The Role of Endoscopic Ultrasound-guided Fine-needle Aspiration of Pelvic Lesions: A Meta-analysis.

BACKGROUND AND AIMS: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is a potentially valuable tool for the diagnosis of pelvic lesions. The aim of this meta­analysis was to evaluate the efficacy and feasibility of EUS-FNA in the diagnosis of pelvic lesions. METHODS: We performed a computerized search of PubMed, EMBASE, Cochrane Library, and Science Citation Index, through March 2023. The main outcome measures examined in the meta-analysis were sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy. RESULTS: We evaluated 22 trials that used surgical pathology or imaging follow-up results as the reference standard. The studies comprised 844 patients. The cumulative sensitivity, specificity, PPV, NPV, and accuracy were 94%, 100%, 100%, 89%, and 96%, respectively. In the subgroup analysis, the prospective studies revealed the cumulative sensitivity, specificity, PPV, NPV, and accuracy were 91%, 100%, 100%, 85%, and 93%, respectively. CONCLUSIONS: In conclusion, we provide evidence that EUS-FNA is a qualitative diagnostic technique with high sensitivity, specificity, PPV, and accuracy. However, its NPV is slightly low, which does not exclude the risk of a missed diagnosis, and more randomized controlled trials or prospective studies are still needed in the future. EUS-FNA is effective and feasible for pelvic space-occupying lesions. This technique has high clinical application value for pelvic lesions.

IFT80 promotes early bone healing of tooth sockets through the activation of TAZ/RUNX2 pathway.

Intraflagellar transport (IFT) proteins have been reported to regulate cell growth and differentiation as the essential functional component of primary cilia. The effects of IFT80 on early bone healing of extraction sockets have not been well studied. To investigate whether deletion of Ift80 in alveolar bone-derived mesenchymal stem cells (aBMSCs) affected socket bone healing, we generated a mouse model of specific knockout of Ift80 in Prx1 mesenchymal lineage cells (Prx1Cre ;IFT80f/f ). Our results demonstrated that deletion of IFT80 in Prx1 lineage cells decreased the trabecular bone volume, ALP-positive osteoblastic activity, TRAP-positive osteoclastic activity, and OSX-/COL I-/OCN-positive areas in tooth extraction sockets of Prx1Cre ; IFT80f/f mice compared with IFT80f/f littermates. Furthermore, aBMSCs from Prx1Cre ; IFT80f/f mice showed significantly decreased osteogenic markers and downregulated migration and proliferation capacity. Importantly, the overexpression of TAZ recovered significantly the expressions of osteogenic markers and migration capacity of aBMSCs. Lastly, the local administration of lentivirus for TAZ enhanced the expression of RUNX2 and OSX and promoted early bone healing of extraction sockets from Prx1Cre ; IFT80f/f mice. Thus, IFT80 promotes osteogenesis and early bone healing of tooth sockets through the activation of TAZ/RUNX2 pathway.

Single-Cell RNA Sequencing Reveals Roles of Fibroblasts During Intestinal Injury and Repair in Rats with Severe Acute Pancreatitis.

Purpose: To explore the molecular mechanisms of intestinal injury and treatment by analyzing changes in cellular heterogeneity and composition in rat ileal tissue during injury and treatment processes. Methods: We constructed a rat model of SAP and evaluated treatment with an injected of monoacylglycerol lipase (MAGL) inhibitor (JZL184) solution using three experimental groups: healthy male Sprague-Dawley (SD) rats injected with vehicle (CON), male SD SAP model rats injected with vehicle (SAP), and male SAP rats injected with JZL184. We obtained and prepared a single-cell suspension of ileal tissue of each rat for single-cell transcriptome sequencing. Results: This project classified changes in cellular heterogeneity and composition in rat ileal tissue during SAP-induced intestinal injury and MAGL treatment. We found that the number of fibroblast clusters was decreased in the SAP group relative to the CON group, and increased after JZL184 treatment. Further analysis of differences in gene expression between cell clusters in each group reveals that fibroblasts had the greatest number of differentially expressed genes. Most notably, expression of genes involved in communication between cells was found to vary during SAP-induced intestinal injury and JZL184 treatment. Among these changes, the degree of difference in expression of genes involved in communication between fibroblasts and other cells was the highest, indicating that fibroblasts in rat ileal tissue affect intestinal injury and repair through cell-to-cell communication. In addition, our results reveal that differentially expressed RNA-binding proteins in fibroblasts may affect their functions in intestinal injury and treatment by affecting the expression of genes regulating communication between cells. Conclusion: These findings emphasize the importance of understanding the interactions between fibroblasts and other cells in the context of intestinal injury, providing valuable insights for further exploring molecular mechanisms and insight for discovering new treatment targets and strategies.

