Uptake, translocation, accumulation, and metabolism of fluroxypyr-meptyl and oxidative stress induction in rice seedling.

Fluroxypyr-meptyl (FLUME) is heterocyclic herbicide with internal absorption and transmission characteristics. Owing to its low cost and rapid efficacy, it has been widely used to control broad-leaved weeds in wheat, corn, and rice fields. However, the uptake, translocation, accumulation, and metabolism of FLUME in rice seedlings and the extent of oxidative stress induced by it remain largely unknown, which consequently restricts the comprehensive risk assessment of FLUME residues in the environment during rice production. Hence, we systematically investigated the growth and physiological responses of rice to FLUME and analyzed its uptake, translocation, accumulation, and metabolism in rice seedlings. The results indicated that under 0-0.12 mg/L FLUME treatment, only a small proportion of FLUME was translocated upward and accumulated in rice shoots following absorption via roots, with all the translocation factor values being < 1. Moreover, the distribution and enrichment ability of FLUME in rice seedlings were greater in roots than in shoots. Furthermore, we revealed that FLUME accumulation in rice seedlings evidently inhibited their growth and activated the defense system against oxidative stress, with an increase in the activity of antioxidant and detoxifying enzymes. In addition, multiple metabolic reactions of FLUME were observed in rice seedlings, including dehalogenation, hydroxylation, glycosylation, acetylation, and malonylation. Our study provides systematic insights into the uptake, translocation, accumulation, and metabolism of FLUME in rice seedlings as well as the oxidative stress induced by FLUME accumulation, which can help improve FLUME applications and environmental risk assessments in crops.

Nacre-mimetic cerium-doped nano-hydroxyapatite/chitosan layered composite scaffolds regulate bone regeneration via OPG/RANKL signaling pathway.

Autogenous bone grafting has long been considered the gold standard for treating critical bone defects. However, its use is plagued by numerous drawbacks, such as limited supply, donor site morbidity, and restricted use for giant-sized defects. For this reason, there is an increasing need for effective bone substitutes to treat these defects. Mollusk nacre is a natural structure with outstanding mechanical property due to its notable "brick-and-mortar" architecture. Inspired by the nacre architecture, our team designed and fabricated a nacre-mimetic cerium-doped layered nano-hydroxyapatite/chitosan layered composite scaffold (CeHA/CS). Hydroxyapatite can provide a certain strength to the material like a brick. And as a polymer material, chitosan can slow down the force when the material is impacted, like an adhesive. As seen in natural nacre, the combination of these inorganic and organic components results in remarkable tensile strength and fracture toughness. Cerium ions have been demonstrated exceptional anti-osteoclastogenesis capabilities. Our scaffold featured a distinct layered HA/CS composite structure with intervals ranging from 50 to 200 µm, which provided a conducive environment for human bone marrow mesenchymal stem cell (hBMSC) adhesion and proliferation, allowing for in situ growth of newly formed bone tissue. In vitro, Western-blot and qPCR analyses showed that the CeHA/CS layered composite scaffolds significantly promoted the osteogenic process by upregulating the expressions of osteogenic-related genes such as RUNX2, OCN, and COL1, while inhibiting osteoclast differentiation, as indicated by reduced TRAP-positive osteoclasts and decreased bone resorption. In vivo, calvarial defects in rats demonstrated that the layered CeHA/CS scaffolds significantly accelerated bone regeneration at the defect site, and immunofluorescence indicated a lowered RANKL/OPG ratio. Overall, our results demonstrate that CeHA/CS scaffolds offer a promising platform for bone regeneration in critical defect management, as they promote osteogenesis and inhibit osteoclast activation.

Impact of a novel prognostic model on allogeneic hematopoietic stem cell transplantation outcomes in patients with CMML.

