Discovery of novel ocotillol derivatives modulating glucocorticoid receptor/NF-κB signaling for the treatment of sepsis.

Glucocorticoids (GCs) have been used in the treatment of sepsis because of their potent anti-inflammatory effects. However, their clinical efficacy against sepsis remains controversial because of glucocorticoid receptor (GR) downregulation and side effects. Herein, we designed and synthesized 30 ocotillol derivatives and evaluated their anti-inflammatory activities. Ocotillol 24(R/S) differential isomers were stereoselective in their pharmacological action. Specifically, 24(S) derivatives had better anti-inflammatory activity than their corresponding 24(R) derivatives. Compound 20 most effectively inhibited NO release (85.97% reduction), and it exerted dose-dependent inhibitory effects on interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) levels. Mechanistic studies revealed that compound 20 reduces the degradation of GR mRNA and GR protein. Meanwhile, compound 20 inhibited the activation of nuclear factor-κB (NF-κB) signaling, thereby inhibiting the nuclear translocation of p65 and attenuating the inflammatory response. In vivo studies revealed that compound 20 attenuated hepatic, pulmonary, and renal pathology damage in mice with sepsis and suppressed the production of inflammatory mediators. These results indicated that compound 20 is a promising lead compound for designing and developing anti-sepsis drugs.

New Insights into MeHg Accumulation in Rice (Oryza sativa L.): Evidence from Cysteine.

The intake of methylmercury (MeHg)-contaminated rice poses immense health risks to rice consumers. However, the mechanisms of MeHg accumulation in rice plants are not entirely understood. The knowledge that the MeHg-Cysteine complex was dominant in polished rice proposed a hypothesis of co-transportation of MeHg and cysteine inside rice plants. This study was therefore designed to explore the MeHg accumulation processes in rice plants by investigating biogeochemical associations between MeHg and amino acids. Rice plants and underlying soils were collected from different Hg-contaminated sites in the Wanshan Hg mining area. The concentrations of both MeHg and cysteine in polished rice were higher than those in other rice tissues. A significant positive correlation between MeHg and cysteine in rice plants was found, especially in polished rice, indicating a close geochemical association between cysteine and MeHg. The translocation factor (TF) of cysteine showed behavior similar to that of the TF of MeHg, demonstrating that these two chemical species might share a similar transportation mechanism in rice plants. The accumulation of MeHg in rice plants may vary due to differences in the molar ratios of MeHg to cysteine and the presence of specific amino acid transporters. Our results suggest that cysteine plays a vital role in MeHg accumulation and transportation inside rice plants.

Measurement constrained emission estimates of alkylated polycyclic aromatic hydrocarbons in the Canadian Athabasca oil sands region.

Alkylated polycyclic aromatic hydrocarbons (APAH) are important contaminants of crude oil production and exhibit similar toxicity to their parent compounds. This study developed an emission inventory of APAH in a major oil sands development region of Alberta, Canada, and validated the inventory with ambient concentration measurements through dispersion modeling. The initial estimate of regional total annual emissions of 21 APAH species was 362 tonnes/year in the last decade, of which 309 and 53 tonnes/year were in particle-bound and gas-phase APAH, respectively. Fugitive dust from oil sands mining activities is the primary source of particle-bound APAH, emitting 274 tonnes/year. Other major sources of APAH include point sources (31), tailings ponds (21), anthropogenic fuel consumption from mine fleet (17), and local transportation (13). The group of species with highest emissions was C1-C4 alkylnaphthalenes (53%), followed by C1-C4 alkylphenanthrenes/anthracenes (19%), C1-C4 fluorenes (13%), and C1-C4 fluoranthenes/pyrenes and C1-C4 benz[a]anthracenes/chrysene/triphenylenes (7% each). CALPUFF dispersion modeling was performed using the APAH emissions as model input. The model-predicted annual average ambient APAH concentrations at 17 monitoring sites were 1%-52% (19% on average) lower than the measurements. Inverse dispersion modeling was then applied to adjust APAH emissions higher by 19% for each of the 21 APAH species, which resulted in a revised estimate of APAH emissions to 431 tonnes/year. With the revised emissions as model input, model bias in the predicted ambient concentration was reduced from -19% to -8%. The model results showed the highest concentrations of APAH were near tailings ponds and open mining faces and downwind areas, with total APAH concentrations being higher than 50 ng/m3.

