Cytotoxicity of vanadium dioxide nanoparticles to human embryonic kidney cell line: Compared with vanadium(IV/V) ions.

Vanadium dioxide (VO2) is a class of thermochromic material with potential applications in various fields. Massive production and wide application of VO2 raise the concern of its potential toxicity to human, which has not been fully understood. Herein, a commercial VO2 nanomaterial (S-VO2) was studied for its potential toxicity to human embryonic kidney cell line HEK293, and two most common vanadium ions, V(IV) and V(V), were used for comparison to reveal the related mechanism. Our results indicate that S-VO2 induces dose-dependent cellular viability loss mainly through the dissolved V ions of S-VO2 outside the cell rather than S-VO2 particles inside the cell. The dissolved V ions of S-VO2 overproduce reactive oxygen species to trigger apoptosis and proliferation inhibition via several signaling pathways of cell physiology, such as MAPK and PI3K-Akt, among others. All bioassays indicate that the differences in toxicity between S-VO2, V(IV), and V(V) in HEK293 cells are very small, supporting that the toxicity is mainly due to the dissolved V ions, in the form of V(V) and/or V(IV), but the V(V)'s behavior is more similar to S-VO2 according to the gene expression analysis. This study reveals the toxicity mechanism of nanosized VO2 at the molecular level and the role of dissolution of VO2, providing valuable information for safe applications of vanadium oxides.

Phytotoxicity of VO2 nanoparticles with different sizes to pea seedlings.

Vanadium dioxide nanoparticles (VO2 NPs) have been massively produced due to their excellent metal-insulator transition characteristics for various applications. Pilot studies indicated the toxicity of VO2 NPs to bacteria and mammalian cells, but the environmental hazards of VO2 NPs to plants have been unrevealed to date. In this study, we reported the inhibitive effects of VO2 NPs to the growth and photosynthesis of pea seedlings. Laboratory synthesized monoclinic VO2 NPs (N-VO2), commercial nanosized VO2 NPs (S-VO2), and commercial microsized VO2 particles (M-VO2) were carefully characterized for environmental toxicity evaluations. VO2 particles were supplemented to culture medium for seed germination and seedling growth. All three VO2 samples did not affect the germination rates of pee seeds, while serious growth inhibition of pea seedlings was observed at 10 mg/L for S-VO2 and N-VO2, and 100 mg/L for M-VO2. VO2 particles had no impact on the chlorophyll contents, but the photosynthesis of leaf was significantly decreased following the consequence of N-VO2 > S-VO2 > M-VO2. The inhibition of photosynthesis was attributed to the damage of acceptor side of photosystem II by VO2 particles at high concentrations. Abundant bioaccumulations of vanadium in roots aroused oxidative damage and changed the root structure. Our results collectively indicated that the phytotoxicity of VO2 NPs was related to the concentration, size and crystalline degree.

A CORM loaded nanoplatform for single NIR light-activated bioimaging, gas therapy, and photothermal therapy in vitro.

Carbon monoxide (CO) can cause mitochondrial dysfunction, inducing apoptosis of cancer cells, which sheds light on a potential alternative for cancer treatment. However, the existing CO-based compounds are inherently limited by their chemical nature, such as high biological toxicity and uncontrolled CO release. Therefore, a nanoplatform - UmPF - that addresses such pain points is urgently in demand. In this study, we have proposed a nanoplatform irradiated by near-infrared (NIR) light to release CO. Iron pentacarbonyl (Fe(CO)5) was loaded in the mesoporous polydopamine layer that was coated on rare-earth upconverting nanoparticles (UCNPs). The absorption wavelength of Fe(CO)5 overlaps with the emission bands of the UCNPs in the UV-visible light range, and therefore the emissions from the UCNPs can be used to incite Fe(CO)5 to control the release of CO. Besides, the catechol groups, which are abundant in the polydopamine structure, serve as an ideal locating spot to chelate with Fe(CO)5; in the meantime, the mesoporous structure of the polydopamine layer improves the loading efficiency of Fe(CO)5 and reduces its biological toxicity. The photothermal effect (PTT) of the polydopamine layer is highly controllable by adjusting the external laser intensity, irradiation time and the thickness of the polydopamine layer. The results illustrate that the combination of CO gas therapy (GT) and polydopamine PTT brought by the final nanoplatform can be synergistic in killing cancer cells in vitro. More importantly, the possible toxic side effects can be effectively prevented from affecting the organism, since CO will not be released in this system without near-infrared light radiation.