Integration of transcriptomics and metabolomics analysis for unveiling the toxicological profile in the liver of mice exposed to uranium in drinking water.

Uranium is a contaminate in the underground water in many regions of the world, which poses health risks to the local populations through drinking water. Although the health hazards of natural uranium have been concerned for decades, the controversies about its detrimental effects continue at present since it is still unclear how uranium interacts with molecular regulatory networks to generate toxicity. Here, we integrate transcriptomic and metabolomic methods to unveil the molecular mechanism of lipid metabolism disorder induced by uranium. Following exposure to uranium in drinking water for twenty-eight days, aberrant lipid metabolism and lipogenesis were found in the liver, accompanied with aggravated lipid peroxidation and an increase in dead cells. Multi-omics analysis reveals that uranium can promote the biosynthesis of unsaturated fatty acids through dysregulating the metabolism of arachidonic acid (AA), linoleic acid, and glycerophospholipid. Most notably, the disordered metabolism of polyunsaturated fatty acids (PUFAs) like AA may contribute to lipid peroxidation induced by uranium, which in turn triggers ferroptosis in hepatocytes. Our findings highlight disorder of lipid metabolism as an essential toxicological mechanism of uranium in the liver, offering insight into the health risks of uranium in drinking water.

Unique microbial landscape in the human oropharynx during different types of acute respiratory tract infections.

BACKGROUND: Secondary bacterial infections and pneumonia are major mortality causes of respiratory viruses, and the disruption of the upper respiratory tract (URT) microbiota is a crucial component of this process. However, whether this URT dysbiosis associates with the viral species (in other words, is viral type-specific) is unclear. RESULTS: Here, we recruited 735 outpatients with upper respiratory symptoms, identified the infectious virus types in 349 participants using multiplex RT-PCR, and profiled their upper respiratory microbiome using the 16S ribosomal RNA gene and metagenomic gene sequencing. Microbial and viral data were subsequently used as inputs for multivariate analysis aimed at revealing viral type-specific disruption of the upper respiratory microbiota. We found that the oropharyngeal microbiota shaped by influenza A virus (FluA), influenza B virus (FluB), respiratory syncytial virus (RSV), and human rhinovirus (HRV) infections exhibited three distinct patterns of dysbiosis, and Veillonella was identified as a prominent biomarker for any type of respiratory viral infections. Influenza virus infections are significantly correlated with increased oropharynx microbiota diversity and enrichment of functional metabolic pathways such as L-arginine biosynthesis and tetracycline resistance gene tetW. We used the GRiD algorithm and found the predicted growth rate of common respiratory pathogens was increased upon influenza virus infection, while commensal bacteria, such as Streptococcus infantis and Streptococcus mitis, may act as a colonization resistance to the overgrowth of these pathogens. CONCLUSIONS: We found that respiratory viral infections are linked with viral type-specific disruption of the upper respiratory microbiota, particularly, influenza infections uniquely associated with increased microbial diversity and growth rates of specific pathogens in URT. These findings are essential for clarifying the differences and dynamics of respiratory microbiota in healthy participants and acute respiratory viral infections, which contribute to elucidating the pathogenesis of viral-host-bacterial interactions to provide insights into future studies on effective prevention and treatment of respiratory tract infections. Video Abstract.

Antimicrobial and Antibiofilm Efficacy and Mechanism of Oregano Essential Oil Against Shigella flexneri.

