Histone demethylase KDM4A mediating macrophage polarization: A potential mechanism of trichloroethylene induced liver injury.

Trichloroethylene (TCE) is a commonly used organic solvent in industry. Our previous studies have found that TCE can cause liver injury accompanied by macrophage polarization, but the specific mechanism is unclear. The epigenetic regulation of macrophage polarization is mainly focused on histone modification. Histone lysine demethylase 4A (KDM4A) is involved in the activation of macrophages. In this study, we used a mouse model we investigated the role of KDM4A in the livers of TCE-drinking mice and found that the expression of KDM4A, M1-type polarization indicators, and related inflammatory factors in the livers of TCE-drinking mice. In the study, BALB/c mice were randomly divided into four groups: 2.5 mg/mL TCE dose group and 5.0 mg/mL TCE dose group, the vehicle control group, and the blank control group. We found that TCE triggered M1 polarization of mouse macrophages, characterized by the expression of CD11c and robust production of inflammatory cytokines. Notably, exposure to TCE resulted in markedly increased expression of KDM4A in macrophages. Functionally, the increased expression of KDM4A significantly impaired the expression of H3K9me3 and H3K9me2 and increased the expression of H3K9me1. In addition, KDM4A potentially represents a novel epigenetic modulator, with its upregulation connected to ß-catenin activation, a signal critical for the pro-inflammatory activation of macrophages. Furthermore, KDM4A inhibitor JIB-04 treatment resulted in a decrease in ß-catenin expression and prevented TCE-induced M1 polarization and the expression of the pro-inflammatory cytokines TNF-α and IL-1ß. These results suggest that the association of KDM4A and Wnt/ß-catenin cooperatively establishes the activation and polarization of macrophages and global changes in H3K9me3/me2/me1. Our findings identify KDM4A as an essential regulator of the polarization of macrophages and the expression of inflammatory cytokines, which might serve as a potential target for preventing and treating liver injury caused by TCE.

Mitochondrial GPX4 acetylation is involved in cadmium-induced renal cell ferroptosis.

Increasing evidences demonstrate that environmental stressors are important inducers of acute kidney injury (AKI). This study aimed to investigate the impact of exposure to Cd, an environmental stressor, on renal cell ferroptosis. Transcriptomics analyses showed that arachidonic acid (ARA) metabolic pathway was disrupted in Cd-exposed mouse kidneys. Targeted metabolomics showed that renal oxidized ARA metabolites were increased in Cd-exposed mice. Renal 4-HNE, MDA, and ACSL4, were upregulated in Cd-exposed mouse kidneys. Consistent with animal experiments, the in vitro experiments showed that mitochondrial oxidized lipids were elevated in Cd-exposed HK-2 cells. Ultrastructure showed mitochondrial membrane rupture in Cd-exposed mouse kidneys. Mitochondrial cristae were accordingly reduced in Cd-exposed mouse kidneys. Mitochondrial SIRT3, an NAD+-dependent deacetylase that regulates mitochondrial protein stability, was reduced in Cd-exposed mouse kidneys. Subsequently, mitochondrial GPX4 acetylation was elevated and mitochondrial GPX4 protein was reduced in Cd-exposed mouse kidneys. Interestingly, Cd-induced mitochondrial GPX4 acetylation and renal cell ferroptosis were exacerbated in Sirt3-/- mice. Conversely, Cd-induced mitochondrial oxidized lipids were attenuated in nicotinamide mononucleotide (NMN)-pretreated HK-2 cells. Moreover, Cd-evoked mitochondrial GPX4 acetylation and renal cell ferroptosis were alleviated in NMN-pretreated mouse kidneys. These results suggest that mitochondrial GPX4 acetylation, probably caused by SIRT3 downregulation, is involved in Cd-evoked renal cell ferroptosis.

The role of PANoptosis in renal vascular endothelial cells: Implications for trichloroethylene-induced kidney injury.