[Regulatory effect of curcumin on splenic inflammation in overtraining rats and its mechanism].

Objective: To study the alleviating effects of curcumin on splenic inflammation in overtraining rats by regulating toll-like receptor 4 (TLR4)-p38 mitogen-activated protein kinase (p38 MAPK)/nuclear factor-kappa B (NF-κB) signaling pathway. Methods: Male Wistar rats of 7-week old were divided into control group (C group, 12), overtraining model group (OM group, 11), curcumin + overtraining model group (COM group, 14). C Group did not undergo any exercise intervention. OM and COM group underwent 8-week incremental load swimming training. During the training, rats in the COM group were treated with 200 mg/ (kg·d) curcumin in the volume as 5 ml/kg, and the other groups were treated with an equal volume of 0.5 % sodium carboxymethylcellulose. 24 hours after the last training, the spleen index was calculated by weighing, the pathological changes of the spleen were observed by light microscopy, and the biochemical indicators of blood and spleen were detected. Results: After 8-week incremental load swimming training, the splenic structure in C group was normal under light microscope; the spleen index of OM group was significantly lower than that of C group (P＜0.01) and pathological changes of inflammation were obvious; the spleen index of COM group was significantly higher than that of OM group (P＜0.05) and pathological changes of inflammation were alleviated. Compared with C group, in OM group, the serum levels of corticosterone (Cor), NF-κB, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and TLR4 expression rate on splenic monocytes surface, splenic TNF-α, IL-6 were increased (P＜0.05 or P＜0.01), the expressions of p38 MAPK, phosphorylated p38 mitogen-activated protein kinase (p-p38 MAPK) and NF-κB in spleen were increased (P＜0.05 or P＜ 0.01); serum testosterone (T), serum and splenic interleukin-10 (IL-10) were decreased (P＜0.01). Compared with OM group, in COM group, serum levels of Cor, NF-κB, TNF-α, IL-6 and TLR4 expression rate on splenic monocytes surface, splenic TNF-α, IL-6 were decreased (P＜0.05 or P＜0.01), the expressions of p38 MAPK, p-p38 MAPK and NF-κB in spleen were decreased (P＜ 0.05); serum T, serum and splenic IL-10 were increased (P＜0.05). The trend of T/Cor ratio between groups was consistent with testosterone change. Conclusion: The 8-week incremental load swimming training aggravated inflammation of spleen in rats, led to pathological inflammatory changes. Curcumin supplementation during training can down-regulate expressions of TLR4-p38 MAPK/NF-κB signaling pathway-related proteins, thereby maintaining a dynamic equilibrium between pro-inflammatory/anti-inflammatory cytokines, protecting the spleen.

Cytotoxicity and genotoxicity of low-dose vanadium dioxide nanoparticles to lung cells following long-term exposure.

Vanadium dioxide nanoparticles (VO2 NPs) have been massively produced and widely applied due to their excellent metal-insulator transition property, making it extremely urgent to evaluate their safety, especially for low-dose long-term respiratory occupational exposure. Here, we report a comprehensive cytotoxicity and genotoxicity study on VO2 NPs to lung cell lines A549 and BEAS-2B following a long-term exposure. A commercial VO2 NP, S-VO2, was used to treat BEAS-2B (0.15-0.6 µg/mL) and A549 (0.3-1.2 µg/mL) cells for four exposure cycles, and each exposure cycle lasted for 4 consecutive days; then various bioassays were performed after each cycle. Significant proliferation inhibition was observed in both cell lines after long-term exposure of S-VO2 at low doses that did not cause apparent acute cytotoxicity; however, the genotoxicity of S-VO2, characterized by DNA damage and micronuclei, was only observed in A549 cells. These adverse effects of S-VO2 were exposure time-, dose- and cell-dependent, and closely related to the solubility of S-VO2. The oxidative stress in cells, i.e., enhanced reactive oxygen species (ROS) generation and suppressed reduced glutathione, was the main toxicity mechanism of S-VO2. The ROS-associated mitochondrial damage and DNA damage led to the genotoxicity, and cell proliferation retard, resulting in the cellular viability loss. Our results highlight the importance and urgent necessity of the investigation on the long-term toxicity of VO2 NPs.

