless of treatment for 7 days or 28 days (P < 0.05). Besides, the BGs-HAEMB-treated groups showed a relatively low cytotoxicity (RGRs ranging from 88.6% to 102.9%) after 1, 3, and 7 days of exposure. Meanwhile, after 28 days of implantation, the inflammatory grade in BGs-HAEMB treated group was assessed as Grade I, in which the average numbers of inflammatory cells (6.7 ± 2.1) were less than 25. Conclusions: BGs-HAEMB exerted a long-term and stable antibacterial effect. The remarkable biocompatibility of BGs-HAEMB in vitro and in vivo confirmed its possible clinical application as a potential alternative in the development of the next generation of endodontic sealers.

Dietary curcumin supplementation relieves hydrogen peroxide-induced testicular injury by antioxidant and anti-apoptotic effects in roosters.

This study was aimed to investigate the effects of dietary curcumin supplementation on the hydrogen peroxide (H2O2)-induced testicular oxidative damage in breeder roosters. Thirty-two 20-week roosters were randomly divided into four groups: (1) basal diet (CON); (2) basal diet with H2O2 challenge (H2O2); (3) basal diet with 200 mg/kg curcumin (CUR); (4) basal diet with 200 mg/kg curcumin and H2O2 challenge (CUR + H2O2). The trial lasted for 8 weeks, H2O2 challenged groups got an intraperitoneal injection of H2O2 at the 50 and 53 days, while the CON and CUR groups received an injection of saline. The results showed that dietary curcumin supplementation significantly decreased abnormal sperm rates in the semen, notably improved seminiferous tubules, increased testis scores, and serum testosterone levels. Curcumin supplementation could also ameliorate the redox damage caused by H2O2, by enhancing the capacities of antioxidant enzymes (CAT, GSH-Px, SOD, and T-AOC), and reducing MDA levels. In addition, curcumin normalized the H2O2-induced negative effects, which included downregulations in spermatogenesis-related genes (STAR, HSD3-ß1, SYCP3, AKT1) and antioxidant genes (HMOX-1, NQO-1), reduced protein expressions of Nrf2, PCNA, and Bcl-2, and increased protein expressions of Caspase 3 and Bax. Moreover, H2O2-induced decreased mRNA expressions of EIF2AK3, Caspase3, and BCL-2 were all reversed by dietary curcumin supplementation. In summary, dietary curcumin supplementation could relieve H2O2-induced oxidative damage and reproduction decline through the Nrf2 signaling pathway and anti-apoptotic effects in roosters.

Global trends and focuses of GLP-1RA in renal disease: a bibliometric analysis and visualization from 2005 to 2022.

Glucagon-like peptide 1 receptor agonist (GLP-1RA) is a new class of glucose-lowing agents with the kidney benefit effect. This paper aims at finding the current state and hotspots of the research on GLP-1RA in kidney disease by using bibliometric methodologies and visualization maps to analyze publications and provide the direction for future studies on that topic. Literature information was obtained by retrieving the WoSCC database. Then, software like Microsoft Excel, VOSviewer, and CiteSpace was used to analyze and process obtained data. Bibliometric analysis and visualization of nations, authors, organizations, journals, keywords, and references were also done by VOSviewer and CiteSpace. A total of 991 publications written by 4747 authors from 1637 organizations in 75 countries on GLP-1RA in renal disease in Web of Science Core Collection were retrieved. The number of publications and citations kept growing from 2015 to 2022. The USA, Univ Copenhagen, and Rossing Peter are the leading country, organization, and author on this topic, respectively. All literature was published in 346 journals, and DIABETES OBESITY & METABOLISM is the journal with the most contributions. Meanwhile, most references are from DIABETES CARE. "Cardiovascular outcome" is the most frequent keyword in the total publications, and the reference cited most times is "Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes" by Marso SP. The topic of GLP-1RA in renal disease has attracted more and more attention all over the world. Existing studies are mainly about clinical use in patients with diabetes, and studies on the mechanism are lacking.

The Synergistic Effects of the Combination of L-Carnitine and Lycopene on the Lycopene Bioavailability and Duodenal Health of Roosters.

The objective of this study was to investigate the impact of Lycopene and L-Carnitine, individually or in combination, on various physiological and molecular factors related to intestinal health and absorption ability in Roosters, such as intestinal morphology, serum biochemical parameters, genes involved in Lycopene uptake, nutritional transport genes, and tight junction genes. The findings of the study revealed that the combination of L-Carnitine and Lycopene supplementation had been found to increase the serum concentration levels of TP and ALB. Interestingly, the relative mRNA expression of genes responsible for Lycopene uptakes, such as SR-BI and BCO2, was higher in the LC group compared to other groups. Additionally, the expression of specific nutritional transport genes in the duodenum was significantly affected by both CAR and LC supplementation groups. The tight junction gene OCLN showed a significant increase in expression in the combination group compared to using either Lycopene or L-Carnitine alone. This study concludes that using Lycopene and L-carnitine in combination in poultry feed can potentially improve intestinal morphology and serum biochemical parameters, increase Lycopene bioavailability, improve nutrients uptake, and enhance the integrity of duodenal tight junctions in Roosters.

