Prediction of bilateral thyroid carcinoma and lateral cervical lymph node metastasis in PTC patients with suspicious thyroid nodules.

PURPOSE: This study aimed to evaluate the factors associated with bilateral papillary thyroid carcinoma (PTC) and lateral cervical lymph node metastasis (LLNM) in patients with suspicious unilateral PTC. METHODS: This study analyzed patients with suspicious unilateral PTC who were enrolled in a university hospital between 2016 and 2019 in Zhejiang, China. Using logistic regression, the study examined the factors associated with bilateral PTC and LLNM in demographic data, anthropometric measurements, lifestyle factors, medical history, preoperative diagnostic tests, and histopathological factors. RESULTS: A total of 256 patients, with a mean age of 49 years, were enrolled. Bilateral PTC was associated with multifocality (aOR: 5.069, 95% CI: 2.440-10.529, P < 0.001), and contralateral nodule in the upper (aOR: 9.073, 95% CI: 2.111-38.985, P = 0.003) and middle (aOR: 9.926, 95% CI: 2.683-36.717, P < 0.001). LLNM was positively associated with bilateral PTC (aOR, 4.283, 95% CI: 1.378-13.308, p = 0.012), male (aOR, 3.377, 95% CI: 1.205-9.461, P = 0.021), upper location of carcinoma (aOR, 3.311, 95% CI: 1.091-10.053, p = 0.035), and punctate echogenic foci (aOR, 3.309, 95% CI: 1.165-9.394, P = 0.025). Contralateral maximal nodule in the upper (aOR: 0.098, 95% CI: 0.015-0.628, p = 0.014), middle (aOR: 0.114, 95% CI: 0.033-0.522, p < 0.001), and lower (aOR, 0.028, 95% CI: 0.003-0.276, P = 0.002) location were inversely associated with LLNM. CONCLUSION: Upper and middle location of contralateral nodule and tumor multifocality predicted the risk bilateral PTC. Bilateral PTC, male, upper tumor location, punctate echogenic foci and contralateral nodule location in the entire lobes were independent predictors for LLNM.

Metabolomic analysis of the serum and urine of rats exposed to diazinon, dimethoate, and cypermethrin alone or in combination.

BACKGROUND: Multiple pesticides are often used in combination for plant protection and public health. Therefore, it is important to analyze the physiological changes induced by multiple pesticides exposure. The objective of this study was to investigate the combined toxicity of the widely-used organophosphorus and pyrethroid pesticides diazinon, dimethoate, and cypermethrin. METHODS: Male Wistar rats were administrated by gavage once daily with the three pesticides individual or in combination for consecutive 28 days. The metabolic components of serum and urine samples were detected by using 1H nuclear magnetic resonance (NMR)-based metabolomics method. Histopathological examination of liver and kidneys and serum biochemical determination were also carried out. RESULTS: The results showed that after the 28-day subacute exposure, serum glutamic transaminase and albumin were significantly increased and blood urea nitrogen was significantly decreased in the rats exposed to the mixture of the pesticides compared with the control rats, suggesting that the co-exposure impaired liver and kidney function. Metabolomics analysis indicated that the indicators 14 metabolites were statistically significant altered in the rats after the exposure of the pesticides. The increase in 3-hydroxybutyric acid in urine or decrease of lactate and N-acetyl-L-cysteine in serum could be a potentially sensitive biomarker of the subchronic combined effects of the three insecticides. The reduction level of 2-oxoglutarate and creatinine in urine may be indicative of dysfunction of liver and kidneys. CONCLUSION: In summary, the exposure of rats to pesticides diazinon, dimethoate, and cypermethrin could cause disorder of lipid and amino acid metabolism, induction of oxidative stress, and dysfunction of liver and kidneys, which contributes to the understanding of combined toxic effects of the pesticides revealed by using the metabolomics analysis of the urine and serum profiles.

Tri-ortho-cresyl phosphate induces hepatic steatosis by mTOR activation and ER stress induction.