Trichloroethylene (TCE), a widely distributed environmental chemical contaminant, is extensively dispersed throughout the environment. Individuals who are exposed to TCE may manifest occupational medicamentose-like dermatitis due to trichloroethylene (OMDT). Renal impairment typically manifests in the initial phase of OMDT and is intricately linked to the disease progression and patient outcomes. Although recombinant human tumor necrosis factor-α receptor II fusion protein (rh TNFR:Fc) has been employed in the clinical management of OMDT, there was no substantial improvement in renal function observed in patients following one week of treatment. This study primarily examined the mechanism of TNFα- and IFNγ-induced endothelial cells (ECs) PANoptosis in TCE-induced kidney injury and hypothesized that the synergistic effect of TNFα and IFNγ could be the key factor affecting the efficacy of rh TNFR:Fc therapy in OMDT patients. A TCE-sensitized mouse model was utilized in this study to investigate the effects of TNFα and IFNγ neutralizing antibodies on renal vascular endothelial cell PANoptosis. The gene of interferon regulatory factor 1 (IRF1) in human umbilical vein endothelial cells (HUVEC) was silenced by using small interfering RNA (siRNA), and the cells were then treated with TNFα and IFNγ recombinant protein to investigate the mechanism of TNFα combined with IFNγ-induced PANoptosis in HUVEC. The findings indicated that mice sensitized to TCE exhibited increased levels of PANoptosis-related markers in renal endothelial cells, and treatment with TNFα and IFNγ neutralizing antibodies resulted in a significant reduction in PANoptosis and improvement in renal function. In vitro experiments demonstrated that silencing IRF1 could reverse TNFα and IFNγ-induced PANoptosis in endothelial cells. These results suggest that the efficacy of rh TNFR:Fc may be influenced by TNFα and IFNγ-mediated PANoptosis in kidney vascular endothelial cells. The joint application of TNFα and IFNγ neutralizing antibody represented a solid alternative to existing therapeutics.

C5b-9 promotes ferritinophagy leading to ferroptosis in renal tubular epithelial cells of trichloroethylene-sensitized mice.

Trichloroethylene (TCE) is a common environmental contaminant that can cause a severe allergic reaction called TCE hypersensitivity syndrome, which often implicates the patient's kidneys. Our previous study revealed that C5b-9-induced tubular ferroptosis is involved in TCE-caused kidney damage. However, the study did not explain how tubule-specific C5b-9 causes free iron overload, a key event in ferroptosis. Here, we aimed to explore the role of NCOA4-mediated ferritinophagy in C5b-9-induced iron overload and ferroptosis in TCE-sensitized mice. Our results showed that TCE sensitization does not affect iron import or export, but does affect iron storage, causing ferritin degradation and free iron overload. In addition, mitochondrial ROS was upregulated, and these changes were blocked by C5b-9 inhibition. Interestingly, TCE-induced ferritin degradation and ferroptosis were significantly antagonized by the application of the mitochondrial ROS inhibitor, Mito-TEMPO. Moreover, all of these modes of action were further verified in C5b-9-attack signalling HK-2 cells. Further investigation demonstrated that C5b-9-upregulated mitochondrial ROS induced a marked increase in nuclear receptor coactivator 4 (NCOA4), a master regulator of ferritinophagy. In addition, the application of NCOA4 small interfering RNA not only significantly reversed ferritinophagy caused by C5b-9 but also reduced C5b-9-induced ferroptosis in HK-2 cells. Taken together, these results suggest that tubule-specific C5b-9 deposition activates NCOA4 through the upregulation of mitochondrial ROS, causing ferritin degradation and elevated free iron, which ultimately leads to tubular epithelial cell ferroptosis and kidney injury in TCE-sensitized mice.

Neuroprotective effects of cordycepin inhibit glutamate-induced apoptosis in hippocampal neurons.