Lixisenatide ameliorated lipopolysaccharide (LPS)-induced expression of mucin and inflammation in bronchial epithelial cells.

Chronic obstructive pulmonary disease (COPD) induces serious social and economic burdens due to its high disability and mortality, the pathogenesis of which is highly involved with inflammation, oxidative stress (OS), and mechanism of mucin 5AC (MUC5AC) secretion. Lixisenatide is a selective glucagon-like peptide 1 receptor agonist recently reported to have anti-inflammatory properties. Our study will focus on the potential impact of lixisenatide on lipopolysaccharide (LPS)-induced mucin secretion and inflammation in 16 human bronchial epithelial (16HBE) cells to check its potential function in COPD. 16HBE cells were treated with LPS, with or without lixisenatide (10 and 20 nM) for 1 day. Remarkably declined cell viability, enhanced lactate dehydrogenase release, activated OS, and elevated release of inflammatory cytokines were observed in LPS-treated 16HBE cells, accompanied by the activation of nuclear factor-κB signaling, all of which were signally reversed by lixisenatide. Moreover, elevated expression and release of MUC5AC were observed in LPS-treated 16HBE cells but were markedly repressed by lixisenatide. Furthermore, the repressed nuclear factor erythroid 2-related factor 2 (Nrf2) level in LPS-treated 16HBE cells was notably rescued by lixisenatide. Lastly, following the knockdown of Nrf2, the protective function of lixisenatide on LPS-triggered MUC5AC release in 16HBE cells was significantly abrogated. Collectively, lixisenatide ameliorated LPS-induced expression of mucin and inflammation in bronchial epithelial cells by regulating Nrf2.

Global trends of targeted therapy for hepatocellular carcinoma: A bibliometric and visualized study from 2008 to 2022.

BACKGROUND: Hepatocellular carcinoma (HCC) is an exceedingly prevalent malignancy with an exceptionally poor prognosis. Targeted therapy is an effective treatment option for patients with advanced HCC. However, there have been no bibliometric analyses of targeted therapies for HCC. METHODS: This study aimed to assess the current status and future directions of targeted therapy for HCC to provide future scholars with clearer research contents and popular themes. Methods: Literature on targeted therapy for HCC from 2008 to 2022 was obtained from the Web of Science (WoS) and assessed using bibliometric methodology. Additionally, the VOS viewer was applied in the visualization study to conduct bibliographic coupling, co-authorship, co-citation, and co-occurrence analyses of publications. RESULTS: A total of 10,779 papers were subsequently selected. Over the past 15 years, there has been a progressive increase in the number of publications on an annualized basis. China released the most publications in the field, whereas the United States had the highest H-index. Cancers published the most papers. Fudan University had the greatest sway in this area. Studies could be divided into 5 clusters: "Gene and expression research," "Mechanism study," "Nanoparticle study," "Targeted drug research," and "Clinical study." CONCLUSIONS: In the upcoming years, more papers on targeted therapy for HCC are expected to be released, demonstrating the potential for this topic to flourish. Particularly, "Clinical study" is the following trendy topic in this field. Other research subfields may likewise exhibit a continuous tendency towards balanced development.

Machine learning-based prediction of surgical benefit in borderline resectable and locally advanced pancreatic cancer.