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell malignancy, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curable treatment. The outcomes after transplant are influenced by both disease characteristics and patient comorbidities. To develop a novel prognostic model to predict the post-transplant survival of CMML patients, we identified risk factors by applying univariable and multivariable Cox proportional hazards regression to a derivation cohort. In multivariable analysis, advanced age (hazard ratio [HR] 3.583), leukocyte count (HR 3.499), anemia (HR 3.439), bone marrow blast cell count (HR 2.095), and no chronic graft versus host disease (cGVHD; HR 4.799) were independently associated with worse survival. A novel prognostic model termed ABLAG (Age, Blast, Leukocyte, Anemia, cGVHD) was developed and the points were assigned according to the regression equation. The patients were categorized into low risk (0-1), intermediate risk (2, 3), and high risk (4-6) three groups and the 3-year overall survival (OS) were 93.3% (95%CI, 61%-99%), 78.9% (95%CI, 60%-90%), and 51.6% (95%CI, 32%-68%; p < .001), respectively. In internal and external validation cohort, the area under the receiver operating characteristic (ROC) curves of the ABLAG model were 0.829 (95% CI, 0.776-0.902) and 0.749 (95% CI, 0.684-0.854). Compared with existing models designed for the nontransplant setting, calibration plots, and decision curve analysis showed that the ABLAG model revealed a high consistency between predicted and observed outcomes and patients could benefit from this model. In conclusion, combining disease and patient characteristic, the ABLAG model provides better survival stratification for CMML patients receiving allo-HSCT.

Abnormal activation of brain regions in idiopathic trigeminal neuralgia patients by fMRI: An activation likelihood estimation meta-analysis.

BACKGROUND: Idiopathic trigeminal neuralgia (ITN) is one of the most common types of neuropathic pain, severely affecting the physiological and psychological wellbeing of patients. Recently, fMRI has been used to examine abnormal activation of brain regions in patients with ITN. However, sample sizes have been small in these few studies, and the abnormally activated brain regions remain unclear. Therefore, in the present study, we retrieved and analyzed literature on the brain areas with abnormal or reduced activation in ITN patients, with the aim of providing insight into the neuropathological basis of the disease and to provide new targets for treatment. METHODS: We retrieved resting state fMRI studies on trigeminal neuralgia patients from PubMed, the Web of Science and Scopus databases until November 2022, and we extracted the coordinates of the sites with increased or decreased activation. We used activation likelihood estimation (ALE) meta-analysis to identify regions of abnormal activation in ITN patients. RESULTS: ALE meta-analysis revealed that the left caudate nucleus and right anterior ventral nucleus of the thalamus are abnormally hyperactivated in ITN patients. Moreover, ITN patients showed reduced activation in the left precuneus, middle temporal gyrus, lingual gyrus, and medial frontal gyrus. CONCLUSION: ALE meta-analysis identified several brain regions with abnormally high or decreased activation in ITN patients. Sites with altered activation may be potential targets for non-invasive brain stimulation as adjunct therapy for ITN.

Measurable residual disease detected by flow cytometry independently predicts prognoses of NPM1-mutated acute myeloid leukemia.

Acute myeloid leukemia (AML) with NPM1 mutation is a distinct genetic entity with favorable outcomes. Nevertheless, emerging evidence suggests that NPM1-mutated AML is still a highly heterogeneous disorder. In this study, 266 patients with AML with NPM1 mutations were retrospectively analyzed to evaluate the associations between variant allele frequency (VAF) of NPM1 mutations, co-mutated genes, measurable residual disease (MRD), and patient outcomes. Multiparameter flow cytometry (MFC) and real-time quantitative polymerase chain reaction (RT-PCR) were used for monitoring MRD. Ultimately, 106 patients were included in the long-term follow-up period. Patients with high NPM1 VAF (≥ 42.43%) had poorer 2-year relapse-free survival (RFS) (55.7% vs. 70.2%, P = 0.017) and overall survival (OS) (63.7% vs. 82.0%, P = 0.027) than those with low VAF. DNMT3A mutations negatively influenced the outcomes of patients with NPM1 mutations. Patients with high DNMT3A VAF or NPM1/DNMT3A/FLT3-ITD triple mutations had shorter RFS and significantly lower OS than that in controls. After two cycles of chemotherapy, patients with positive MFC MRD results had lower RFS (MRD+ vs. MRD-:44.9% vs. 67.6%, P = 0.007) and OS (61.5% vs. 76.6%, P = 0.011) than those without positive MFC MRD results. In multivariate analysis, high NPM1 VAF (hazard ratio [HR] = 2.045; P = 0.034) and positive MRD after two cycles of chemotherapy (HR = 3.289; P = 0.003) were independent risk factors for RFS; MRD positivity after two cycles of chemotherapy (HR = 3.293; P = 0.008) independently predicted the OS of the patients. These results indicate that VAF of both NPM1 gene itself or certain co-occurring gene pre-treatment and MRD post-treatment are potential markers for restratifying the prognoses of patients AML having NPM1 mutations.