Glutamate is a neurotransmitter that can cause excitatory neurotoxicity when its extracellular concentration is too high, leading to disrupted calcium balance and increased production of reactive oxygen species (ROS). Cordycepin, a nucleoside adenosine derivative, has been shown to protect against excitatory neurotoxicity induced by glutamate. To investigate its potential neuroprotective effects, the present study employed fluorescence detection and spectrophotometry techniques to analyze primary hippocampal-cultured neurons. The results showed that glutamate toxicity reduced hippocampal neuron viability, increased ROS production, and increased intracellular calcium levels. Additionally, glutamate-induced cytotoxicity activated acetylcholinesterase and decreased glutathione levels. However, cordycepin inhibited glutamate-induced cell death, improved cell viability, reduced ROS production, and lowered Ca2+ levels. It also inhibited acetylcholinesterase activation and increased glutathione levels. This study suggests that cordycepin can protect against glutamate-induced neuronal injury in cell models, and this effect was inhibited by adenosine A1 receptor blockers, indicating that its neuroprotective effect is achieved through activation of the adenosine A1 receptor.

Expression and electrophysiological characteristics of VGSC during mouse myoblasts differentiation.

Voltage-gated sodium channels (VGSC) are essential for triggering and relaying action potentials (AP), which perform critical functions in a variety of physiological processes, such as controlling muscle contractions and facilitating the release of neurotransmitters. In this study, we used a mouse C2C12 cell differentiation model to study the molecular expression and channel dynamics of VGSC and to investigate the exact role of VGSC in the development of muscle regeneration. Immunofluorescence, Real-time quantitative polymerase chain reaction, Western blot, and whole-cell patch clamp were employed for this purpose in mouse myoblasts. The findings revealed an increase in intracellular sodium concentration, NaV1.4 gene expression, and protein expression with the progress of differentiation (days 0, 1, 3, 5 and 7). Furthermore, VGSC dynamics exhibit the following characteristics: ① The increase of sodium current (INa); ② The decrease in the activation threshold and the voltage trigger maximum of INa; ③ A positive shift in the steady-state inactivation curve; ④ The recovery of INa during repolarization is delayed, the activity-dependent decay rate of INa was accelerated, and the proportionate amount of the fraction of activated channels was reduced. Based on these results, it is postulated that the activation threshold of AP could be decreased, and the refractory period could be extended with the extension of differentiation duration, which may contribute to muscle contraction. Taken together, VGSC provides a theoretical and empirical basis for exploring potential targets for neuromuscular diseases and other therapeutic muscle regeneration dysfunctions.

C5a/C5aR1 axis as a key driver promotes epithelial-to-mesenchymal transition in airway epithelial cells in silica nanoparticles-induced pulmonary fibrosis.

Previous studies have shown that silica nanoparticles (SiNPs) exposure can affect the respiratory, cardiovascular, reproductive and other systems, with the lung being the primary target organ for the direct effect, causing damage with a central feature of pulmonary inflammation and fibrosis. However, the underlying mechanisms of pulmonary fibrosis due to SiNPs are not fully understood. The aim of the study was to investigate the role of complement anaphylatoxin C5a in SiNPs-induced pulmonary fibrosis. A mouse model of SiNPs-induced pulmonary fibrosis was established, and pulmonary fibrosis-related indicators, epithelial-to-mesenchymal transition (EMT), C5a/C5aR1 and high mobility group protein B1 (HMGB1) proteins were measured. An in vitro study using the human lung epithelial cell line BEAS-2B investigated whether C5a leads to epithelial-to-mesenchymal trans-differentiation. In vivo studies revealed that SiNPs-induced pulmonary fibrosis mainly manifested as EMT trans-differentiation in airway epithelial cells, which subsequently led to excessive deposition of extracellular matrix (ECM). Furthermore, we found that C5a and C5aR1 proteins were also increased in SiNPs-induced pulmonary fibrosis tissue. In vitro studies also showed that C5a directly activated HMGB1/RAGE signaling and induced EMT in BEAS-2B cells. Finally, treatment of SiNPs-exposed mice with the C5aR1 inhibitor PMX205 effectively reduced C5aR1 levels and inhibited the activation of HMGB1/RAGE signaling and the expression of EMT-related proteins, culminating in a significant alleviation of pulmonary fibrosis. Taken together, our results suggest that C5a/C5aR1 is the main signaling pathway for SiNPs-induced pulmonary fibrosis, which induces EMT in airway epithelial cells via the HMGB1/RAGE axis.