Effects of VO2 nanoparticles on human liver HepG2 cells: Cytotoxicity, genotoxicity, and glucose and lipid metabolism disorders.

The rapid development of smart materials stimulates the production of vanadium dioxide (VO2) nanomaterials. This significantly increases the population exposure to VO2 nanomaterials via different pathways, and thus urges us to pay more attentions to their biosafety. Liver is the primary accumulation organ of nanomaterials in vivo, but the knowledge of effects of VO2 nanomaterials on the liver is extremely lacking. In this work, we comprehensively evaluated the effects of a commercial VO2 nanoparticle, S-VO2, in a liver cell line HepG2 to illuminate the potential hepatic toxicity of VO2 nanomaterials. The results indicated that S-VO2 was cytotoxic and genotoxic to HepG2 cells, mainly by inhibiting the cell proliferation. Apoptosis was observed at higher dose of S-VO2, while DNA damage was detected at all tested concentrations. S-VO2 particles were internalized by HepG2 cells and kept almost intact inside cells. Both the particle and dissolved species of S-VO2 contributed to the observed toxicities. They induced the overproduction of ROS, and then caused the mitochondrial dysfunction, ATP synthesis interruption, and DNA damages, consequently arrested the cell cycle in G2/M phase and inhibited the proliferation of HepG2 cells. The S-VO2 exposure also resulted in the upregulations of glucose uptake and lipid content in HepG2 cells, which were attributed to the ROS production and autophagy flux block, respectively. Our findings offer valuable insights into the liver toxicity of VO2 nanomaterials, benefiting their safely practical applications.

A Case with Rectal Cancer Relapses After Clinical Complete Remission Following Neoadjuvant Chemoradiotherapy.

Despite advancements in diagnosis and therapy, relapse of rectal cancer after clinical complete remission (cCR) remains a frequent event. The key factors influencing the treatment strategy for the management of patients achieving cCR following neoadjuvant chemoradiotherapy (Neo-CRT) remain to be identified. We present the case of a 64-year-old man with rectal cancer. The patient was initially admitted to the hospital in September 2011 with a 3-month history of change in his stools. Following his re-hospitalization in November 2011, a biopsy specimen of the neoplasm suggested the presence of rectal adenocarcinoma; laboratory investigations also revealed elevated levels of carcinoembryonic antigens (CEA; carbohydrate antigen 199) in the serum. Subsequently, the patient received Neo-CRT, as well as symptomatic and supportive treatment. The level of serum CEA returned to normal, without signs of swollen lymph nodes in the pelvic cavity. The patient was diagnosed with rectal cancer based on the elevated level of serum CEA, colonoscopy, and contrast-enhanced magnetic resonance imaging. He relapsed 4 months after cCR following Neo-CRT and underwent laparoscopic Miles' surgery in April 2013. The relapse may have been mainly attributed to residual tumor cells. This case report and literature review may contribute to the clinical recognition of treatment for patients with rectal cancer achieving cCR following Neo-CRT.

Down-regulation of mir-542-3p promotes neointimal formation in the aging rat.

AIM: To explore mir-542-3p mediated inhibition of vascular smooth muscle cell (VSMC) proliferation through the inhibition of Syk activation. METHODS AND RESULTS: MicroRNA (mir)-542-3p was selected for analysis based on miRNA microarray and qRT-PCR results. In vitro mir-542-3p expression was significantly downregulated in old (o)VSMCs compared with young (y)VSMCs under serum stimulation conditions. Upregulation of mir-542-3p in oVSMCs significantly inhibited VSMC proliferation, whereas downregulation of mir-542-3p in yVSMCs increased VSMC proliferation. We identified spleen tyrosine kinase (Syk) as a direct target of mir-542-3p by database search, and showed that its expression and phosphorylation were higher in oVSMCs than in yVSMCs after serum stimulation. Luciferase assays confirmed that Syk is a direct target of miR-3542-3p. Knock-down of mir-542-3p in yVSMCs inhibited the activation of the Syk downstream effectors STAT3 and STAT5, whereas mir-542-3p overexpression enhanced STAT3 and STAT5 activities. In a rat balloon injury model, mir-542-3p inhibited neointima formation and proliferating cell nuclear antigen (PCNA) protein expression. CONCLUSION: Mir-542-3p modulates VSMC proliferation via the Syk/STAT3-STAT5 axis. Downregulation of mir-542-3p may explain age-related neointimal hyperplasia in rats.