Current and emerging molecular and epigenetic disease entities in acute myeloid leukemia and a critical assessment of their therapeutic modalities.

Acute myeloid leukemia (AML) is the most frequently diagnosed acute leukemia, and its incidence increases with age. Although the etiology of AML remains unknown, exposure to genotoxic agents or some prior hematologic disorders could lead to the development of this condition. The pathogenesis of AML involves the development of malignant transformation of hematopoietic stem cells that undergo successive genomic alterations, ultimately giving rise to a full-blown disease. From the disease biology perspective, AML is considered to be extremely complex with significant genetic, epigenetic, and phenotypic variations. Molecular and cytogenetic alterations in AML include mutations in those subsets of genes that are involved in normal cell proliferation, maturation and survival, thus posing significant challenge to targeting these pathways without attendant toxicity. In addition, multiple malignant cells co-exist in the majority of AML patients. Individual subclones are characterized by unique genetic and epigenetic abnormalities, which contribute to the differences in their response to treatment. As a result, despite a dramatic progress in our understanding of the pathobiology of AML, not much has changed in therapeutic approaches to treat AML in the past four decades. Dose and regimen modifications with improved supportive care have contributed to improved outcomes by reducing toxicity-related side effects. Several drug candidates are currently being developed, including targeted small-molecule inhibitors, cytotoxic chemotherapies, monoclonal antibodies and epigenetic drugs. This review summarizes the current state of affairs in the pathobiological and therapeutic aspects of AML.

Anlotinib-Induced Hypertension: Current Concepts and Future Prospects.

BACKGROUND: Anlotinib is a new tyrosine kinase inhibitor developed in China that targets the receptors for vascular endothelial growth factor, platelet-derived growth factor, fibroblast growth factor, and stem cell factor. Therefore, anlotinib inhibits tumor angiogenesis, representing a new therapeutic alternative for lung cancer. Hypertension is one of its most common adverse effects, leading to discontinuation of the drug and limited clinical usefulness. OBJECTIVE: The present review aims to summarize the evidence on the prevalence, physiopathology, and management of anlotinib-induced hypertension, as well as its effect on the cancer prognosis. METHODS: Searches in Medline, Cochrane Central Library, and Embase were performed using the following terms: anlotinib, adverse effect, hypertension, clinical trial, vascular endothelial growth factor, and anti-angiogenic drugs. Citations were also identified by checking the reference sections of selected papers. RESULTS: Except for a phase I clinical trial with a small sample size (n = 6), almost all the clinical trials on anlotinib have reported the development of anlotinib-induced hypertension. In these trials, the incidence of hypertension ranged from 13% to 67.7%, and that of grade 3/4 hypertension ranged from 4.8% to 16%. Alterations in nitric oxide, endothelin-1, microvascular rarefaction, selective vasoconstrictions, and renal injury have been cited as potential mechanisms leading to anlotinib-induced hypertension. When needed, treatment may include general hygienic measures and pharmacotherapy in some cases. CONCLUSION: To effectively manage anlotinib-induced hypertension, early prevention, a reasonable dosage regimen, and appropriate treatment are critical to effectively manage anlotinib-induced hypertension. Additionally, anlotinib-induced hypertension may be considered a marker for predicting efficacy.

Comparison of 3D Printing Rapid Prototyping Technology with Traditional Radiographs in Evaluating Acetabular Defects in Revision Hip Arthroplasty: A Prospective and Consecutive Study.