FlbZIP12 gene enhances drought tolerance via modulating flavonoid biosynthesis in Fagopyrum leptopodum.

Karst lands provide a poor substrate to support plant growth, as they are low in nutrients and water content. Common buckwheat (Fagopyrum esculentum) is becoming a popular crop for its gluten-free grains and their high levels of phenolic compounds, but buckwheat yields are affected by high water requirements during grain filling. Here, we describe a wild population of drought-tolerant Fagopyrum leptopodum and its potential for enhancing drought tolerance in cultivated buckwheat. We determined that the expression of a gene encoding a Basic leucine zipper (bZIP) transcription factor, FlbZIP12, from F. leptopodum is induced by abiotic stresses, including treatment with the phytohormone abscisic acid, salt, and polyethylene glycol. In addition, we show that overexpressing FlbZIP12 in Tartary buckwheat (Fagopyrum tataricum) root hairs promoted drought tolerance by increasing the activities of the enzymes superoxide dismutase and catalase, decreasing malondialdehyde content, and upregulating the expression of stress-related genes. Notably, FlbZIP12 overexpression induced the expression of key genes involved in flavonoid biosynthesis. We also determined that FlbZIP12 interacts with protein kinases from the FlSnRK2 family in vitro and in vivo. Taken together, our results provide a theoretical basis for improving drought tolerance in buckwheat via modulating the expression of FlbZIP12 and flavonoid contents.

IP3R-dependent mitochondrial dysfunction mediates C5b-9-induced ferroptosis in trichloroethylene-caused immune kidney injury.

Patients with occupational medicamentose-like dermatitis due to trichloroethylene often suffer from immune kidney injury. Our previous study reveals that C5b-9-dependent cytosolic Ca2+ overload-induced ferroptosis is involved in trichloroethylene sensitized kidney injury. However, how C5b-9 causes cytosolic Ca2+ rise and the specific mechanism whereby overloaded Ca2+ induces ferroptosis remain unknown. The purpose of our study was to explore the role of IP3R-dependent mitochondrial dysfunction in C5b-9 mediated ferroptosis in trichloroethylene sensitized kidney. Our results showed that IP3R was activated, and mitochondrial membrane potential was decreased in the renal epithelial cells of trichloroethylene-sensitized mice, and these changes were antagonized by CD59, a C5b-9 inhibitory protein. Moreover, this phenomenon was reproduced in a C5b-9-attacked HK-2 cell model. Further investigation showed that RNA interference with IP3R not only alleviated C5b-9-induced cytosolic Ca2+ overload and mitochondrial membrane potential loss but also attenuated C5b-9-induced ferroptosis in HK-2 cells. Mechanistically, IP3R-dependent cytosolic Ca2+ overload activated the mitochondrial permeability transition pore, resulting in the loss of mitochondrial membrane potential and ferroptosis of HK-2 cells. Finally, cyclosporin A, a mitochondrial permeability transition pore inhibitor, not only ameliorated IP3R-dependent mitochondrial dysfunction but also blocked C5b-9-induced ferroptosis. Taken together, these results suggest that IP3R-dependent mitochondrial dysfunction plays an important role in trichloroethylene sensitized renal tubular ferroptosis.

HMGB 1 acetylation mediates trichloroethylene-induced immune kidney injury by facilitating endothelial cell-podocyte communication.