INTRODUCTION: Surgery represents a primary therapeutic approach for borderline resectable and locally advanced pancreatic cancer (BR/LAPC). However, BR/LAPC lesions exhibit high heterogeneity and not all BR/LAPC patients who undergo surgery can derive beneficial outcomes. The present study aims to employ machine learning (ML) algorithms to identify those who would obtain benefits from the primary tumor surgery. METHODS: We retrieved clinical data of patients with BR/LAPC from the Surveillance, Epidemiology, and End Results (SEER) database and classified them into surgery and non-surgery groups based on primary tumor surgery status. To eliminate confounding factors, propensity score matching (PSM) was employed. We hypothesized that patients who underwent surgery and had a longer median cancer-specific survival (CSS) than those who did not undergo surgery would certainly benefit from surgical intervention. Clinical and pathological features were utilized to construct six ML models, and model effectiveness was compared through measures such as the area under curve (AUC), calibration plots, and decision curve analysis (DCA). We selected the best-performing algorithm (i.e., XGBoost) to predict postoperative benefits. The SHapley Additive exPlanations (SHAP) approach was used to interpret the XGBoost model. Additionally, data from 53 Chinese patients prospectively collected was used for external validation of the model. RESULTS: According to the results of the tenfold cross-validation in the training cohort, the XGBoost model yielded the best performance (AUC = 0.823, 95%CI 0.707-0.938). The internal (74.3% accuracy) and external (84.3% accuracy) validation demonstrated the generalizability of the model. The SHAP analysis provided explanations independent of the model, highlighting important factors related to postoperative survival benefits in BR/LAPC, with age, chemotherapy, and radiation therapy being the top three important factors. CONCLUSION: By integrating of ML algorithms and clinical data, we have established a highly efficient model to facilitate clinical decision-making and assist clinicians in selecting the population that would benefit from surgery.

Contributions of the oil sands sources to the ambient concentrations and deposition of particulate elements in the Canadian Athabasca oil sands region.

In this study, model sensitivity tests were conducted to investigate the relative contributions between emission sources of oil sands (OS) activities and other sources to the ambient concentrations and deposition of 29 particulate elements in the Athabasca oil sands region (AOSR) of Canada. Element emission sources from a recently developed emission database were grouped into three source sectors for elements in PM2.5 (OS-Industrial, OS-Dust, and Non-OS) and two source sectors for elements in PM2.5-10 (OS-All and Non-OS). The OS-Dust and OS-Industrial sectors (combined as one sector for PM2.5-10; OS-All) included element sources linked to dust and other industrial activities from the OS activities, respectively, whereas the Non-OS sector included remaining sources in the region, unrelated to the OS activities. The OS-Industrial, OS-Dust, and Non-OS emissions (tonnes/year) of all elements in PM2.5 were 326, 1430, and 562, respectively. The OS-All and Non-OS emissions (tonnes/year) of all elements in PM2.5-10 were 5890 and 2900, respectively. The element concentrations were simulated by the CALPUFF dispersion model. The sum of the domain averaged annual mean concentrations of all elements in PM2.5 and PM2.5-10 from all sources were 57.3 ng/m3 and 30.4 ng/m3, respectively. Except for Co (PM2.5 and PM2.5-10), Sb (PM2.5-10), and Sn (PM2.5-10), major proportions (≥ 59 %) of the ambient concentrations of the individual elements were linked to the OS source sector. Overall, the OS sector was responsible for 78 % and 68 % of the sum of the mean ambient concentrations of all elements in PM2.5 and PM2.5-10, respectively, which are close to the corresponding emission contributions (76 % and 67 %, respectively). Likewise, the bulk proportion (∼74 %) of the sum of the total atmospheric deposition of all elements was also associated with the OS sources. Carcinogenic and non-carcinogenic risks associated with inhalation exposure to airborne elements were below the recommended threshold risk levels.

Combination of Merocel sponge with Lipopolysaccharide to establish rat rhinosinusitis model

Abstract Objective The study aimed to investigate the feasibility of establishing rhinosinusitis model in rats combinated with Lipopolysaccharide (LPS) and merocel sponge. Methods SD (Sprague Dawley) rats that underwent nasal obstruction using Merocel sponge packing, rats with LPS instillation alone, and rats with both nasal obstruction and LPS instillation were used to establish rat models of rhinosinusitis. After the models were established, the nasal symptoms of rats were recorded, the histopathological examination and Transmission Electron Microscopy (TME) of the sinus tissue were performed and the levels of Tumor Necrosis Factor-α (TNF-α), Interleukin-6 (IL-6) in the blood were also analyzed. The expressions of Aquaporin-5 (AQP5), Occludin, Toll-Like Receptor-4 (TLR4), Medullary differentiation factor 88 (MyD88) and phosphorylated (p)-p65 protein were detected by Western blot to evaluate the effect and mechanism of the experimental models. Results We found that compared with the control group and LPS group, the sinusitis symptom scores in the Merocel sponge combined with LPS group were significantly increased; the respiratory epithelia of the maxillary sinus were degenerated, cilia were detached, and even inflammatory cell infiltration occurred; the levels of TNF-α and IL-6 were increased; the expression of AQP5 and Occludin protein was decreased; and the expressions of TLR4, MyD88, and p-p65 protein were increased. Conclusion For the first time, we successfully established a rat rhinosinusitis model using Merocel sponge with LPS and explored the possible mechanism of LPS action.