The aim of this study was to assess the antimicrobial activity of oregano essential oil (OEO) against Shigella flexneri and eradication efficacy of OEO on biofilm. The results showed that the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) of OEO against S. flexneri were 0.02% (v/v) and 0.04% (v/v), respectively. OEO effectively killed S. flexneri in Luria-Bertani (LB) broth and contaminated minced pork (the initial population of S. flexneri was about 7.0 log CFU/mL or 7.2 log CFU/g), and after treatment with OEO at 2 MIC in LB broth or at 15 MIC in minced pork, the population of S. flexneri decreased to an undetectable level after 2 or 9 h, respectively. OEO increased intracellular reactive oxygen species concentration, destroyed cell membrane, changed cell morphology, decreased intracellular ATP concentration, caused cell membrane depolarization, and destroyed proteins or inhibited proteins synthesis of S. flexneri. In addition, OEO effectively eradicated the biofilm of S. flexneri by effectively inactivating S. flexneri in mature biofilm, destroying the three-dimensional structure, and reducing exopolysaccharide biomass of S. flexneri. In conclusion, OEO exerts its antimicrobial action effectively and also has a valid scavenging effect on the biofilm of S. flexneri. These findings suggest that OEO has the potential to be used as a natural antibacterial and antibiofilm material in the control of S. flexneri in meat product supply chain, thereby preventing meat-associated infections.

Endoscopic-Directed Trans-Gastric Retrograde Cholangiopancreatography in Patients With Roux-en-Y gastric Bypasses: A Meta-Analysis.

BACKGROUND AND AIM: Endoscopic ultrasound-directed trans-gastric retrograde cholangiopancreatography (EDGE) is a new procedure for treating pancreaticobiliary diseases in patients with Roux-en-Y gastric bypass (RYGB). The aim of this meta­analysis was to determine the overall outcomes and safety of EDGE. MATERIALS AND METHODS: We performed a computerized search of the main databases, including PubMed, EMBASE, Cochrane Library, and Science Citation Index, through October 2022. The main outcome measures examined in the meta-analysis were technical and clinical success rates and overall adverse event (AE) rate, especially the lumen-apposing metal stent (LAMS) dislodgement rate. AE rates were assessed according to LAMS size (15 vs. 20 mm), number of stages (single vs. two) and access route (gastrogastric vs. jejuno-gastric). RESULTS: Fourteen trials with a total of 574 patients who had undergone 585 EDGE procedures were included in this study. The cumulative technical and clinical success and AE rates were 98%, 94%, and 14%, respectively. The commonest AE was LAMS dislodgement (rate 4%). The overall AE rate was lower in the 20-mm LAMS than in the 15-mm LAMS group (odds ratio [OR]=5.79; 95% confidence interval [CI]: 2.35 to 14.29). There were no significant differences in AE rate between number of stages (OR=1.36; 95% CI: 0.51 to 3.64) or differing access routes (OR=1.03; 95% CI 0.48 to 2.22). CONCLUSION: We here provide evidence that EDGE for endoscopic retrograde cholangiopancreatography yields good treatment outcomes in patients with RYGBs. The AE rate is significantly lower with 20-mm versus 15-mm LAMS; thus, the former is likely preferable.

Influencing factors of early dramatic recovery of neurological function after intravenous thrombolysis in patients with branch atheromatous disease.