OBJECTIVE: To compare rapid prototyping technology (RP tech) in revision total hip arthroplasty (RTHA) with traditional examination methods and to see how they are different in evaluating acetabular anatomy and designing surgical procedure. METHODS: From February 2014 to March 2018, 43 RTHA patients with complex acetabulum defects were enrolled in this prospective study regardless of age or gender. Incomplete and unclear data were excluded. Three types of radiographic examination were performed on each patient before the revision surgery. Four groups of evaluations were designed: (i) X-ray; (ii) computed tomography (CT-scan); (iii) RP tech; and (iv) CT-aided RP tech. Discrepancies between preoperative radiographic analysis and intra-operative findings were separately compared by a team of surgeons. Premade surgical plans based on each evaluation method were compared with the final surgical procedure. The compliance of anatomic evaluation and surgical plan-design based on 3D RP tech and traditional radiographs were ranked manually by a of team surgeons into: (i) complete accordance; (ii) general accordance; and (iii) undetermined structure/procedure. The difference in ranks between RP tech and traditional radiographic methods were analyzed with a nonparametric Kruskal-Wallis test. P < 0.05 was considered significant. Multiple adjustments were taken for the statistical tests level according to the Bonferroni method. RESULTS: For anatomic analysis, the accordance in four groups of evaluating methods differed from each other (P < 0.05) except for the comparison of RP tech and CT-aided RP tech. RP tech displayed better anatomic evaluating accuracy than traditional methods (X-ray and CT) with the "complete accordance" rates of these groups being 88.37%, 4.65% and 27.91%, respectively. But CT-aided RP tech did not improve accuracy significantly compared with using RP tech individually, although the value seems high in the CT-aided RP group with the "complete accordance" rate of 95.35%. For surgery design, RP tech significantly showed better applicable surgical design compared with X-ray and CT (P < 0.05), and the "complete accordance" rates were 88.37%, 6.98% and 23.26%, but no significant difference was observed between RP tech and CT-aided RP tech, and the "complete accordance" rate of CT-aided RP tech group was 97.67%. RP tech showed remarkable improvement in bone defect assessment and surgical plan design. CONCLUSION: Using RP technology improved both sensibility and accuracy in acetabular defect evaluation with better locating and evaluating efficiency compared with X-ray and CT-scans. It also improved surgical schedule designing in complex acetabular defecting revision surgery. In particularly complex cases, CT aided RP tech may increase the accuracy of RP tech.

Can kissing cause paraquat poisoning: A case report and review of literature.

BACKGROUND: Paraquat is an effective, broad-spectrum, highly toxic quaternary ammonium herbicide. Paraquat poisoning has been reported frequently in recent years. It has severe lung, kidney, liver, and nervous system toxicity, and there is currently no specific antidote. Paraquat poisoning may follow ingestion, inhalation, and skin contact. There have been no previous reports of paraquat poisoning that resulted from kissing. This rare case provides a new reference for the prevention of paraquat poisoning. CASE SUMMARY: A 27-year-old man came to the emergency department complaining that he had come into contact with paraquat by kissing his girlfriend, who had taken 80-120 mL 20% paraquat. After admission, his lung computed tomography (CT) showed increased lung markings. Redness and a burning sensation developed on his tongue, which progressed to painful erosions and coalescent ulcers. The final diagnosis was mild paraquat poisoning. Anti-inflammatory, antioxidant, and symptomatic treatment were initiated and continued for 7 d. Dyspnea did not occur, subsequent lung CT showed no significant changes, and the tongue pain was slightly improved. One month after discharge, the tongue injury was resolved. CONCLUSION: This case indicated that the tongue and lung tissues are particularly vulnerable to paraquat toxicity, even after a limited exposure.

OX40 as a novel target for the reversal of immune escape in colorectal cancer.

First-generation immunological checkpoint inhibitors, such as CTLA-4, PD-L1 and PD-1 exhibit significant advantages over conventional cytotoxic drugs, such as oxaliplatin and 5-FU, for the treatment of colorectal cancer. However, these inhibitors are not ideal due to their low objective response rate and the vulnerability of these treatment methods when faced with emerging drug resistant cancers. This study summarizes the immunological characteristics of colorectal cancer treatment, and analyzes the ways in which OX40 may improve the efficacy of these treatments. Activation of the OX40 signaling pathway can enhance the activity of CD4+/CD8+ T cells and inhibit the function of Treg. Simultaneously, OX40 can directly inhibit the expression of Foxp3, affect the inhibitory function of Treg, and inhibit the immunosuppressive factors in the tumor microenvironment so as to reverse immune escape and reverse drug resistance. Therefore, OX40 is an important target for treating colorectal cancer in "cold tumors" with less immunogenicity.