More and more clinical evidence shows that occupational medicamentose-like dermatitis due to trichloroethylene (OMDT) patients often present immune kidney damage. However, the exact mechanisms of cell-to-cell transmission in TCE-induced immune kidney damage remain poorly understood. The present study aimed to explore the role of high mobility group box-1 (HMGB 1) in glomerular endothelial cell-podocyte transmission. 17 OMDT patients and 34 controls were enrolled in this study. We observed that OMDT patients had renal function injury, endothelial cell activation and podocyte injury, and these indicators were associated with serum HMGB 1. To gain mechanistic insight, a TCE-sensitized BALB/c mouse model was established under the interventions of sirtuin 1 (SIRT 1) activator SRT 1720 (0.1 ml, 5 mg/kg) and receptor for advanced glycation end products (RAGE) inhibitor FPS-ZM 1 (0.1 ml, 1.5 mg/kg). We identified HMGB 1 acetylation and its endothelial cytoplasmic translocation following TCE sensitization, but SRT 1720 abolished the process. RAGE was located on podocytes and co-precipitated with extracellular acetylated HMGB 1, promoting podocyte injury, while SRT 1720 and FPS-ZM 1 both alleviated podocyte injury. The results demonstrate that interventions to upstream and downstream pathways of HMGB 1 may weaken glomerular endothelial cell-podocyte transmission, thereby alleviating TCE-induced immune renal injury.

Mendelian randomization analyses of associations between breast cancer and bone mineral density.

The purpose of this study was to verify whether there is a causal relationship between breast cancer and bone mineral density (BMD). Summary statistics for exposures and outcomes were obtained from corresponding genome-wide association studies. The bidirectional and multivariate mediated Mendelian randomization (MR) analyses were performed. In the bidirectional MR analysis, breast cancer might reduce the BMD of the heel (HE-BMD) (FDR = 1.51 × 10-4) as might its ER+ subtype (FDR = 1.51 × 10-4). From BMD to breast cancer, no significant association was found (FDR > 0.05). The mediating MR analysis showed that Higher free testosterone (FT) only mediated the causal relationship between breast cancer and HE-BMD by 2.9%; both ER+ type and FT were independent factors of HE-BMD (ER+: P = 0.021; FT: P = 6.88 × 10-6). Higher FT could increase the risk of breast cancer (FDR = 1.21 × 10-3) as could total testosterone (TT) (FDR = 5.81 × 10-3). Similarly, higher FT could increase the risk of ER+ subtype (FDR = 2.51 × 10-6) as could TT (FDR = 5.55 × 10-4). These results indicate that BMD is not a risk factor for breast cancer but breast cancer and its ER+ subtype are risk factors for BMD loss. Furthermore, higher FT and TT levels are associated with both an increased incidence of breast cancer and increased bone density.

Outer-synchronization criterions for asymmetric recurrent time-varying neural networks described by differential-algebraic system via data-sampling principles.

Asymmetric recurrent time-varying neural networks (ARTNNs) can enable realistic brain-like models to help scholars explore the mechanisms of the human brain and thus realize the applications of artificial intelligence, whose dynamical behaviors such as synchronization has attracted extensive research interest due to its superior applicability and flexibility. In this paper, we examined the outer-synchronization of ARTNNs, which are described by the differential-algebraic system (DAS). By designing appropriate centralized and decentralized data-sampling approaches which fully account for information gathering at the times t k and t k i . Using the characteristics of integral inequalities and the theory of differential equations, several novel suitable outer-synchronization conditions were established. Those conditions facilitate the analysis and applications of dynamical behaviors of ARTNNs. The superiority of the theoretical results was then demonstrated by using a numerical example.

Highly Enhanced Photocatalytic Performances of Composites Consisting of Silver Phosphate and N-Doped Carbon Nanomesh for Oxytetracycline Degradation.