Tri-ortho-cresyl phosphate (TOCP), an organophosphorus compound (OP), which is widely used as plasticizer, flame retardant and other industrial products, has been reported to cause multiple toxicities including neurotoxicity and reproductive toxicity. However, it remains to be elusive whether TOCP induces hepatotoxicity. The purpose of this study was to investigate the effect of TOCP on hepatocytes and the lipid metabolism in particular. The adult mice were given a single dose of TOCP (800 mg/kg, p.o.) and the histological changes in liver tissue and lipid content in serum were determined. The results showed that more vacuoles and lipid droplets were observed in the liver of the mice exposed to TOCP. And triglyceride concentrations in serum and liver tissue significantly increased. However, the histopathological changes of the liver and the elevated triglyceride levels in the exposed mice can be reversed by endoplasmic reticulum (ER) stress inhibitor 4-phenylbutyric acid and mTOR signal inhibitor rapamycin. It was also found that the changes of expression levels of the biomarkers of ER stress and mTOR signaling pathway, such as GRP78, CHOP, and p-mTOR, in the exposed mice were consistent with those observed in the cultured primary hepatocytes treated with the same chemicals. These results showed that TOCP activated mTOR signal and ER stress to induce de novo lipid synthesis, which led to the hepatic steatosis in mouse.

Alternative Splicing Factor Heterogeneous Nuclear Ribonucleoprotein U as a Promising Biomarker for Gastric Cancer Risk and Prognosis with Tumor-Promoting Properties.

Gastric cancer (GC) is a major global health concern with poor outcomes. Heterogeneous nuclear ribonucleoprotein U (HNRNPU) is a multifunctional protein that participates in pre-mRNA packaging, alternative splicing regulation, and chromatin remodeling. Its potential role in GC remains unclear. In this study, the expression characteristics of HNRNPU were analyzed by The Cancer Genome Atlas data, Gene Expression Omnibus data, and then further identified by real-time quantitative PCR and immunohistochemistry using tissue specimens. From superficial gastritis, atrophic gastritis, and hyperplasia to GC, the in situ expression of HNRNPU protein gradually increased, and the areas under the curve for diagnosis of GC and its precancerous lesions were 0.911 and 0.847, respectively. A nomogram integrating HNRNPU expression, lymph node metastasis, and other prognostic indicators exhibited an area under the curve of 0.785 for predicting survival risk. Knockdown of HNRNPU significantly inhibited GC cell proliferation, migration, and invasion and promoted apoptosis in vitro. In addition, RNA-sequencing analysis showed that HNRNPU could affect alternative splicing events in GC cells, with functional enrichment analysis revealing that HNRNPU may exert malignant biological function in GC progression through alternative splicing regulation. In summary, the increased expression of HNRNPU was significantly associated with the development of GC, with a good performance in diagnosing and predicting the prognostic risk of GC. Functionally, HNRNPU may play an oncogenic role in GC by regulating alternative splicing.

Hyperbranched polyamidoamine-RGD peptide/si-circICA1 in the treatment of invasive thyroid cancer through targeting of the miR-486-3p/SERPINA1 axis.

Aim: This study aimed to identify molecular markers associated with papillary thyroid cancer (PTC) and investigate the therapeutic potential of targeted nanoscale drugs. Materials & methods: We analyzed the effects of circICA1 and miR-486-3p on B-CPAP cells' proliferation, apoptosis, migration and invasion. The regulation of the miR-486-3p/SERPINA1 axis was explored using quantitative real-time reverse transcription PCR and western blot analyses for metastasis. In vivo, we evaluated the effects of hyperbranched polyamidoamine-RGD peptide/si-circICA1 on PTC growth and metastasis. Results: Enhanced miR-486-3p expression inhibits B-CPAP cells' proliferation and invasion. si-circICA1 delivered via hyperbranched polyamidoamine-RGD peptide nanoparticles shows potential for treating metastasis in PTC. Conclusion: This study identifies key molecular mechanisms underlying PTC invasiveness and suggests a promising therapeutic strategy for PTC using targeted nanoscale drugs.

The role of intercellular junction proteins in the penetration resistance of Drosophila larvae to avermectin.