BACKGROUND: Intravenous thrombolysis can significantly improve the neurological function of patients with acute ischemic stroke. However, the expected early dramatic recovery (EDR) of neurological function after thrombolysis is not achieved in some patients with branch atheromatous disease (BAD). Here we evaluated the factors associated with EDR after thrombolysis in BAD patients. METHODS: We conducted a retrospective study on 580 consecutive BAD patients. All patients met the diagnostic criteria of BAD and received intravenous recombinant tissue-type plasminogen activator (rt-PA). EDR was defined when the improvement of National Institutes of Health Stroke Scale (NIHSS) score was >8 points within 2 or 24 hours after rt-PA, or the total NIHSS score was 0 or 1. The factors associated with EDR were analyzed with multivariate logistic regression analysis. RESULTS: Among 580 patients, the incidence of EDR was 35.2% (204 cases). Compared with patients without EDR, patients with EDR had lower incidence of diabetes (15.7% vs 29.3%, P < .001), lower NIHSS scores at 2 and 24 hours after rt-PA (P < .001), less cerebral hemorrhage (0% vs 5.3%, P = .001), and shorter onset to treatment time (OTT) (P < .001). Multivariate logistic regression analysis in propensity score-matched cohort showed that EDR was associated with OTT (adjusted OR = 0.994; 95% CI, 0.989-0.999) and NIHSS score after rt-PA (adjusted OR = 0.768; 95% CI, 0.663-0.890). Notably, diabetes (adjusted OR = 0.477, 95% CI, 0.234-0.972) was an independent factor related to EDR of neurological function in BAD patients. In the subgroup analysis, a lower incidence of diabetes (adjusted OR = 0.205, 95% CI: 0.059-0.714, P = .013) and a lower NIHSS score after thrombolysis in patients with paramedian pontine infarction (adjusted OR = 0.809, 95% CI: 0.656-0.997, P = .047) were significantly associated with EDR. CONCLUSION: Diabetes is not conducive to EDR of neurological function in patients with BAD, especially in patients with paramedian pontine infraction. Low NIHSS score and short OTT after thrombolysis may be closely related to EDR after intravenous thrombolysis.

Efficient encapsulation of fat-soluble food-derived biofunctional substances (curcumin as an example) in dual-modified starch-based nanoparticles containing large conjugated systems.

Acid-ethanol hydrolysis and subsequent cinnamic acid (CA) esterification were employed to prepare a series of dual-modified starches efficiently loaded with curcumin (Cur) utilizing large conjugation systems provided by CA. Structures of the dual-modified starches were confirmed by IR and NMR, and their physicochemical properties were characterized by SEM, XRD and TGA. The nanoparticles fabricated from the dual-modified starch have perfect spherical shape (250.7-448.5 nm, polydispersity index <0.3), excellent biosafety (no hematotoxicity, no cytotoxicity, no mutagenicity) and high loading of Cur (up to 26.7 % loading). By XPS analysis, this high loading was believed to be supported by the synergistic effect of hydrogen bonding (provided by hydroxyl groups) and π-π interactions (provided by large conjugation system). In addition, the encapsulation of dual-modified starch nanoparticles effectively enhanced the water solubility (18-fold) and physical stability (6-8-fold) of free Cur. In vitro gastrointestinal release showed that Cur-encapsulated dual-modified starch nanoparticles were released more preferably than free Cur and that the Korsmeyer-Peppas model was the most suitable release model. These studies suggest that dual-modified starches containing large conjugation systems would be a better alternative for encapsulating fat-soluble food-derived biofunctional substances in functional food and pharmaceutical applications.

Isoliquiritigenin regulates microglial M1/M2 polarisation by mediating the P38/MAPK pathway in cerebral stroke.

OBJECTIVES: Regulation of microglia polarisation may be a new way to treat ischaemic stroke based on its effects on brain injury. Isoliquiritigenin (ILG) is a flavonoid with neuroprotective function. The study investigated whether ILG regulated microglial polarisation and affects brain injury. METHODS: Here, a transient middle cerebral artery occlusion (tMCAO) model in vivo and lipopolysaccharide (LPS)-induced BV2 cells in vitro were established. Brain damage was assessed using a 2,3,5-triphenyl-tetrazolium-chloride staining assay. Microglial polarisation was analysed using enzyme linked immunosorbent assay, quantitative real-time polymerase chain reaction, and immunofluorescence assay. The levels of p38/MAPK pathway-related factors were measured by western blot. KEY FINDINGS: ILG suppressed infarct volume and neurological function of tMCAO rats. Moreover, ILG facilitated M2 microglia polarisation and suppressed M1 polarisation in the tMCAO model and LPS-induced BV2 cells. Moreover, ILG reduced the phosphorylation of p38, MAPK activated protein kinase 2, and heat shock protein 27 induced by LPS. Rescue study showed that activating the p38/MAPK pathway reversed the microglia polarisation induced by ILG and inactivating the p38/MAPK pathway enchanced the microglia polarisation. CONCLUSION: ILG promoted microglia M2 polarisation by inactivating the p38/MAPK pathway, suggesting that ILG has the potential for the treatment of ischaemic stroke.