Photocatalytic technology based on silver phosphate (Ag3PO4) has excellent potential in removing antibiotic pollutants, but the low separation rate of photogenerated hole-electron pairs restricts the application of the photocatalyst. In this study, it was found that the combination of nitrogen-doped carbon (NDC) with carbon defects and Ag3PO4 can significantly enhance the photocatalytic ability of Ag3PO4. After it was exposed to visible light for 5 min, the photocatalytic degradation efficiency of oxytetracycline (OTC) by the composite photocatalyst Ag3PO4@NDC could reach 100%. In addition, the structure of NDC, Ag3PO4, and Ag3PO4@NDC was systematically characterized by SEM, TEM, XRD, Raman, and EPR. The XPS results revealed intense interface interaction between Ag3PO4 and NDC, and electrons would transfer from Ag3PO4 to the NDC surface. A possible mechanism for enhancing the photocatalytic reaction of the Ag3PO4@NDC composite catalyst was proposed. This study provides a highly efficient visible light catalytic material, which can be a valuable reference for designing and developing a new highly efficient visible light catalyst.

Renal tubular in TCE-sensitization-induced immune kidney injury: Role of mitochondrial DNA in activating the cGAS-STING signaling pathway.

Occupational medicamentose-like dermatitis due to trichloroethylene (OMDT) is a systemic allergic disease similar to drug eruption-like dermatitis that occurs in workers after exposure to trichloroethylene. In addition to skin and mucosa damage, OMDT patients often accompanied by severe multiorgan damage, including kidney injury. However, the mechanism remains unclear. The aim of our research was to explore the role of increased cytosolic mitochondrial DNA in the activation of cGAS-STING signaling and in the kidney injury of trichloroethylene sensitization mice using a mouse model and an in vitro model. By analyzing the kidneys of TCE-sensitized mice, we found obvious tubular mitochondrial damage, decreased expression of COX-IV and TFAM proteins and increased cytosolic mitochondrial DNA in TCE-sensitized-positive mice. Further study found that cytosolic mitochondrial DNA activated cGAS-STING signaling, resulting in the nuclear translocation of P-IRF3 and NF-κB P65 and the transcription and synthesis of type Ⅰ interferons and cytokines, which ultimately led to immune kidney injury in trichloroethylene-sensitized mice. Interestingly, pretreatment with C-176, a STING inhibitor, not only blocked the nuclear translocation of P-IRF3 and NF-κB P65, but also alleviated the kidney injury induced by TCE sensitization. Consistently, in vitro studies also found that mitochondrial DNA pretreatment can activate the cGAS-STING pathway, causing the nuclear translocation of P-IRF3 and NF-κB P65 and the transcription of type Ⅰ interferons and cytokines in HK-2 cells. Overall, our results suggested that cytosolic mitochondrial DNA plays an important role in the activation of the cGAS-STING pathway and TCE sensitization-induced immune kidney injury.

Trichloroethylene induces immune renal tubular injury through SIRT 1/HSP 70/TLR 4 pathway in BALBc mice.

Trichloroethylene (TCE) is a volatile chlorinated solvent widely used for cleaning and degreasing industrial metal parts. Due to the widespread use and improper disposal of TCE, exposure to TCE causes a variety of adverse effects on human and animal health. However, the underlying mechanism of the damage remains unclear. The purpose of this study is to investigate the role of Sirtuin-1 (SIRT 1) in TCE-induced immune renal tubular injury. 6-8-week-old female BALB/c mice were used to construct a TCE sensitized mouse model. SIRT 1 activator, SRT 1720 (0.1 ml, 5 mg/kg) and toll like receptor 4 (TLR 4) inhibitor, TAK-242 (0.1 ml, 3 mg/kg) were used for treatment. Results show that SIRT 1 and heat shock protein 70 (HSP 70) levels are significantly down-regulated in renal tubules, serum and urine HSP 70 levels are significantly increased, and inflammatory cytokines levels are significantly increased in renal tubules in TCE-sensitized positive mice. After SRT 1720 treatment, intracellular HSP 70 level is significantly increased and extracellular HSP 70 level is decreased, and inflammatory cytokines levels get alleviated. In addition, HSP 70 and Toll-like Receptor 4 (TLR 4) proteins exist an interaction that can be significantly attenuated by SIRT 1. Subsequently, inflammation of the renal tubules mediated by SIRT 1 downregulation is attenuated after TAK-242 treatment. In conclusion, SIRT 1 alleviates renal tubular epithelial cells immune injury by inhibiting the release of HSP 70 and thereby weakening interaction with HSP 70 and TLR 4.