Atmospheric deposition mapping of particulate elements in the Canadian Athabasca oil sands region.

This study used a deposition modeling framework to generate gridded dry, wet, and total (dry + wet) deposition fluxes of 27 particulate elements over the Canadian Athabasca oil sands region and its surrounding areas for the years 2016-2017. The framework employed the element concentrations from the CALPUFF dispersion model outputs that were bias-corrected against measured concentrations, modeled dry deposition velocities, precipitation analysis data, and literature values of element-specific fine mode fractions and scavenging ratios by rain and snow. The annual total deposition (mg/m2/year) of all elements (EM) across the domain ranged from 4.49 to 5450 and the mean and median deposition were 60.9 and 31.0, respectively. Total EM deposition decreased rapidly within a short distance from the oil sands mining area. Annual mean total deposition (mg/m2/year) of EM was 717 in Zone 1 (within 30 km from a reference point, representing the center of the oil sands mining area), 115 in Zone 2 (30-100 km from the reference point), and 35.4 in Zone 3 (beyond 100 km from the reference point). The deposition of individual elements was primarily governed by their respective concentrations and among all elements the annual mean total deposition (µg/m2/year) over the domain varied five orders of magnitude ranging from 0.758 (Ag) to 20,000 (Si). Annual mean dry and wet deposition (mg/m2/year) of EM over the domain were 15.7 and 45.2, respectively. Aside from S, which has relatively lower precipitation scavenging efficiencies, wet deposition was the dominant deposition type in the region contributing from 51% (Pb) to 86% (Ca) of the respective total deposition. Total EM deposition over the domain in the warm season (66.2 mg/m2/year) was slightly higher than that in the cold season (55.6 mg/m2/year). Deposition of individual elements in Zone 1 were generally lower than their deposition at other sites across North America.

Combination of Merocel sponge with Lipopolysaccharide to establish rat rhinosinusitis model.

OBJECTIVE: The study aimed to investigate the feasibility of establishing rhinosinusitis model in rats combinated with Lipopolysaccharide (LPS) and merocel sponge. METHODS: SD (Sprague Dawley) rats that underwent nasal obstruction using Merocel sponge packing, rats with LPS instillation alone, and rats with both nasal obstruction and LPS instillation were used to establish rat models of rhinosinusitis. After the models were established, the nasal symptoms of rats were recorded, the histopathological examination and Transmission Electron Microscopy (TME) of the sinus tissue were performed and the levels of Tumor Necrosis Factor-α (TNF-α), Interleukin-6 (IL-6) in the blood were also analyzed. The expressions of Aquaporin-5 (AQP5), Occludin, Toll-Like Receptor-4 (TLR4), Medullary differentiation factor 88 (MyD88) and phosphorylated (p)-p65 protein were detected by Western blot to evaluate the effect and mechanism of the experimental models. RESULTS: We found that compared with the control group and LPS group, the sinusitis symptom scores in the Merocel sponge combined with LPS group were significantly increased; the respiratory epithelia of the maxillary sinus were degenerated, cilia were detached, and even inflammatory cell infiltration occurred; the levels of TNF-α and IL-6 were increased; the expression of AQP5 and Occludin protein was decreased; and the expressions of TLR4, MyD88, and p-p65 protein were increased. CONCLUSION: For the first time, we successfully established a rat rhinosinusitis model using Merocel sponge with LPS and explored the possible mechanism of LPS action.

A population-based study of synchronous distant metastases and prognosis in patients with PDAC at initial diagnosis.

