Proteomics study the potential targets for Rifampicin-resistant spinal tuberculosis.

Introduction: The escalating global surge in Rifampicin-resistant strains poses a formidable challenge to the worldwide campaign against tuberculosis (TB), particularly in developing countries. The frequent reports of suboptimal treatment outcomes, complications, and the absence of definitive treatment guidelines for Rifampicin-resistant spinal TB (DSTB) contribute significantly to the obstacles in its effective management. Consequently, there is an urgent need for innovative and efficacious drugs to address Rifampicin-resistant spinal tuberculosis, minimizing the duration of therapy sessions. This study aims to investigate potential targets for DSTB through comprehensive proteomic and pharmaco-transcriptomic analyses. Methods: Mass spectrometry-based proteomics analysis was employed to validate potential DSTB-related targets. PPI analysis confirmed by Immunohistochemistry (IHC) and Western blot analysis. Results: The proteomics analysis revealed 373 differentially expressed proteins (DEPs), with 137 upregulated and 236 downregulated proteins. Subsequent Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses delved into the DSTB-related pathways associated with these DEPs. In the context of network pharmacology analysis, five key targets-human leukocyte antigen A chain (HLAA), human leukocyte antigen C chain (HLA-C), HLA Class II Histocompatibility Antigen, DRB1 Beta Chain (HLA-DRB1), metalloproteinase 9 (MMP9), and Phospholipase C-like 1 (PLCL1)-were identified as pivotal players in pathways such as "Antigen processing and presentation" and "Phagosome," which are crucially enriched in DSTB. Moreover, pharmaco-transcriptomic analysis can confirm that 58 drug compounds can regulate the expression of the key targets. Discussion: This research confirms the presence of protein alterations during the Rifampicin-resistant process in DSTB patients, offering novel insights into the molecular mechanisms underpinning DSTB. The findings suggest a promising avenue for the development of targeted drugs to enhance the management of Rifampicin-resistant spinal tuberculosis.

A Mechanistic Study of the Osteogenic Effect of Arecoline in an Osteoporosis Model: Inhibition of Iron Overload-Induced Osteogenesis by Promoting Heme Oxygenase-1 Expression.

Iron overload-associated osteoporosis presents a significant challenge to bone health. This study examines the effects of arecoline (ACL), an alkaloid found in areca nut, on bone metabolism under iron overload conditions induced by ferric ammonium citrate (FAC) treatment. The results indicate that ACL mitigates the FAC-induced inhibition of osteogenesis in zebrafish larvae, as demonstrated by increased skeletal mineralization and upregulation of osteogenic genes. ACL attenuates FAC-mediated suppression of osteoblast differentiation and mineralization in MC3T3-E1 cells. RNA sequencing analysis suggests that the protective effects of ACL are related to the regulation of ferroptosis. We demonstrate that ACL inhibits ferroptosis, including oxidative stress, lipid peroxidation, mitochondrial damage, and cell death under FAC exposure. In this study, we have identified heme oxygenase-1 (HO-1) as a critical mediator of ACL inhibiting ferroptosis and promoting osteogenesis, which was validated by HO-1 knockdown and knockout experiments. The study links ACL to HO-1 activation and ferroptosis regulation in the context of bone metabolism. These findings provide new insights into the mechanisms underlying the modulation of osteogenesis by ACL. Targeting the HO-1/ferroptosis axis is a promising therapeutic approach for treating iron overload-induced bone diseases.

Selenium Nanoparticles Attenuate Cobalt Nanoparticle-Induced Skeletal Muscle Injury: A Study Based on Myoblasts and Zebrafish.