C5b-9 mediates ferroptosis of tubular epithelial cells in trichloroethylene-sensitization mice.

Occupational medicamentose-like dermatitis due to trichloroethylene (OMDT) is a key but unresolved question. OMDT patients often present multiple organ damage, including kidney damage. However, the underlying mechanism remains unknown. The purpose of our study was to explore the effect of tubule-specific C5b-9 deposition induced by TCE sensitization on renal tubular ferroptosis and its mechanism. By analyzing pathological changes of TCE-sensitization-mice kidney, we observed a significant renal tubular ferroptosis, which was alleviated by CD59, a C5b-9 inhibitory protein. Moreover, this phenomenon was also replicated in a C5b-9-attacked HK-2 cell model. Further experiments identified that C5b-9 induced cytosolic Ca2+ overload in renal tubular epithelia cells from TCE-sensitization-mice and HK-2 cells. Furthermore, in vitro experiments showed that BAPTA-AM, an intracellular Ca2+ chelator, could rescued ferroptosis induced by C5b-9 in HK-2 cells. Taken together, TCE sensitization induced renal tubular ferroptosis is mediated by C5b-9 and cytosolic Ca2+ overload may play a key role.

Wnt 5a mediated inflammatory injury of renal tubular epithelial cells dependent on calcium signaling pathway in Trichloroethylene sensitized mice.

Patients with trichloroethene-induced Trichloroethylene hypersensitivity syndrome (THS) often present kidney injury. However, the role of Wnt 5a/Ca2+ pathway in renal tubular injury in Trichloroethylene (TCE) sensitized mice remains unclear. This study aimed to investigate how Wnt 5a/Ca2+ pathway induced renal tubular epithelial cell injury in TCE sensitized mice. A total of 84 female BALB/c Specific Pathogen Free mice aged 6-8 weeks were used to establish TCE sensitized mouse models. Renal histology and serum levels of α1-MG and ß2-MG were used to assess the renal injury. The renal protein levels of Wnt 5a, ROR2, FZD5, PLC, p-CaMKII, IκB α, p-IκB α, NF-κB(p65), TNF α, IL 6 and IL 1ß were measured. The levels of serum α1-MG and ß2-MG and TNF α, IL 6 and IL 1ß levels in the kidney tissue were significantly increased in TCE sensitized positive group. However, Box5 pretreatment inhibited the expression of PLC, p-CaMKII, p65 and attenuated the injury of renal tubular epithelial cells and suppressed the upregulated expression of the above cytokines. In addition, KN93 also reduced nuclear translocation of p65 and renal injury as well as the elevated cytokines by inhibiting CaMKII. These data identify Wnt 5a binding to ROR2 and FZD5, p65 nuclear translocation, and inflammatory cytokine release as a novel mechanism for renal tubular epithelial cells injury by sensitization with TCE. Box5 or KN93 pretreatment can block the expression of inflammatory cytokines and reduce the injury of renal tubular epithelial cells.

Efficacy and safety of thalidomide in preventing oral mucositis in patients with nasopharyngeal carcinoma undergoing concurrent chemoradiotherapy: A multicenter, open-label, randomized controlled trial.