Objective: Cancer of the pancreas is a life-threatening condition and has a high distant metastasis (DM) rate of over 50% at diagnosis. Therefore, this study aimed to determine whether patterns of distant metastases correlated with prognosis in pancreatic ductal adenocarcinoma (PDAC) with metastatic spread, and build a novel nomogram capable of predicting the 6, 12, 18-month survival rate with high accuracy. Methods: We analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database for cases of PDAC with DM. Kaplan-Meier analysis, log-rank tests and Cox-regression proportional hazards model were used to assess the impact of site and number of DM on the cancer-specific survival (CSS) and over survival (OS). A total of 2709 patients with DM were randomly assigned to the training group and validation group in a 7:3 ratio. A nomogram was constructed by the dependent risk factors which were determined by multivariate Cox-regression analysis. An assessment of the discrimination and ability of the prediction model was made by measuring AUC, C-index, calibration curve and decision curve analysis (DCA). In addition, we collected 98 patients with distant metastases at the time of initial diagnosis from Ningbo University Affiliated LiHuili Hospital to verify the efficacy of the prediction model. Results: There was a highest incidence of liver metastases from pancreatic cancer (2387,74.36%), followed by lung (625,19.47%), bone (190,5.92%), and brain (8,0.25%). The prognosis of liver metastases differed from that of lung metastases, and the presence of multiple organ metastases was associated with poorer prognosis. According to univariate and multivariate Cox-regression analyses, seven factors (i.e., diagnosis age, tumor location, grade of tumor differentiation, T-stage, receipt of surgery, receipt of chemotherapy status, presence of multiple organ metastases) were included in our nomogram model. In internal and external validation, the ROC curves, C-index, calibration curves and DCA were calculated, which confirmed that this nomogram can precisely predict prognosis of PDAC with DM. Conclusion: Metastatic PDAC patients with liver metastases tended to have a worse prognosis than those with lung metastases. The number of DM had significant effect on the overall survival rate of metastatic PDAC. This study had a high prediction accuracy, which was helpful clinicians to analyze the prognosis of PDAC with DM and implement individualized diagnosis and treatment.

Emissions database development and dispersion model predictions of airborne particulate elements in the Canadian Athabasca oil sands region.

This study developed an emission inventory for 29 elements in PM2.5 and PM2.5-10 covering an area of approximately 300 by 420 km2 in the Athabasca Oil Sands Region in northern Alberta, Canada. Emission sources were aggregated into nine categories, of which the Oil Sands (OS) Sources emitted the most, followed by the Non-OS Dust sources for both fine and coarse elements over the study area. The top six fine particulate elements include Si, Ca, Al, Fe, S, and K (933, 442, 323, 269, 116, and 103 tonnes/year, respectively), the sum of which accounted for 20.5% of the total PM2.5 emissions. The top five coarse elements include Si, Ca, Al, Fe, and K (3713, 1815, 1198, 1073, and 404 tonnes/year), and their sum accounted for 29% of the total PM2.5-10 emissions. Using this emission inventory as input, the CALPUFF dispersion model simulated reasonable element concentrations in both PM2.5 and PM2.5-10 when compared to measurements collected at three sites during 2016-2017. Modeled PM10 concentrations of all elements were very close to the measurements at an industrial site with the highest ambient concentration, overestimated by 65% at another industrial site with moderate ambient concentration, and underestimated by 27% at a remote site with very low ambient concentration. Model-measurement differences of annual average concentrations were within 20% for Si, Ca, Al, Fe, Ti, Mn, and Cu in PM2.5, and were 20-50% for K, S, and Zn in PM2.5 at two sites located within the OS surface mineable area. Model-measurement differences were larger, but still within a factor of two for elements in PM2.5-10 at these two sites and for elements in both PM2.5 and PM2.5-10 at a background site.

Percutaneous endoscopic decompression for calcified thoracic disc herniation using a novel T rigid bendable burr.

BACKGROUND: The basic endoscopic instruments are not suitable for removing calcified or hard discs in patients with thoracic disc herniations (TDH). We describe a percutaneous endoscopic technique for the treatment of calcified TDH using an endoscopic drill system with a T rigid bendable burr. METHODS: Eleven patients (8 males, mean age 42.1 years) with single-segmental calcified TDH were treated with percutaneous endoscopic surgeries. RESULTS: Our technique using this endoscopic drill system with a T rigid bendable burr is safe and effective for the treatment of calcified TDH. CONCLUSIONS: Percutaneous endoscopic decompression using the T rigid bendable burr is a safe and reproducible surgical procedure for the treatment of calcified TDH.