Roles of glutathione peroxidase 4 on the mercury-triggered ferroptosis in renal cells: implications for the antagonism between selenium and mercury.

Understanding of how mercury species cause cellular impairments at the molecular level is critical for explaining the detrimental effects of mercury exposure on the human body. Previous studies have reported that inorganic and organic mercury compounds can induce apoptosis and necrosis in a variety of cell types, but more recent advances reveal that mercuric mercury (Hg2+) and methylmercury (CH3Hg+) may result in ferroptosis, a distinct form of programmed cell death. However, it is still unclear which protein targets are responsible for ferroptosis induced by Hg2+ and CH3Hg+. In this study, human embryonic kidney 293T cells were used to investigate how Hg2+ and CH3Hg+ trigger ferroptosis, given their nephrotoxicity. Our results demonstrate that glutathione peroxidase 4 (GPx4) plays a key role in lipid peroxidation and ferroptosis in renal cells induced by Hg2+ and CH3Hg+. The expression of GPx4, the only lipid repair enzyme in mammal cells, was downregulated in response to Hg2+ and CH3Hg+ stress. More importantly, the activity of GPx4 could be markedly inhibited by CH3Hg+, owing to the direct binding of the selenol group (-SeH) in GPx4 to CH3Hg+. Selenite supplementation was demonstrated to enhance the expression and activity of GPx4 in renal cells, and consequently relieve the cytotoxicity of CH3Hg+, suggesting that GPx4 is a crucial modulator implicated in the Hg-Se antagonism. These findings highlight the importance of GPx4 in mercury-induced ferroptosis, and provide an alternative explanation for how Hg2+ and CH3Hg+ induce cell death.

Clinical Significance of NKD Inhibitor of WNT Signaling Pathway 1 (NKD1) in Glioblastoma.

Introduction: As the most malignant type of gliomas, glioblastoma is characterized with disappointing prognosis. Here, we aimed to investigate expression and function of NKD inhibitor of Wnt signaling pathway 1 (NKD1), an antagonist of Wnt-beta-catenin signaling pathways, in glioblastoma. Methods: The mRNA level of NKD1 was firstly retrieved from TCGA glioma dataset to evaluate its correlation with clinical characteristics and its value in prognosis prediction. Then, its protein expression level in glioblastoma was tested by immunohistochemistry staining in a retrospectively cohort collected from our medical center (n = 66). Univariate and multivariate survival analyses were conducted to assess its effect on glioma prognosis. Two glioblastoma cell lines, U87 and U251, were used to further investigate the tumor-related role of NKD1 through overexpression strategy in combination with cell proliferation assays. Immune cell enrichment in glioblastoma and its correlation with NKD1 level was finally assessed using bioinformatics analyses. Results: NKD1 shows a lower expression level in glioblastoma compared to that in the normal brain or other glioma subtypes, which is independently correlated to a worse prognosis in both the TCGA cohort and our retrospective cohort. Overexpressing NKD1 in glioblastoma cell lines can significantly attenuate cell proliferation. In addition, expression of NKD1 in glioblastoma is negatively correlated to the T cell infiltration, indicating it may have crosstalk with the tumor immune microenvironment. Conclusions: NKD1 inhibits glioblastoma progression and its downregulated expression indicates a poor prognosis.

Thorium(IV) triggers ferroptosis through disrupting iron homeostasis and heme metabolism in the liver following oral ingestion.