Insecticide resistance has become an increasingly serious challenge for agriculture in the world. To reveal the mechanisms of insecticide resistance, majority of studies have been carried out on the insensitivity of insecticide targets and the metabolism of insecticides. However, the mechanism of the insecticide penetration resistance in insects remains unclear. This study aimed to reveal the mechanism underlying the penetration resistance of Drosophila larvae to insecticide avermectin (AVM). Levels of intercellular junction proteins (IJPs) in the larvae were determined by Western blotting analysis and immunofluorescence assay. The result showed that the expression of IJPs septate junction and adherens junction proteins increased in the AVM-resistant insects compared with those in the AVM-susceptible ones, and the upregulation of the IJPs was mediated by the activation of protein kinase C (PKC) pathway. That AVM induced the activation of PKC was found not only in the Drosophila larvae but also in Drosophila S2 cells. These findings revealed that AVM could activate PKC pathway in Drosophila larvae, which mediated the upregulation of the IJPs and then led to the resistance to AVM, suggesting that the chemicals that can disrupt PKC activation may potentially be used to circumvent the resistance to AVM in insects.

The alteration of the expression level of neuropathy target esterase in human neuroblastoma SK-N-SH cells disrupts cellular phospholipids homeostasis.

Neuropathy target esterase (NTE) has been proven to act as a lysophospholipase (LysoPLA) and phospholipase B (PLB) in mammalian cells. In this study, we took human neuroblastoma SK-N-SH cells as the research object and explored the effect of NTE on phospholipid homeostasis. The results showed that phosphatidylcholine (PC) and lysophosphatidylcholine (LPC) levels significantly increased (> 40%), while glycerophosphocholine (GPC) decreased (below 60%) after NTE gene was knockdown in the cells (NTE < 30% of control), which were prepared by gene silencing with dsRNA-NTE. However, in the NTE-overexpressed cells (NTE > 50% of control), which were prepared by expressing recombinant catalytic domain of NTE, LPC remarkably decreased (below 80%) and GPC enhanced (> 40%). Mipafox, a neuropathic organophosphorus compound (OP), significantly inhibited NTE-LysoPLA and NTE-PLB activities (> 95-99% inhibition at 50 µM), which was accompanied with a decreased GPC level (below 40%) although no change of the PC and LPC levels was observed; while paraoxon, a non-neuropathic OP, suppresses neither the activities of NTE-phospholipases nor the levels of PC, LPC, and GPC. Thus, we concluded that both the stable up- or down-regulated expression of NTE gene and the loss of NTE-LysoPLA/PLB activities disrupts phospholipid homeostasis in the cells although the inhibition of NTE activity only decreased GPC content without altering PC and LPC levels.

Ivermectin inhibits tumor metastasis by regulating the Wnt/ß-catenin/integrin ß1/FAK signaling pathway.

Tumor metastasis is the major cause of cancer mortality; therefore, it is imperative to discover effective therapeutic drugs for anti-metastasis therapy. In the current study, we investigated whether ivermectin (IVM), an FDA-approved antiparasitic drug, could prevent cancer metastasis. Colorectal and breast cancer cell lines and a cancer cell-derived xenograft tumor metastasis model were used to investigate the anti-metastasis effect of IVM. Our results showed that IVM significantly inhibited the motility of cancer cells in vitro and tumor metastasis in vivo. Mechanistically, IVM suppressed the expressions of the migration-related proteins via inhibiting the activation of Wnt/ß-catenin/integrin ß1/FAK and the downstream signaling cascades. Our findings indicated that IVM was capable of suppressing tumor metastasis, which provided the rationale on exploring the potential clinical application of IVM in the prevention and treatment of cancer metastasis.

Long-term low-dose exposure of permethrin induces liver and kidney damage in rats.

BACKGROUND: Permethrin is one of the pyrethroid insecticides, which is widely used in agriculture and public health. Although acute toxicity of the insecticide has been studied, the chronic toxicity upon the long-term exposure has not been clear yet. The purpose of the current study is to investigate the organ toxicities of permethrin following its long-term low-dose exposure. METHODS: Male Wistar rats were daily administrated orally with permethrin (75 mg/kg body weight/day, gavage) for 90 days, and then the samples of biofluids (blood and urine) and organs including liver and kidney were collected. The serum and urine samples were measured by biochemical assay and the tissues of kidney and liver were examined and analyzed by histopathological method. RESULTS: The results showed that no change was found in serum and urine biochemical parameters for the toxicity; however, significant changes including hyperchromatic nuclei swollen in the hepatic parenchymal cells and the swelling proximal tubules in the kidneys were observed in the tissue structures of liver and kidneys in the histopathological sections. CONCLUSION: These results indicate that low-dose long-term exposure of permethrin can cause chronic toxicity with slight liver and kidney damage.