Water-soluble iron in PM2.5 in winter over six Chinese megacities: Distributions, sources, and environmental implications.

Water-soluble iron (ws-Fe) in PM2.5 plays a crucial role in biogeochemical cycles and atmospheric chemical processes. The anthropogenic sources of ws-Fe have attracted considerable attention owing to its high solubility. However, few studies have investigated the content of PM2.5 ws-Fe in the urban environment. In the present study, we characterized the spatial distributions of ws-Fe in six Chinese megacities in the winter of 2019. Furthermore, we investigated the speciation of PM2.5 ws-Fe (ws-Fe(II) and ws-Fe(III)), potential sources of ws-Fe, and association between ws-Fe and particle-bound reactive oxygen species (ROS). Higher ws-Fe concentrations were observed in northern cities (Harbin, Beijing, and Xi'an) than in southern cities (Chengdu, Wuhan, and Guangzhou). Moreover, atmospheric ws-Fe concentrations in urban China were several folds higher than those in urban areas of the United States and several orders of magnitude higher than those in remote oceans, indicating that China is a key contributor to global atmospheric ws-Fe. The dominant form of ws-Fe was ws-Fe(III) in Beijing, whereas ws-Fe(II) was more abundant in the other five cities. The concentrations of ws-Fe and ws-Fe(II) concentrations increased with increasing PM2.5 levels in all the six cities, however, we did not observe any consistent pattern of ws-Fe(III) concentration. Biomass burning was a dominant source of ws-Fe in all cities except Beijing. A strong positive correlation was observed between particle-bound ROS content and ws-Fe; this finding is consistent with those of previous studies indicating that ws-Fe in PM2.5 notably influences atmospheric chemical processes and human health.

Celastrol inhibits rheumatoid arthritis by inducing autophagy via inhibition of the PI3K/AKT/mTOR signaling pathway.

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder of the synovial joints. Celastrol (Cel) is a quinone-methylated triterpenoid extracted from Tripterygium wilfordii Hook F (TwHF) that has been proven to be effective in treating RA. However, the underlying molecular mechanism of celastrol in the treatment of RA remains unknown. This study explored the protective effect of celastrol against RA and the specific mechanisms of celastrol in vitro and in vivo. METHODS: A chicken type II collagen (CII)-induced arthritis (CIA) mouse model was used to explore the anti-arthritic effects of celastrol, and paw swelling degree, the poly-arthritis index score and serum cytokine levels were determined. Pathological morphology was observed using hematoxylin and eosin (H&E) staining. The influences of celastrol on the proliferation of tumor necrosis factor-α (TNF-α)-induced fibroblast-like synoviocytes (FLSs) were tested by Cell Counting Kit-8 (CCK-8) assays and5-ethynyl-2'-deoxyuridine (EdU) staining assays. The level of autophagy was detected by transmission electron microscopy (TEM). Furthermore, the PI3K/AKT/mTOR pathway and the status of autophagy in the CIA model and FLSs were also detected by western blot and immunofluorescence staining. RESULTS: The results showed that celastrol decreased arthritis severity and inhibited TNF-α-induced FLSs proliferation. Additionally, celastrol decreased the secretion of pro-inflammatory cytokines. Moreover, celastrol increased autophagosome levels and LC3B protein expression in TNF-α-treated FLSs. Furthermore, celastrol increased the protein expression of LC3-II and Beclin-1 and decreased the phosphorylation degree of mTOR and AKT. CONCLUSION: In conclusion, our findings confirmed that celastrol ameliorates RA via the up-regulation of autophagy by inhibiting the PI3K/AKT/mTOR axis.

Case Report: Adult degenerative scoliosis in two patients treated with percutaneous spinal endoscopic-assisted lumbar interbody fusion and percutaneous pedicle screw fixation.