Graphene-modified CePO4 nanorods effectively treat breast cancer-induced bone metastases and regulate macrophage polarization to improve osteo-inductive ability.

BACKGROUND: Breast cancer bone metastasis has become one of the most common complications; however, it may cause cancer recurrence and bone nonunion, as well as local bone defects. METHODS: Herein, In vitro, we verified the effect of bioscaffold materials on cell proliferation and apoptosis through a CCK8 trial, staining of live/dead cells, and flow cytometry. We used immunofluorescence technology and flow cytometry to verify whether bioscaffold materials regulate macrophage polarization, and we used ALP staining, alizarin red staining and PCR to verify whether bioscaffold material promotes bone regeneration. In vivo, we once again studied the effect of bioscaffold materials on tumors by measuring tumor volume in mice, Tunel staining, and caspase-3 immunofluorescence. We also constructed a mouse skull ultimate defect model to verify the effect on bone regeneration. RESULTS: Graphene oxide (GO) nanoparticles, hydrated CePO4 nanorods and bioactive chitosan (CS) are combined to form a bioactive multifunctional CePO4/CS/GO scaffold, with characteristics such as photothermal therapy to kill tumors, macrophage polarization to promote blood vessel formation, and induction of bone formation. CePO4/CS/GO scaffold activates the caspase-3 proteasein local tumor cells, thereby lysing the DNA between nucleosomes and causing apoptosis. On the one hand, the as-released Ce3+ ions promote M2 polarization of macrophages, which secretes vascular endothelial growth factor (VEGF) and Arginase-1 (Arg-1), which promotes angiogenesis. On the other hand, the as-released Ce3+ ions also activated the BMP-2/Smad signaling pathway which facilitated bone tissue regeneration. CONCLUSION: The multifunctional CePO4/CS/GO scaffolds may become a promising platform for therapy of breast cancer bone metastases.

Folic acid and RAAS blockers in ischemia/reperfusion-induced hepatic injury: A current mechanistic concept for understanding the incidence, significance & outcome.

Hepatic ischemia-reperfusion injury (IRI) is not only one of the pathophysiological process involving the liver, but also a complex systemic process affecting multiple tissues and organs. IRI after liver transplant occurs due to in major resections and occlusion of vessels, or during the perioperative period, leads to acute liver failure which shows the dynamic process that involves two interrelated phases of local ischemic insult and inflammation-mediated reperfusion injury and has an impact on morbidity and mortality. The renin-angiotensin-aldosterone system (RAAS) is activated locally in the injured cells by the occurrence of I/R, which plays an essential role in the fate of the damaged tissue. However, a preclinical study explores the protective role of RAAS inhibitor in acute liver injury in a model of inflammation caused by ischemia and reperfusion. In-addition to RAAS blockers in monotherapy does not effectively block the complete pathway. Thus, the present study is designed to explore the effect of combined folic acid with RAAS blockers in combination, produce a synergistic effect. Moreover, in this review, we will describe the understanding of the possible incidence of downregulatory molecular mechanisms associated with renin-angiotensin-aldosterone system and the significance & outcome of the combination of folic acid and RAAS blockers in liver injury due to ischemia/reperfusion.

The Recombinant Protein EphB4-Fc Changes the Ti Particle-Mediated Imbalance of OPG/RANKL via EphrinB2/EphB4 Signaling Pathway and Inhibits the Release of Proinflammatory Factors In Vivo.