Sleep quality changes in insomniacs and non-insomniacs after acute altitude exposure and its relationship with acute mountain sickness.

OBJECTIVE: We aimed to observe the changes in subjective sleep quality among insomniacs and non-insomniacs after acute ascending to 3,700 m and its possible relationship with acute mountain sickness (AMS). METHODS: A total of 600 adult men were recruited. Subjects' subjective sleep quality was evaluated by the Athens Insomnia Scale. AMS was assessed using the Lake Louise scoring system. Arterial oxygen saturation was measured. RESULTS: Despite insomnia resolution in only a few subjects, the prevalence of insomnia among insomniacs remained stable at 90% after rapid ascent to 3,700 m. However, among non-insomniacs, the prevalence of insomnia sharply increased to 32.13% in the first day of altitude exposure and progressively reduced to 4.26% by the 60th day of altitude stay. Moreover, the prevalences of insomnia symptoms decreased more markedly from day 1 to day 60 at 3,700 m among non-insomniacs than among insomniacs. At 3,700 m, the prevalence of AMS among insomniacs was 79.01%, 60.49%, and 32.10% on the first, third, and seventh days, respectively, which was significantly higher than that among non-insomniacs. Multivariate regression revealed that elevated Athens Insomnia Scale scores are an independent risk factor for AMS (adjusted odds ratio 1.388, 95% confidence interval: 1.314-1.464, P<0.001), whereas high arterial oxygen saturation and long duration of altitude exposure are protective factors against AMS. CONCLUSION: Our results suggest that the effect of high-altitude exposure on subjective sleep quality is more marked, but disappears more quickly, among non-insomniacs than among insomniacs, whereas AMS is especially common among insomniacs. Moreover, poor subjective sleep quality is a risk factor for AMS.

Pivotal role of activating transcription factor 6α in myocardial adaptation to chronic hypoxia.

Hypoxic states are generally associated with cardiovascular disease. Adaptation to chronic hypoxia is one well-defined means of improving cardiac tolerance to certain kinds of stresses. However, the details of the mechanisms underlying myocardial adaptation to chronic hypoxia are still poorly understood. Hypoxia stresses the endoplasmic reticulum and activates unfolded protein response. However, the behavior of individual signaling pathways can vary markedly over time. By examining myocardial samples from patients with cyanotic congenital cardiac defects, we detected endoplasmic reticulum stress and found that, out of all the components of the unfolded protein response, only activating transcription factor 6α limb was activated in cyanotic patients. The activation of activating transcription factor 6α and expression of glucose regulated protein 78 were notably induced in cardiac myocytes cultured for prolonged hypoxia (1% O(2) for 48 h). When the activation of activating transcription factor 6α under prolonged hypoxia was blocked by chemical inhibitor Brefeldin A, the rate of apoptosis among cardiac myocytes increased and levels of cleaved caspase 3 and cleaved poly ADP ribose polymerase also increased significantly. After the expression of activating transcription factor 6α was knocked down, the activity of cardiac myocytes under prolonged hypoxia decreased and the phosphorylation of c-Jun NH2-terminal kinases increased during the re-oxygenation process (after 72 h of hypoxia). Together, these results indicate that activating transcription factor 6α plays a pivotal role in myocardial adaptation to chronic hypoxia and that the activation of activating transcription factor 6α is one possible mechanism of myocardial preconditioning.

Increase of macrophage migration inhibitory factor (MIF) expression in cardiomyocytes during chronic hypoxia.

BACKGROUND: Macrophage migration inhibitory factor (MIF) might play an important role in the myocardium during chronic hypoxia because MIF protects the heart during myocardial ischemia by activating 5'-adenosine monophosphate activated protein kinase (AMPK). METHODS: We investigated 35 infants with cyanotic or acyanotic cardiac defects and H9c2 embryonic rat cardiomyocytes to examine the effect of chronic hypoxia on the expression of MIF in vivo and in vitro, respectively. RESULTS: We found out an increase of endogenous cardiac MIF expression positively correlated with degree of hypoxia. Also, AMPK activation was elevated while MIF expression was increased in cells exposed to long periods of hypoxia in vitro. There was no significant difference in the growth ratio of cells cultivated in long periods of hypoxia and normoxia. CONCLUSIONS: The expression of MIF is significantly increased in cardiomyocytes exposed to chronic hypoxia, and the activation of AMPK was increased accordingly.