Adult degenerative scoliosis (ADS) is a serious disease that often affects middle-aged and elderly people. ADS does not only cause sagittal and coronal deformity of the lumbar spine but also causes severe back and leg pain secondary to the compression of the neural structures. Open surgery remains the main method for correcting the occurring deformity and decompression of the neural structures; however, its benefit is limited in cases of large trauma. Minimally invasive spinal (MIS) surgery is an alternative method that has recently witnessed rapid development. It has the advantage of providing rapid recovery with less trauma as compared to conventional open surgery. We report two cases of ADS treated with percutaneous spinal endoscopic-assisted lumbar interbody fusion (EALIF) and percutaneous pedicle screw fixation. Both cases had moderate deformities of the lumbar spine (load-sharing classification 4-7 points) with severe back and leg pain, and they underwent successful MIS surgery. At 6 months of follow-up, the visual analog scale and Oswestry disability index scores of both patients improved and the deformity was corrected. For moderate ADS, percutaneous spinal EALIF and percutaneous pedicle screw fixation may achieve an effective correction of the deformity with direct decompression of neural structures.

ROS-mediated liposomal dexamethasone: a new FA-targeted nanoformulation to combat rheumatoid arthritis via inhibiting iRhom2/TNF-α/BAFF pathways.

Rheumatoid arthritis (RA) is an autoimmune inflammatory disorder that has seriously affected human health worldwide and its current management requires more successful therapeutic approaches. The combination of nanomedicines and pathophysiology into one system may provide an alternative strategy for precise RA treatment. In this work, a practical ROS-mediated liposome, abbreviated as Dex@FA-ROS-Lips that comprised synthetic dimeric thioether lipids (di-S-PC) and a surface functionalized with folic acid (FA), was proposed for dexamethasone (Dex) delivery. Incorporation with thioether lipids and a FA segment significantly improved the triggered release and improved the triggered release of cytotoxic Dex as well as the active targeting of RA, altering its overall pharmacokinetics and safety profiles in vivo. As proof, the designed Dex@FA-ROS-Lips demonstrated effective internalization by LPS-activated Raw264.7 macrophages with FA receptor overexpression and released Dex at the inflammatory site due to the ROS-triggered disassembly. Intravenous injection of this Dex@FA-ROS-Lips into adjuvant-induced arthritis (AIA) mice led to its incremental accumulation in inflamed joint tissues and significantly alleviated the cartilage destruction and joint swelling via suppression of proinflammatory cytokines (iRhom2, TNF-α and BAFF), as compared to the effect of commercial free Dex. Importantly, the Dex@FA-ROS-Lips nanoformulation showed better hemocompatibility with less adverse effects on the body weight and immune organ index of AIA mice. The anti-inflammatory mechanism of Dex@FA-ROS-Lips was further studied and it was found that it is possibly associated with the down-regulation of iRhom2 and the activation of the TNF-α/BAFF signaling pathway. Therefore, the integration of nanomedicines and the RA microenvironment using multifunctional Dex@FA-ROS-Lips shall be a novel RA treatment modality with full clinical potential, and based on the enhanced therapeutic effect, the signaling pathway of iRhom2/TNF-α/BAFF reasonably explained the mechanism of Dex@FA-ROS-Lips in anti-RA, which suggested a molecular target for RA therapy and other inflammatory diseases.

Measurement of size-segregated airborne particulate bound polycyclic aromatic compounds and assessment of their human health impacts - A case study in a megacity of southwest China.

Particle size distribution of particulate polycyclic aromatic compounds (PACs) is one of the important factors controlling human exposure to PACs in air. In this study, size-segregated airborne particle samples were collected in a megacity in southwest China to analyze PACs concentrations and evaluate related health risks. Annual average concentrations of Σ19PAHs (polycyclic aromatic hydrocarbons, 17.4 ng/m3) and Σ10OPAHs (oxygenated PAHs, 15.3 ng/m3) were one order of magnitude higher than those of Σ9MPAHs (methyl PAHs, 0.97 ng/m3) and Σ27NPAHs (nitrated PAHs, 1.54 ng/m3). More than 55% of PACs masses were associated with fine particles (aerodynamic diameter Dae < 2.1 µm). Inhalation exposure assessment showed that less than 60% of particulate bound PACs could deposit in the respiratory tract, which implies that the traditional model using ambient concentration of PACs would overestimate the inhalation risk. On the other hand, incremental lifetime cancer risks from dermal absorption (ILCRderm) were comparable to those from inhalation (ILCRinh) exposure despite the much lower daily dermal absorption dose than the daily inhalation dose, which implies that the health impact might be underestimated if only considering inhalation exposure. Cancer risks from inhalation exposure were mainly attributed to fine particles while those from dermal exposure were mostly associated with coarse particles. Although neither ILCRderm nor ILCRinh exceeded the threshold value of 10-6 set by USEPA, the total ILCR exceeded this criterion, manifesting potential health risks from exposure to airborne particulate PACs in this region.