Aseptic loosening caused by wear particles is one of the common complications after total hip arthroplasty. We investigated the effect of the recombinant protein ephB4-Fc (erythropoietin-producing human hepatocellular receptor 4) on wear particle-mediated inflammatory response. In vitro, ephrinB2 expression was analyzed using siRNA-NFATc1 (nuclear factor of activated T-cells 1) and siRNA-c-Fos. Additionally, we used Tartrate-resistant acid phosphatase (TRAP) staining, bone pit resorption, Enzyme-linked immunosorbent assay (ELISA), as well as ephrinB2 overexpression and knockdown experiments to verify the effect of ephB4-Fc on osteoclast differentiation and function. In vivo, a mouse skull model was constructed to test whether the ephB4-Fc inhibits osteolysis and inhibits inflammation by micro-CT, H&E staining, immunohistochemistry, and immunofluorescence. The gene expression of ephrinB2 was regulated by c-Fos/NFATc1. Titanium wear particles activated this signaling pathway to the promoted expression of the ephrinB2 gene. However, ephrinB2 protein can be activated by osteoblast membrane receptor ephB4 to inhibit osteoclast differentiation. In in vivo experiments, we found that ephB4 could regulate Ti particle-mediated imbalance of OPG/RANKL, and the most important finding was that ephB4 relieved the release of proinflammatory factors. The ephB4-Fc inhibits wear particle-mediated osteolysis and inflammatory response through the ephrinB2/EphB4 bidirectional signaling pathway, and ephrinB2 ligand is expected to become a new clinical drug therapeutic target.

Protective Effects and Mechanisms of Action of Ulinastatin against Cerebral Ischemia-Reperfusion Injury.

BACKGROUND: Cerebral ischemia-reperfusion injury is an extremely complicated pathological process that is clinically characterized by high rates of disability and mortality. It is imperative to explore some effective neuroprotective agents for its treatment. Ulinastatin is a protease inhibitor with anti-inflammatory and antioxidant activity. For the past few years, new studies of ulinastatin for the treatment of ischemic brain injury have emerged. OBJECTIVE: We conducted a review to summarize the mechanisms of ulinastatin and analyze its neuroprotective action against cerebral ischemia-reperfusion injury. METHODS: We reviewed and summarized pertinent reports published between 1993 and 2019 from PubMed, Web of Science, and Embaseby searching for the scientific terms ulinastatin, cerebral ischemia-reperfusion injury, neuroprotective, stroke, cardiac arrest, and brain edema. RESULTS: The protective mechanisms of ulinastatin in the key steps of cerebral ischemia-reperfusion injury include inhibition of inflammatory response, oxidative stress, neuronal apoptosis, neuronal autophagy, and aquaporin- 4 expression as well as improvement in blood-brain barrier permeability. In addition, we provide a perspective on potential research directions and clinical safety. CONCLUSION: Ulinastatin seems to have the potential to alleviate cerebral ischemia-reperfusion injury. These findings may be valuable to further promote the research and development of drug candidates and provide novel and reliable references for rational drug use.

Quercetin inhibits macrophage polarization through the p-38α/ß signalling pathway and regulates OPG/RANKL balance in a mouse skull model.

Aseptic loosening caused by wear particles is a common complication after total hip arthroplasty. We investigated the effect of the quercetin on wear particle-mediated macrophage polarization, inflammatory response and osteolysis. In vitro, we verified that Ti particles promoted the differentiation of RAW264.7 cells into M1 macrophages through p-38α/ß signalling pathway by using flow cytometry, immunofluorescence assay and small interfering p-38α/ß RNA. We used enzyme-linked immunosorbent assays to confirm that the protein expression of M1 macrophages increased in the presence of Ti particles and that these pro-inflammatory factors further regulated the imbalance of OPG/RANKL and promoted the differentiation of osteoclasts. However, this could be suppressed, and the protein expression of M2 macrophages was increased by the presence of the quercetin. In vivo, we revealed similar results in the mouse skull by µ-CT, H&E staining, immunohistochemistry and immunofluorescence assay. We obtained samples from patients with osteolytic tissue. Immunofluorescence analysis indicated that most of the macrophages surrounding the wear particles were M1 macrophages and that pro-inflammatory factors were released. Titanium particle-mediated M1 macrophage polarization, which caused the release of pro-inflammatory factors through the p-38α/ß signalling pathway, regulated OPG/RANKL balance. Macrophage polarization is expected to become a new clinical drug therapeutic target.