Cobalt alloys have numerous applications, especially as critical components in orthopedic biomedical implants. However, recent investigations have revealed potential hazards associated with the release of nanoparticles from cobalt-based implants during implantation. This can lead to their accumulation and migration within the body, resulting in adverse reactions such as organ toxicity. Despite being a primary interface for cobalt nanoparticle (CoNP) exposure, skeletal muscle lacks comprehensive long-term impact studies. This study evaluated whether selenium nanoparticles (SeNPs) could mitigate CoNP toxicity in muscle cells and zebrafish models. CoNPs dose-dependently reduced C2C12 viability while elevating reactive oxygen species (ROS) and apoptosis. However, low-dose SeNPs attenuated these adverse effects. CoNPs downregulated myogenic genes and α-smooth muscle actin (α-SMA) expression in C2C12 cells; this effect was attenuated by SeNP cotreatment. Zebrafish studies confirmed CoNP toxicity, as it decreased locomotor performance while inducing muscle injury, ROS generation, malformations, and mortality. However, SeNPs alleviated these detrimental effects. Overall, SeNPs mitigated CoNP-mediated cytotoxicity in muscle cells and tissue through antioxidative and antiapoptotic mechanisms. This suggests that SeNP-coated implants could be developed to eliminate cobalt nanoparticle toxicity and enhance the safety of metallic implants.

Spatial and temporal variations of surface background ozone in China analyzed with the grid-stretching capability of GEOS-Chem High Performance.

Surface background ozone, defined as the ozone in the absence of domestic anthropogenic emissions, is important for developing emission reduction strategies. Here we apply the recently developed GEOS-Chem High Performance (GCHP) global atmospheric chemistry model with ∼0.5° stretched resolution over China to understand the sources of Chinese background ozone (CNB) in the metric of daily maximum 8 h average (MDA8) and to identify the drivers of its interannual variability (IAV) from 2015 to 2019. The GCHP ozone simulations over China are evaluated with an ensemble of surface and aircraft measurements. The five-year national-mean CNB ozone is estimated as 37.9 ppbv, with a spatially west-to-southeast downward gradient (55 to 25 ppbv) and a summer peak (42.5 ppbv). High background levels in western China are due to abundant transport from the free troposphere and adjacent foreign regions, while in eastern China, domestic formation from surface natural precursors is also important. We find greater importance of soil nitric oxides (NOx) than biogenic volatile organic compound emissions to CNB ozone in summer (6.4 vs. 3.9 ppbv), as ozone formation becomes increasingly NOx-sensitive when suppressing anthropogenic emissions. The percentage of daily CNB ozone to total surface ozone generally decreases with increasing daily total ozone, indicating an increased contribution of domestic anthropogenic emissions on polluted days. CNB ozone shows the largest IAV in summer, with standard deviations (seasonal means) of ∼5 ppbv over Qinghai-Tibet Plateau (QTP) and >3.5 ppbv in eastern China. CNB values in QTP are strongly correlated with horizontal circulation anomalies in the middle troposphere, while soil NOx emissions largely drive the IAV in the east. El Nino can inhibit CNB ozone formation in Southeast China by increased precipitation and lower temperature locally in spring, but enhance CNB in Southwest China through increased biomass burning emissions in Southeast Asia.

Ginsenoside Rg1 modulates PI3K/AKT pathway for enhanced osteogenesis via GPER.

BACKGROUND: Osteoporosis is a systemic skeletal disorder characterized by decreased bone density and the degradation of bone tissue microarchitecture. Ginsenoside Rg1, derived from Panax ginseng, has been a part of traditional Chinese medicine in China for centuries, particularly for treating osteoporosis. However, there remains limited research on the osteogenic potential of Rg1 within the glucocorticoid-induced osteoporosis (GIOP) model and its specific mechanisms. PURPOSE: The primary objective of this study is to investigate the osteogenic potential of Rg1 within the GIOP model and explore the signaling pathways associated with its in vivo and in vitro effects. METHODS: Cell proliferation, differentiation and mineralization were evaluated by the Cell counting kit 8(CCK8) assay, alkaline phosphatase (ALP) test and Alizarin Red S staining, respectively. The qPCR technique was used to determine the relative expression of mRNA and the western blot was used to determine the relative expression of protein. In vivo experiments, spinal vertebrae staining in zebrafish larvae was accomplished by alizarin red S staining. RESULTS: Zebrafish larvae's hatching, survival, malformation, and heart rate were unaffected by 50 µM of Rg1 in vivo, while the MEC3T3-E1 cell line's proliferation was unaffected by 50 µM of Rg1 in vitro. Meanwhile, Rg1 was shown to improve osteogenic differentiation or bone formation as well as the level of mRNA expression of osteogenic markers in vivo and in vitro. Treatment with Rg1 significantly increased the expression of G protein-coupled estrogen receptor (GPER) and pAKT. In addition, the GPER inhibitor G15 could significantly reduce the mRNA and protein expression levels of GPER and phosphorylated AKT, LY294002, a PI3K/AKT pathway inhibitor, markedly suppresses the expression of phosphorylated AKT, yet shows no significant impact on GPER expression. Both G15 and LY294002 can significantly blocked the Rg1-mediated enhancement of osteogenesis capacity in the GIOP model. In contrast, when both the agonists G1 of GPER and LY294002 were added, G1 increased the relative expression of mRNA and protein of GPER, but not the expression of osteogenic capacity and osteogenic markers. CONCLUSIONS: This study investigates the mineralization effects and mechanisms of Ginsenoside Rg1 both in vitro and in vivo. For the first time, we propose that Rg1 might regulate osteogenesis by modulating AKT phosphorylation through mediating GPER expression within the PI3K/AKT pathway in the GIOP model. This discovery introduces novel targets and avenues for osteoporosis treatment.