Thorium is a byproduct of the rare earth mining industry and can be utilized as fuel for the next-generation nuclear power facilities, which may pose health risks to the population. Although published literature has shown that the toxicity of thorium possibly originates from its interactions with iron/heme-containing proteins, the underlying mechanisms are still largely unclear. Since the liver plays an irreplaceable role in iron and heme metabolism in the body, it is essential to investigate how thorium affects iron and heme homeostasis in hepatocytes. In this study, we first assessed the liver injury in mice exposed to tetravalent thorium (Th(IV)) in the form of thorium nitrite via the oral route. After a two-week oral exposure, thorium accumulation and iron overload were observed in the liver, which are both closely associated with lipid peroxidation and cell death. Transcriptomics analysis revealed that ferroptosis, which has not previously been documented in cells for actinides, is the main mechanism of programmed cell death induced by Th(IV). Further mechanistic studies suggested that Th(IV) could activate the ferroptotic pathway through disrupting iron homeostasis and generating lipid peroxides. More significantly, the disorder of heme metabolism, which is crucial for maintaining intracellular iron and redox homeostasis, was found to contribute to ferroptosis in hepatocytes exposed to Th(IV). Our findings may shed light on a key mechanism of hepatoxicity in response to Th(IV) stress and provide in-depth understanding of the health risk of thorium.

NLRP3 Regulates Mandibular Healing through Interaction with UCHL5 in MSCs.

NLRP3 has been involved in several physiological and pathological processes. However, the role and mechanism of NLRP3 activation in mandibular healing remain unclear. Here, a full-thickness mandibular defect model by osteotomy was established in wild-type (WT) and Prx1-Cre/ROSAnTnG mice to demonstrate the NLRP3 inflammasome activation in mandibular healing. We found that NLRP3 was activated in mesenchymal stem cells (MSCs)-mediated mandibular healing and was prominent in Prx1+ cells. Inhibition of NLRP3 exerted a positive effect on bone formation without changing the number of Prx1-cre+ cells in the defect areas. In addition, NLRP3 deficiency promoted osteoblast differentiation. We next screened for the deubiquitinating enzymes that were previously reported to be associated with NLRP3, and identified UCHL5 as a regulator of NLRP3 activation in mandibular healing. Mechanistically, NLRP3 directly bound to UCHL5 and maintained its stability through reducing ubiquitin-proteasome pathway degradation in mandibular MSCs. At last, UCHL5 inhibition enhanced osteoblast differentiation by promoting NLRP3 ubiquitination and degradation. Thus, our results provided the proof that NLRP3 acted as a negative modulator in mandibular healing and extended the current knowledge regarding posttranslational modification of NLRP3 by UCHL5.

Association of genetic variants of CircCHST15 with oral squamous cell carcinoma in the Chinese Han population.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is the most common cancer in the oral cavity. The relationship between the genetic susceptibility of circCHST15 and OSCC remains unclear. METHODS: Genetic variants of circCHST15 were screened using a genotyping analysis from 1044 patients with OSCC and 3199 healthy participants. The circCHST15 expression was detected in 32 pairs of OSCC tissues. The circular RNA quantitative trait locus analysis and the reporter gene assay were performed for verification. RESULTS: The circCHST15 expression was upregulated in OSCC (Wilcoxon p < 1e-3). The genotyping analysis screened out 61 loci in circCHST15 associated with the risk of OSCC. After adjustment and annotation, rs28707473 (A > C, odds ratio = 1.21, 95% CI: 1.076-1.361, p = 1.453e-3) was selected. This genetic variation could elevate the circCHST15 expression level possibly by altering the structure of circular RNAs and affecting transcription factor binding. CONCLUSIONS: The results of this study suggested that genetic variants of circCHST15 may contribute to OSCC susceptibility.

hsa_circ_0000264 promotes tumor progression via the hsa-let-7b-5p/HMGA2 axis in head and neck squamous cell carcinoma.