[Large-scale Hospital Material Supply Chain Practice under Closed-loop Management].

In the context of public health emergencies, a Hospital used the existing SPD supply chain model as a basis, research and practice proceeded simultaneously and formed a set of "three-group three-port" emergency plan by itself. The program played a positive role and effectiveness in this emergency incident, assisting the hospital to obtain a valuable experience in closed-loop management of emergency supplies. This article elaborated on how the hospital can supply materials in case of emergency medical supplies shortage after emergencies by focusing on the three groups of closed-loop working group, inventory management group, and material procurement group, and the three ports of material storage port, logistics receiving and dispatching port, and closed-loop releasing port. In the case of emergency medical supplies being in short supply after emergencies, how can hospitals ensure adequate and balanced supply of supplies; barrier-free demand information; command and dispatch without chaos and reasonable deployment; materials receiving and dispatching are efficient and distributed in an orderly manner.

Tri-ortho-cresyl phosphate induces axonal degeneration in chicken DRG neurons by the NAD+ pathway.

Wallerian degeneration (WD) is a well-known process by which degenerating axons and myelin are cleared after nerve injury. Although organophosphate-induced delayed neuropathy (OPIDN) is characterized by Wallerian-like degeneration of long axons in human and sensitive animals, the precise pathological mechanism remains unclear. In this study, we cultured embryonic chicken dorsal root ganglia (DRG) neurons, the model of OPIDN in vitro, to investigate the underlying mechanism of axon degeneration induced by tri-ortho-cresyl phosphate (TOCP), an OPIDN inducer. The results showed that TOCP exposure time- and concentration-dependently induced a serious degeneration and fragmentation of the axons from the DRG neurons. A collapse of mitochondrial membrane potential and a dramatic depletion of ATP levels were found in the DRG neurons after TOCP treatment. In addition, nicotinamide nucleotide adenylyl transferase 2 (NMNAT2) expression and nicotinamide adenine dinucleotide (NAD+) level was also found to be decreased in the DRG neurons exposed to TOCP. However, the TOCP-induced Wallerian degeneration in the DRG neurons could be inhibited by ATP supplementation. And exogenous NAD+ or NAD+ processor nicotinamide riboside can rescue TOCP-induced ATP deficiency and prevent TOCP-induced axon degeneration of the DRG neurons. These findings may shed light on the pathophysiological mechanism of TOCP-induced axonal damages, and implicate the potential application of NAD+ to treat OPIDN.

SYT7 plays a role in promoting thyroid cancer by mediating HMGB3 ubiquitination.

Thyroid cancer is one of the most common endocrine malignancies. It is necessary to discover more effective molecular targets for the treatment of thyroid cancer. The results of immunohistochemical staining, qPCR and Western blot indicated that the expression of SYT7 in thyroid cancer tissues and cells was higher than that in paracarcinoma tissues and normal thyroid cells. Through cell function testing experiments, it was found that SYT7 knockdown inhibited the proliferation and migration of thyroid cancer cells and promoted cell apoptosis, while SYT7 overexpression had the opposite effect. Similarly, SYT7 downregulation also suppressed tumor growth in vivo. HMGB3 was confirmed to be the downstream gene of SYT7 by GeneChip and Ingenuity Pathway Analysis. Besides, through UbiBrowser database predictions and Co-IP assays, we found that SYT7 interacted with BRCA1 to inhibit HMGB3 ubiquitination and thus upregulated the protein level of HMGB3. Similar to SYT7, HMGB3 was significantly upregulated in thyroid cancer. HMGB3 knockdown inhibited the proliferation and migration of thyroid cancer cells and promoted cell apoptosis. Furthermore, HMGB3 knockdown restored the promotion of cell proliferation and migration caused by SYT7 overexpression. SYT7 and HMGB3 were upregulated in thyroid cancer, and SYT7 regulated the expression of HMGB3 through BRCA1-mediated ubiquitination of HMGB3 to promote thyroid cancer progression.