Increased aerosol scattering contributes to the recent monsoon rainfall decrease over the Gangetic Plain.

The climate effects of atmospheric aerosols remain highly uncertain. Part of the uncertainty arises from the fact that scattering and absorbing aerosols have distinct or even opposite effects. Thus their relative fraction is critical in determining the overall aerosol climate effect. This study combines observations and global model simulations to demonstrate that changes in the fraction of scattering and absorbing aerosols play an important role in driving the monsoon precipitation decrease over northern India since the 1980s, especially over the Gangetic Basin. Increased aerosol scattering, or decreased aerosol absorption, manifested as a significant increase of aerosol single scattering albedo (SSA), causes strong cooling in the upper atmosphere. This suppresses vertical convection and thus reduces precipitation. Further analysis of the Couple Model Intercomparison Project Phase 6 multi-model-mean historical simulation shows that failing to capture the SSA increase over northern India is likely an important cause of the simulated precipitation trend bias in this area.

Dendrobium offificinale polysaccharides prevents glucocorticoids-induced osteoporosis by destabilizing KEAP1-NRF2 interaction.

Glucocorticoid-induced osteoporosis (GIOP) represents the foremost cause of secondary osteoporosis and fragility fractures. Novel therapeutic strategies for GIOP are needed, with improved safety profiles and reduced costs compared to current options. Dendrobium officinale (D. officinale) is a traditional Chinese medicine that has been reported to have beneficial effects on bone metabolism. Here, we sought to investigate the impacts of D. officinale polysaccharides (DOP), the main active constituents of D. officinale, on GIOP in vivo models and dexamethasone (DEX)-treated osteoblast lineage cells. We found that low concentrations of DOP are relatively safe in vitro and in vivo, respectively. Importantly, we found that DOP treatment significantly inhibited DEX-induced osteoporosis in two in vivo models, zebrafish and mice, while boosting osteogenic differentiation of hBMSCs exposed to DEX. Futhermore, our data reveal that DOP elevates nuclear Nrf2 levels under DEX treatment, by suppressing of Nrf2 ubiquitination. Leveraging Keap1b knockout zebrafish and RNAi approach, we demonstrated that DOP disrupts the association of Nrf2/Keap1, resulting in the inhibition of Nrf2 ubiquitination. Taken together, these results illuminate that DOP stimulates osteogenesis in the presence of DEX by destabilizing the Nrf2/Keap1 interaction. These findings suggest that DOP may serve as a novel drug against osteoporosis caused by glucocorticoids.

Identification of an α-l-iduronidase (IDUA) M1T mutation in a Chinese family with autosomal recessive mucopolysaccharidosis I.