OBJECTIVE: Circular RNAs (CircRNAs) are involved in various tumors. However, their role in head and neck squamous cell carcinoma (HNSCC) is unknown. CircRNA sequencing data showed that hsa_circ_0000264 is significantly upregulated in HNSCC tissues. In this study, we aimed to investigate the role of hsa_circ_0000264 in HNSCC and elucidate its underlying regulation mechanism. MATERIALS AND METHODS: RNase R treatment was performed to confirm the loop structure of hsa_circ_0000264. Fluorescence in situ hybridization was performed to show the subcellular localization of hsa_circ_0000264. We then performed wound healing assay, Transwell assay, Western blot, and in vivo experiments to determine the effect of alterations in hsa_circ_0000264 expression. We performed RNA pull-down and dual luciferase reporter assay to identify and confirm the binding sites in RNAs. RESULTS: hsa_circ_0000264 was upregulated in HNSCC tissues and cells, and its loop structure was confirmed. Knockdown of hsa_circ_0000264 inhibited the migration, invasion, and epithelial-to-mesenchymal transition of HNSCC cells in vivo and in vitro. Mechanistically, hsa_circ_000026 upregulation can upregulate the expression of high mobility group AT-hook 2 (HMGA2) by sponging hsa-let-7b-5p, which in turn promotes HNSCC progression. CONCLUSION: Our results showed that hsa_circ_0000264 promotes HNSCC progression via the hsa-let-7b-5p/HMGA2 axis, and hsa_circ_0000264 can serve as a potential target for HNSCC treatment.

Engineered Macrophages: A Safe-by-Design Approach for the Tumor Targeting Delivery of Sub-5 nm Gold Nanoparticles.

Ultrasmall nanoparticles (NPs) are a promising platform for the diagnosis and therapy of cancer, but the particles in sizes as small as several nanometers have an ability to translocate across biological barriers, which may bring unpredictable health risks. Therefore, it is essential to develop workable cell-based tools that can deliver ultrasmall NPs to the tumor in a safer manner. Here, this work uses macrophages as a shuttle to deliver sub-5 nm PEGylated gold (Au) NPs to tumors actively or passively, while reducing the accumulation of Au NPs in the brain. This work demonstrates that sub-5 nm Au NPs can be rapidly exocytosed from live macrophages, reaching 45.6% within 24 h, resulting in a labile Au NP-macrophage system that may release free Au NPs into the blood circulation in vivo. To overcome this shortcoming, two straightforward methods are used to engineer macrophages to obtain "half-dead" and "dead" macrophages. Although the efficiency of engineered macrophages for delivering sub-5 nm Au NPs to tumors is 2.2-3.8% lower than that of free Au NPs via the passive enhanced permeability and retention effect, this safe-by-design approach can dramatically reduce the accumulation of Au NPs in the brain by more than one order of magnitude. These promising approaches offer an opportunity to expand the immune cell- or stem cell-mediated delivery of ultrasmall NPs for the diagnosis and therapy of diseases in a safer way in the future.

A rescue diet raises the plasma calcium concentration and ameliorates rheumatoid arthritis in mice: Role of CaSR-mediated inhibition of osteoclastogenesis.

Calcium modulates bone cell recruitment, differentiation, and function by binding to the calcium-sensing receptor (CaSR). However, the function of CaSR induced by high extracellular calcium (Ca2+ e ) in the regulation of osteoclast formation in rheumatoid arthritis (RA) remains unknown. Here, we used TNFα-transgenic (TNFTG ) RA mice and their wildtype (WT) littermates fed a normal or a rescue diet (high calcium, high phosphorus, and high lactose diet, termed rescue diet) to compare their joint bone phenotypes. In comparison to TNFTG mice fed the normal diet, articular bone volume and cartilage area are increased, whereas inflamed area, eroded surface, TRAP+ surface, and osteoclast-related genes expression are decreased in TNFTG mice fed the rescue diet. Besides, TNFTG mice fed the rescue diet were found to exhibit more CaSR+ area and less NFATc1+ /TRAP+ area. Furthermore, at normal Ca2+ e concentrations, osteoclast precursors (OCPs) from TNFTG mice formed more osteoclasts than OCPs from WT mice, but the number of osteoclasts gradually decreased when the Ca2+ e concentration increased. Meanwhile, the expression of CaSR increased responding to a high level of Ca2+ e , whereas the expression of NF-κB/NFATc1 signaling molecules decreased. At last, the knockdown of CaSR blocked the inhibition of osteoclast differentiation attributed to high Ca2+ e . Taken together, our findings indicate that high Ca2+ e inhibits osteoclast differentiation in RA mice partially through the CaSR/NF-κB/NFATc1 pathway.