Why are Drosophila larvae more sensitive to avermectin than adults?

The insects have different physiological and morphological characteristics in various developmental stages. The difference in the characteristics may be related to the different sensitivity of insects to insecticides. In avermectin resistant strain screening assay, we found that the Drosophila larvae displayed a higher sensitivity to the insecticidal effect of avermectin, compared with adults. In this study, we found that the Drosophila larvae have relatively thicker chitin layer, faster avermectin metabolism and lower P-glycoprotein (P-gp) level, when compared with the adults. Besides, the expression levels of the molecular targets of avermectin, glutamate-gated chloride channel and γ-aminobutyric acid (GABA)-gated chloride channel, are lower in the larval stage than the adult. These results suggested that lower P-gp level in the body especially in brain may be the major reason for the higher sensitivity of Drosophila larvae to the insecticide. In summary, these results shed new light on the concept that different developmental stages of insects display different sensitivity to the same insecticide, which also provided a physiological explanation of the relevant mechanism of the difference of sensitivity of insect at its larval and adult stages to insecticide.

Body fluids from the rat exposed to chlorpyrifos induce cytotoxicity against the corresponding tissue-derived cells in vitro.

BACKGROUND: This study aims to establish an in vitro monitoring approach to evaluate the pesticide exposures. We studied the in vitro cytotoxicity of three different body fluids of rats to the respective corresponding tissue-derived cells. METHODS: Wistar rats were orally administrated daily with three different doses of chlorpyrifos (1.30, 3.26, and 8.15 mg/kg body weight/day, which is equal to the doses of 1/125, 1/50, and 1/20 LD50, respectively) for consecutive 90 days. Blood samples as well as 24-hour urine and fecal samples were collected and processed. Then, urine, serum, and feces samples were used to treat the correspondent cell lines, i.e., T24 bladder cancer cells, Jurkat lymphocytes, and HT-29 colon cancer cells respectively, which derived from the correspondent tissues that could interact with the respective corresponding body fluids in organism. Cell viability was determined by using MTT or trypan blue staining. RESULTS: The results showed that urine, serum, and feces extract of the rats exposed to chlorpyrifos displayed concentration- and time-dependent cytotoxicity to the cell lines. Furthermore, we found that the cytotoxicity of body fluids from the exposed animals was mainly due to the presence of 3, 4, 5-trichloropyrindinol, the major toxic metabolite of chlorpyrifos. CONCLUSIONS: These findings indicated that urine, serum, and feces extraction, especially urine, combining with the corresponding tissue-derived cell lines as the in vitro cell models could be used to evaluate the animal exposure to pesticides even at the low dose with no apparent toxicological signs in the animals. Thus, this in vitro approach could be served as complementary methodology to the existing toolbox of biological monitoring of long-term and low-dose exposure to environmental pesticide residues in practice.

Tri-ortho-cresyl phosphate exposure leads to low egg production and poor eggshell quality via disrupting follicular development and shell gland function in laying hens.

Tri-ortho-cresyl phosphate (TOCP) has been used commercially as a plasticizer and a flame retardant, which has been reported to cause multiple toxicities in humans and other animals. However, the effect of TOCP on female reproductive system is still unclear. The aim of this investigation was to evaluate the reproductive toxicity of TOCP in female avian and investigate its molecular mechanism. In the current study, 50 adult hens were given a single oral dose of TOCP (750 mg/kg). Egg laid by the hens were harvested and counted. Egg quality is assessed by determining the shell strength and thickness. Samples of ovary, shell gland, and serum were collected on day 0, 2, 7, and 21 after the administration. The morphological and pathological changes in tissues were examined. Cell death, follicular development, and steroidogenesis were determined to assess the toxicity of TOCP on laying hens. The results showed that egg production, egg weight, and eggshell strength significantly decreased after TOCP exposure. The calcium levels in serum and eggshell decreased and the expression levels of the eggshell formation-related genes calbindin-D28k (CaBP-D28k) and carbonic anhydrase 2 (CA2) were downregulated. The inhibitory effects of TOCP on follicular development and steroidogenesis were observed with changes in the levels of the related proteins such as forkhead box O1 (FoxO1) and mothers against decapentaplegic homolog 2/3 (Smad2/3). Cell death was identified, which might lead to follicular development disorder. Taken together, TOCP reduced the quantity and quality of the eggs laid by the hens through disrupting follicular development, steroidogenesis, and shell gland function.