Burden and trends of brain and central nervous system cancer from 1990 to 2019 at the global, regional, and country levels.

BACKGROUND: Regularly updated epidemiological data on the burden of brain and central nervous system (CNS) cancers are important in the prioritization of research and the allocation of resources. This study aimed to investigate incidence, mortality, disability, and trends in brain and CNS cancers between 1990 and 2019. METHODS: Epidemiological data, including the cancer incidence, mortality, disability-adjusted life years(DALYs), age-standardized incidence rate (ASIR), age-standardized mortality rate (ASMR), and age-standardized DALY rate (per 100,000 population) stratified by region, country, sex, and age group were retrieved and extracted using the Global Health Data Exchange (GHDx) query tool. RESULTS: In 2019, there were 347,992(262,084-388,896) global cases of brain and CNS cancers, which showed a significant increase (94.35%) from the period between 1990 to 2019. The global ASIR in 2019 was 4.34 (3.27-4.86) per 100, 000 population, which showed an increasing trend for the years 1990-2019 (13.82% [-27.27-32.83]). In 2019, there were 246,253 (185,642-270,930) global deaths caused by brain and CNS cancers, which showed a significant increase (76.36%) during the study period. The global ASMR in 2019 was 3.05(2.29-3.36) per 100, 000 population, which did not change significantly over the study period (-1.19% [-36.79-13.86]). In 2019, there were 8,659,871 DALYs, which was a 109.04% increase compared with 1990. Similarly, during 1990-2019, the age-standardized DALY rate decreased by 10.39%. Additionally, 76.60% of the incident cases, 72.98% of the deaths, and 65.16% of the DALYs due to brain and CNS cancers occurred in the high-income and upper-middle-income regions. CONCLUSIONS: In conclusion, brain and CNS cancers remain a major public health burden, particularly in high-income regions. The global incidence, deaths, and DALYs of brain and CNS cancers were shown to have increased significantly from 1990 to 2019. The global ASIR kept rising steadily, while the ASMR and age-standardized DALY rate declined over the past three decades.

Troxerutin Abrogates Ischemic/Reperfusion-Induced Brain Injury through Ameliorating Oxidative Stress and Neuronal Inflammation by Inhibiting the Expression of NLRP3 in Sprague Dawley Rats.

Cerebral ischemic reperfusion (I/R) infarction is mostly associated with serious brain injury, cognitive damage, and neurological deficits. The oxidative stress mechanisms in the neurological region lead to higher reactive oxygen species production followed by oxidative stress, inflammation of neurons, and death of brain cells. The current work aims to evaluate the effect of troxerutin (TXN) on cerebral injury stimulated by I/R-induced ischemic stroke and examines the mechanistic effect of TXN on neuroinflammation in the Sprague Dawley model. The experimental rats were randomized in to four groups: (i) sham control, (ii) I/R + vehicle, (iii) I/R + 10 mg/kg bw TXN, and (iv) I/R + 20 mg/kg bw TXN. In the TXN administration and control, groups were injected intraperitoneally 15 min before reperfusion and every day for 7 days, except the sham group. Orally administered TXN (10 and 20 mg/kg/bw) modulated the water content, lowered the infarct volume, and abrogated score defects of neuron and changes in the brain tissue sample. In our study, the TXN-stimulated cerebral injury exhibited leakage of thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (LOOH) of the neuronal sample of tissues and showed higher antioxidant enzymes superoxide dismutase, catalase, the oxidized form of glutathione peroxidase, and the reduced form of glutathione levels. This biochemical result was additionally proved by histopathological assessment. Changes were made in antioxidant and inflammatory markers expressions interleukin-6 (IL-6), IL-4, IL-10, vascular endothelial growth factor, and cerebral induced rats. The overall findings showed that TXN protected the brain tissues from neuroinflammatory oxidative stress by reducing cerebral injury in Sprague Dawley rats. Further, the messenger RNA expression of cerebral I/R-induced animal tissues down-regulated NLRP3, caspase-1, tumor necrosis factor-α, ASC, IL-1ß, and Toll-like receptor 3 (TLR3). Therefore, the TXN action on TLR3 induced brain stroke is an excellent therapeutic approach for brain damage.

G2SAT: Learning to Generate SAT Formulas.

The Boolean Satisfiability (SAT) problem is the canonical NP-complete problem and is fundamental to computer science, with a wide array of applications in planning, verification, and theorem proving. Developing and evaluating practical SAT solvers relies on extensive empirical testing on a set of real-world benchmark formulas. However, the availability of such real-world SAT formulas is limited. While these benchmark formulas can be augmented with synthetically generated ones, existing approaches for doing so are heavily hand-crafted and fail to simultaneously capture a wide range of characteristics exhibited by real-world SAT instances. In this work, we present G2SAT, the first deep generative framework that learns to generate SAT formulas from a given set of input formulas. Our key insight is that SAT formulas can be transformed into latent bipartite graph representations which we model using a specialized deep generative neural network. We show that G2SAT can generate SAT formulas that closely resemble given real-world SAT instances, as measured by both graph metrics and SAT solver behavior. Further, we show that our synthetic SAT formulas could be used to improve SAT solver performance on real-world benchmarks, which opens up new opportunities for the continued development of SAT solvers and a deeper understanding of their performance.