Mucopolysaccharidoses (MPS) are a group of rare congenital metabolic disorders caused by the deficiency or low activity of enzymes required for glycosaminoglycans degradation. Mutations in the α-l-iduronidase gene (IDUA) are associated with mucopolysaccharidosis type I (MPS I). Our study here aims to identify an MPS-related gene mutation in a typical patient with MPS and to further explore the possible pathogenic mechanism. We identified a homozygous c. 2T>C (p.M1T) change in IDUA as the pathogenic mutation in this individual (both parents were identified as carriers of the mutation), with IDUA enzyme activity significantly decreased. We further established an MPS I-related zebrafish model using IDUA-specific morpholino (MO) to suppress gene expression, and found that IDUA-MO zebrafish exhibited characteristic disease phenotypes with deficiency of IDUA. Transcriptome profiling of zebrafish larvae revealed 487 genes that were significantly altered when IDUA was depleted. TP53 signaling and LC3/GABARAP family protein-mediated autophagy were significantly upregulated in IDUA-MO zebrafish larvae. Moreover, leukotriene A4 hydrolase-mediated arachidonic acid metabolism was also upregulated. Introduction of wild-type human IDUA mRNA rescued developmental defects and aberrant signaling in IDUA-MO zebrafish larvae. In conclusion, our study provides potential therapeutic targets for the treatment of MPS I.

The impact of synoptic patterns on summertime ozone pollution in the North China Plain.

Surface ozone pollution is a challenging environmental issue in most parts of China. In particular, the North China Plain (NCP) region suffers from the severest ozone pollution throughout the country. In addition to the emission of precursors, ozone concentration is closely related to meteorological conditions resulting from regional atmospheric circulation. In this study, we investigate the relationship between synoptic patterns and summertime ozone pollution in the NCP using the objective principal component analysis in T-mode (T-PCA) classification method. Four dominant synoptic patterns are identified during the summers of 2014-2018. The heaviest ozone pollution is found to be associated with a high pressure anomaly over the Northwest Pacific and a distinct low pressure center in Northeast China. The southwesterly wind surrounding the low pressure center brings dry, warm air from inland South China, resulting in a high temperature, low humidity environment in the NCP, which favors the chemical formation of surface ozone. Locally, this type is associated with a moderate planetary boundary layer height (PBLH) of ~860 m and a stronger warm anomaly within the boundary layer than the upper level. We also notice a non-linear relationship between surface ozone concentration and the PBLH, i.e., ozone concentration first increases with PBLH till ~0.9 km, and then remains stable. This initial increase may relate to enhanced mixing with upper levels where ozone concentration is typically higher than that near the surface. However, when PBLH further increases, this downward mixing effect is balanced with the stronger upward turbulent mixing so that surface ozone shows little change. The synoptic patterns identified here, however, is unlikely responsible for the observed increasing trend in ozone concentration over the NCP region. Our study sheds light on the meteorological contribution to surface ozone pollution in North China and provides a reference for the pollution control and prediction.

Spatiotemporal and probability variations of surface PM2.5 over China between 2013 and 2019 and the associated changes in health risks: An integrative observation and model analysis.

We used statistical methods and the GEOS-Chem model to interpret the observed spatiotemporal and probability variations of surface PM2.5 concentrations in China from December 2013 to November 2019, as well as to assess the drivers for the variations and the implications for health risks associated with long-term and short-term exposure to PM2.5. Annual and seasonal PM2.5 concentrations have decreased over most areas in China during the 6-year period. We decomposed the observed day-to-day variation of PM2.5 concentrations in eastern Chinese cities and found that it showed two distinct major spatial modes, which fluctuated in strength seasonally. The first mode, characterized by most of Eastern China being in the same phase, was mainly associated with the regional ventilation of pollutants. The second mode showed a dipolar pattern between the Beijing-Tianjin-Hebei area and the Yangtze River Delta area and was more prominent in summer. Using model simulations, we showed that this dipole mode was chemically driven by the secondary formation of sulfate in summer. We further used a gamma distribution to succinctly interpret the changes in the probability distributions of PM2.5. We found that the nationwide decline in seasonal mean PM2.5 concentrations mainly reflected decreased occurrences of extremely high PM2.5 concentrations, which was strongly driven by the interannual variation of meteorology. These changes in the annual means and probability distributions of PM2.5 since December 2013 has led to significant decline of the estimated mortality risks associated with long-term and short-term PM2.5-exposures. Regions that were less polluted saw the largest relative benefit per unit decrease in PM2.5 concentration, due to the steepness of the exposure-response curve at the low-concentration end. Our integrated methodology effectively diagnosed the drivers of PM2.5 variability and the associated health risks and can be used as part of the decision tool for PM2.5 pollution management over China.