Factors Associated with Malignancy in Patients with Maximal Thyroid Nodules ≥2 Cm.

PURPOSE: The relationship between large thyroid nodules and the risk of malignancy is controversial. This study aimed to examine the relationship between thyroid nodule size and the risk of malignancy of maximal thyroid nodules ≥2 cm and the risk of accompanied by occult thyroid carcinoma. METHODS: This was a retrospective study of patients who underwent near-total or total thyroidectomy for thyroid nodules from January 2016 to January 2019 at the First Affiliated Hospital,Zhejiang University School of Medicine. Clinical, biochemical, and pathological characteristics were examined for association with malignancy using univariable, multivariable, and receiver operating characteristic curve analyses. RESULTS: Finally, 367 patients (277 females (75.5%) and 90 males (24.5%)) with a mean age of 49.0±13.5 years were included. Multivariable logistic regression analysis showed that age (OR=0.959, 95% CI: 0.939-0.979, P<0.001), Hashimoto's thyroiditis (OR=2.437, 95% CI: 1.162-5.112, P=0.018), the diameter of maximal nodule (small) (OR=0.706, 95% CI: 0.541-0.919, P=0.010), and punctate echogenic foci (OR=2.837, 95% CI: 1.598-5.286, P<0.001) were independently associated with malignancy. Of 223 patients who had non-suspicious malignant nodules (TI-RADS <4), 12.7% (n=29) patients showed malignancy at postoperative pathology. Only age was associated with occult PTC in the univariable analyses (OR=0.962, 95% CI: 0.934-0.991, P=0.011). When TPOAb was used as a continuous variable for statistical analysis, it showed a significant difference in the ROC curve, and the results showed TPOAb >31.4 mIU/L was more associated with occult PTC (P=0.006). A predictive model including four independent risk factors of malignancy showed an optimal discriminatory accuracy (area under the curve, AUC) of 0.783 (95% CI=0.732-0.833). CONCLUSION: Relatively young age (<54.5 years), Hashimoto's thyroiditis, the diameter of the maximal nodule, and punctate echogenic foci were independently associated with thyroid malignancy in patients with maximal thyroid nodules ≥2 cm. Young age (<54.5 years) and TPOAb >31.4 mIU/L were associated with occult PTC.

Individual and combined hepatocytotoxicity of DDT and cadmium in vitro.

The organochlorine insecticide dichlorodiphenyltrichloroethane (DDT) and heavy metal cadmium (Cd) are widespread environmental pollutants. They are persistent in the environment and can accumulate in organisms. Although the individual toxicity of DDT and Cd has been well documented, their combined toxicity is still not clear. Since liver is their common target, in this study, the individual and combined toxicity of DDT and Cd in human liver carcinoma HepG2 and human normal liver THLE-3 cell lines were investigated. The results showed that DDT and Cd inhibited the viability of HepG2 and THLE-3 cells dose-dependently and altered lysosomal morphology and function. Intracellular reactive oxygen species and lipid peroxidation levels were induced by DDT and Cd treatment. The combined cytotoxicity of DDT and Cd was greater than their individual cytotoxicity, and the interaction between Cd and DDT was additive on the inhibition of cell viability and lysosomal function of HepG2 cells. The interaction was antagonistic on the inhibition of cell viability of THLE-3 cells. These results may facilitate the evaluation of the cumulative risk of pesticides and heavy metal residues in the environment.

Paeoniflorin Derivative in Paeoniae Radix Aqueous Extract Suppresses Alpha-Toxin of Staphylococcus aureus.