Celastrol inhibits rheumatoid arthritis through the ROS-NF-κB-NLRP3 inflammasome axis.

Emerging evidence indicates that NOD-like receptor protein 3 (NLRP3) inflammasome-induced inflammation plays a critical role in the pathogenesis of rheumatoid arthritis (RA). Celastrol (Cel) is a quinone-methylated triterpenoid extracted from Tripterygium wilfordii that is used to treat RA. However, researchers have not determined whether Cel exerts anti-RA effects by regulating the activation of the NLRP3 inflammasome. In the present study, complete Freund's adjuvant (CFA)- induced rats and human mononuclear macrophages (THP-1 cells) were used to explore the anti-RA effects of Cel and its underlying mechanism. Joint swelling, the arthritis index score, inflammatory cell infiltration, and synovial hyperplasia in CFA-induced rats were correspondingly reduced after Cel treatment. The secretion of interleukin (IL)-1ß and IL-18 in the serum of CFA-induced rats and supernatants of THP-1 cells exposed to Cel was significantly decreased. These inhibitory effects occurred because Cel blocked the nuclear factor-kappa B (NF-κB) signaling pathway and inhibited the activation of the NLRP3 inflammasome. Furthermore, Cel inhibited reactive oxygen species (ROS) production induced by lipopolysaccharide (LPS) and adenosine triphosphate (ATP). We speculated that Cel relieves RA symptoms and inhibits inflammation by inhibiting the ROS-NF-κB-NLRP3 axis.

Characterization and source apportionment of airborne particulate elements in the Athabasca oil sands region.

The oil sands industries in Alberta, Canada are potential sources of particulate-bound elements in the region. This study explored the ambient concentrations and size distributions, and conducted source apportionment of 48 particulate elements, based on samples collected in 2016-2017 at four air monitoring sites in the Athabasca oil sands region: Fort McKay (AMS1), Buffalo Viewpoint (AMS4), Wapasu Creek (AMS17), and Stoney Mountain (AMS18). Element concentrations in fine and coarse particulate matter (PM2.5 and PM2.5-10 respectively) at the four sites were generally lower than their typical concentrations at other urban and industrial sites in North America. Among all elements, S was the most abundant in PM2.5 with mean concentrations ranging from 189 ng/m3 (AMS18) to 284 ng/m3 (AMS1). Of the trace, toxic elements in PM2.5, Zn was the most abundant with mean concentrations ranging from 3.43 ng/m3 (AMS18) to 5.37 ng/m3 (AMS4). Positive Matrix Factorization (PMF) modeling of the element concentrations in PM2.5 was used for source apportionment for Zone1 (including AMS 1, 4, and 17, situated closer to industrial activities) and for Zone2 (including AMS18, a background site). The sources of elements for Zone1, included crustal dust, bitumen processing, haul road dust, and biomass burning that explained ~33%, ~43%, ~15%, and ~9% of the total resolved elemental mass, respectively. The sources of elements for Zone2, included Pb-rich source, biomass burning, fugitive oil sands, crustal dust, and bitumen processing explaining ~8%, ~7%, ~3%, ~22%, and ~60% of the total resolved elemental mass, respectively. Elemental mass concentrations of the bitumen processing source factor at Zone2 was two-thirds of that in Zone1. Overall, mass proportions of the bitumen processing source factor at all four sites were significant, suggesting that the oil sands industries played a key role in ambient element concentration levels in the region.