High-Throughput Absolute Quantification Sequencing Reveals that a Combination of Leguminous Shrubs Is Effective in Driving Soil Bacterial Diversity During the Process of Desertification Reversal.

Desertification leads to the extreme fragility of ecosystems and seriously threatens ecosystem functioning in desert areas. The planting of xerophytes, especially leguminous shrubs, is an effective and common means to reverse desertification. Soil microorganisms play a crucial role in nutrient cycling and energy flow in ecosystems. However, the effects of introducing leguminous shrubs on soil microbial diversity and the relevant mechanisms are not clear. Here, we employed the high-throughput absolute quantification 16S rRNA sequencing method to analyze the diversity of soil bacteria in sand-fixing areas of mixed shrublands with three combinations of shrubs, i.e., C. korshinskii × Corethrodendron scoparium (CaKCoS), C. korshinskii × Calligonum mongolicum (CaKCaM), and C. scoparium × C. mongolicum (CoSCaM), in the south of the Mu Us Sandy Land, China. This area suffered from moving dunes 20 years ago, but after introducing these shrubs to fix the dunes, the ecosystem was restored. Additionally, the effects of soil physicochemical properties on soil bacterial composition and diversity were analyzed with redundancy analysis (RDA) and structural equation modeling (SEM). It was found that the Shannon index of soil bacteria in CaKCoS was significantly higher than that in CaKCaM and CoSCaM, and the abundance of the dominant phyla, including Actinobacteria, Proteobacteria, Acidobacteria, Chloroflexi, Planctomycetes, Thaumarchaeota, Armatimonadetes, candidate_division_WPS-1, and Nitrospirae, increased significantly in CaKCoS and CaKCaM compared to that in CoSCaM. RDA showed that the majority of soil properties, such as total nitrogen (TN), available potassium (AK), N:P ratio, soil moisture (SM), and available phosphorus (AP), were important soil environmental factors affecting the abundance of the dominant phyla, and RDA1 and RDA2 accounted for 56.66% and 2.35% of the total variation, respectively. SEM showed that the soil bacterial α-diversity was positively affected by the soil organic carbon (SOC), N:P ratio, and total phosphorus (TP). Moreover, CaKCoS had higher SM, total carbon (TC), total potassium (TK), and AP than CaKCaM and CoSCaM. Collectively, these results highlight a conceptual framework in which the combination of leguminous shrubs can effectively drive soil bacterial diversity by improving soil physicochemical properties and maintaining ecosystem functioning during desertification reversal.

Dual-modified starch nanoparticles containing aromatic systems with highly efficient encapsulation of curcumin and their antibacterial applications.

A series of cinnamic acid (CA)-esterified debranched starch (CDS) containing aromatic systems were prepared and successfully fabricated as nanoparticles to encapsulate curcumin by taking advantage of the additional π-π interactions provided from CA. The CDS nanoparticles (CDS NPs) have good dispersion (polydispersity index of 0.124-0.314) and sizes range of 130-330 nm. The excellent biosafety of CDS NPs was demonstrated by hemolysis, cytotoxicity and mutagenicity assays. Efficient encapsulation (LC = 26.86 %) and sustained release of curcumin were achieved, and the curcumin-encapsulated CDS NPs (CDS-Cur NPs) increased 266-fold water solubility and 2.3-6.5-fold photothermal stability for curcumin, compared to free curcumin. Functional studies showed that CDS-Cur NPs exhibited superior biofilm scavenging ability, with a 2-4.3-fold improvement compared to free curcumin. In addition, CDS-Cur NPs also exhibited far superior antibacterial effects than free curcumin in a bacteriostatic food model of chicken breast. This study not only provides a new scheme for the efficient loading of curcumin, but also provides new ideas for the usage of starch-based materials in antibacterial applications.