The emergence and dissemination of bacterial infections is paralyzing our public health systems worldwide. Worse still, there are no effective antibiotics against bacterial toxins, which facilitate the infection. Natural herbs that target bacterial toxins may be a better choice for therapy of infectious diseases. However, most natural drugs present unknown compositions and unclear mechanisms. Here we demonstrated that the Chinese herb Paeoniae Radix aqueous extract (PRAE) could suppress alpha-toxin (α-toxin) of Staphylococcus aureus. We observed that the paeoniflorin derivative (PRAE-a) derivative in PRAE significantly abolished the hemolytic activity of S. aureus α-toxin. The analyses of high-performance liquid chromatography (HPLC), mass spectrometer (MS), Fourier transform infrared spectrometer (FTIR), and nuclear magnetic resonance (NMR) showed that PRAE-a was a glycoside compound with a paeoniflorin nucleus. We further found that PRAE-a disrupted the pore-forming ability of α-toxin by prevention of the dimer to heptamer. Therefore, PRAE-a proved to be an effective therapy for S. aureus lung infections in mice by inhibiting α-toxin. Collectively, these results highlighted that PRAE-a can be used as an antibacterial agent to attenuate S. aureus virulence by targeting α-toxin.

Lapatinib alleviates TOCP-induced axonal damage in the spinal cord of mouse.

Neuregulin-1 (NRG1), a family of EGF-like factors that activates ErbB receptors, can regulate the proliferation, migration, and myelinating of Schwann cells. We previously reported that NRG1/ErbB signal is responsible for organophosphate (OP)-induced delayed neuropathy (OPIDN) in hens, a susceptive animal model to neuropathic organophosphorous compounds. Our previous study discovered that a neuropathic OP, tri-o-cresyl phosphate (TOCP) activated NRG1/ErbB signaling pathway in both spinal cord and sciatic nerves of hens during the formation of OPIDN and lapatinib, a non-selective antagonist of ErbB1 and ErbB2 receptors, alleviated the toxicity. In this study, we intended to further look into the potential role of NRG1 in the pathogenesis of TOCP-induced axon damage in spinal cord and sciatic nerves and whether lapatinib could also rescue this damage in mice, an OPIDN-resistant animal model. The results revealed that no obvious toxic signs were observed after single TOCP exposure. However, slight histopathological wreck in lumbar spinal cord and sciatic nerves was found following TOCP intoxication, and the damage in sciatic nerves was characterized by axon degeneration of myelin sheath but not the loss of neural skeleton. Only histopathological damage induced by TOCP in spinal cord could be prevented by lapatinib. The translational expression of NRG1/ErbB signaling molecules was analyzed by both in vivo and in vitro studies. In general, NRG1/ErbB pathway was activated by TOCP while combined treatment with lapatinib attenuated TOCP-induced NRG1/ErbB signaling cascade. The results implied that NRG1/ErbB system may predominately play functional role in spinal cord (central nervous system) but not in sciatic nerves (peripheral nervous system) of mouse subjected to neurotoxic OP, which was confirmed by the study in vitro that lapatinib was not able to attenuate TOCP-induced neurotoxicity in rodent Schwann cell line RSC 96 cells.

Decrease of an intracellular organic osmolyte contributes to the cytotoxicity of organophosphate in neuroblastoma cells in vitro.

Organophosphorus compounds (OP) causes prominent delayed neuropathy in vivo and cytotoxicity to neuronal cells in vitro. The primary target protein of OP's neurotoxicity is neuropathy target esterase (NTE), which can convert phosphatidylcholine (PC) to glycerophosphocholine (GPC). Recent studies reveal that autophagic cell death is important for the initiation and progression of OP-induced neurotoxicity both in vivo and in vitro. However, the mechanism of how OP induces autophagic cell death is unknown. Here it is found that GPC is an important organic osmolyte in the neuroblastoma cells, and treatment with tri-o-cresyl phosphate (TOCP), a representative OP, leads to the decrease of GPC and imbalance of extracellular and intracellular osmolality. Knockdown of GPC metabolizing enzyme glycerophosphodiester phosphodiesterase domain containing 5 (GDPD5) reverses TOCP-induced autophagic cell death, which further supports the notion that the reduced GPC level leads to the autophagic cell death. Furthermore, it is found that autophagic cell death is due to the induction of reactive oxygen species (ROS) and mitochondrial damage by imbalance of osmolality with TOCP treatment. In summary, this study reveals that TOCP treatment decreases GPC level and intracellular osmolality, which induces ROS and mitochondrial damage and leads to the cell death and neurite degradation by autophagy. This study lays the foundation for further investigations on the potential therapeutic approaches for OP neurotoxicity or NTE mutation-related neurological diseases.