BACKGROUND: This multicenter clinical trial was designed to evaluate the efficacy and safety of thalidomide (THD) in preventing oral mucositis (OM) in patients with nasopharyngeal carcinoma (NPC) undergoing concurrent chemoradiotherapy (CCRT). METHODS: Patients with locally advanced NPC were randomly assigned to either a THD group or a control group. All 160 patients received radical intensity-modulated radiotherapy plus cisplatin-based concurrent chemotherapy and basic oral hygiene guidance. Patients in the THD group received additional THD at the beginning of CCRT. The primary end points were the latency period and the incidence of OM. The secondary end points were mouth and throat soreness (MTS), weight loss, short-term efficacy, and adverse events. RESULTS: The median latency period of OM was 30 and 14 days in the THD and control groups, respectively (hazard ratio, 0.32; 95% confidence interval, 0.23-0.35; P < .0001). The incidence of OM and severe OM (World Health Organization grade 3 or higher) was significantly lower in the THD group than the control group (87.5% vs 97.5% [P = .016] and 27.5% vs 46.3% [P = .014], respectively). THD treatment also remarkably reduced the intensity of MTS and the degree of weight loss. In comparison with the control group, the incidence of nausea, vomiting, and insomnia was significantly decreased, whereas the incidence of dizziness and constipation was obviously increased in the THD group. The objective response rates 3 months after CCRT were similar between the groups. CONCLUSIONS: THD prolonged the latency period, reduced the incidence of OM, and did not affect the short-term efficacy of CCRT in patients with NPC. LAY SUMMARY: Oral mucositis is the most common complication of nasopharyngeal carcinoma during chemoradiotherapy; it decreases the patient's quality of life, and ideal mucosal protective agents are lacking. A few basic research and preclinical studies have shown that thalidomide may be an approach to ameliorating oral mucositis. The results of the current study confirm that thalidomide has a protective effect against oral mucositis in patients who have received chemoradiotherapy for nasopharyngeal carcinoma.

Predicting Nomogram for Severe Oral Mucositis in Patients with Nasopharyngeal Carcinoma during Intensity-Modulated Radiation Therapy: A Retrospective Cohort Study.

BACKGROUND: Oral mucositis is an acute adverse reaction with high incidence during radiotherapy. Severe oral mucositis can seriously affect patients' quality of life and compliance with radiotherapy. The aim of this study was to identify the risk factors for severe oral mucositis and to develop a nomogram for predicting severe oral mucositis in patients with nasopharyngeal carcinoma. METHODS: One hundred and ninety patients with nasopharyngeal carcinoma were retrospectively screened in this study. Least absolute shrinkage and selection operator regression and multivariate logistic regression analyses were performed to identify the best predictors of severe oral mucositis. A nomogram was constructed based on the factors. Finally, the discriminative ability of the nomogram was evaluated. RESULTS: Four independent factors predicting severe oral mucositis were identified: age, N stage, the cycle of induction chemotherapy, and dose-volumetric parameter V40 (%) of oral cavity. The area under the receiver of operating characteristic curve of the nomogram was 0.759 (95% confidence interval: 0.691-0.827). CONCLUSIONS: A predictive nomogram for severe oral mucositis was established and validated in this study. The nomogram provides a reliable and practical model for clinically predicting the probability of severe oral mucositis in patients with nasopharyngeal carcinoma before intensity-modulated radiation therapy.

Sorting OAM modes with metasurfaces based on raytracing improved optical coordinate transformation.

Optical coordinate transformation (OCT) has attracted widespread attention in the field of orbital angular momentum (OAM) (de)multiplexing or manipulation, but the performance of OCT would suffer from its distortion. In this paper, we quantitatively analyze the distortion of OCT from the perspective of ray optics and explain its rationality to work under non-normal incident light. For the special case of log-polar coordinate transformation (LPCT), we use a raytracing assisted optimization scheme to improve its distortion, which is related to a Zernike polynomial based phase compensation. After raytracing optimization, the root mean square error (RMSE) of the focused rays is reduced to 1/5 of the original value and the physical optic simulation also shows great improvement. In the experiment, we use three phase masks which are realized by metasurfaces, the measured results show well consistency with the simulation. Results in this paper have great potential to improve the performance of OCT related applications.