NF-κB induces miR-148a to sustain TGF-ß/Smad signaling activation in glioblastoma.

BACKGROUND: Inflammatory cytokines and transforming growth factor-ß (TGF-ß) are mutually inhibitory. However, hyperactivation of nuclear factor-κB (NF-κB) and TGF-ß signaling both emerge in glioblastoma. Here, we report microRNA-148a (miR-148a) overexpression in glioblastoma and that miR-148a directly suppressed Quaking (QKI), a negative regulator of TGF-ß signaling. METHODS: We determined NF-κB and TGF-ß/Smad signaling activity using pNF-κB-luc, pSMAD-luc, and control plasmids. The association between an RNA-induced silencing complex and QKI, mitogen-inducible gene 6 (MIG6), S-phase kinase-associated protein 1 (SKP1), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA was tested with microribonucleoprotein immunoprecipitation and real-time PCR. Xenograft tumors were established in the brains of nude mice. RESULTS: QKI suppression induced an aggressive phenotype of glioblastoma cells both in vitro and in vivo. Interestingly, we found that NF-κB induced miR-148a expression, leading to enhanced-strength and prolonged-duration TGF-ß/Smad signaling. Notably, these findings were consistent with the significant correlation between miR-148a levels with NF-κB hyperactivation and activated TGF-ß/Smad signaling in a cohort of human glioblastoma specimens. CONCLUSIONS: These findings uncover a plausible mechanism for NF-κB-sustained TGF-ß/Smad activation via miR-148a in glioblastoma, and may suggest a new target for clinical intervention in human cancer.

Nanotechnology in Agriculture: Manganese Ferrite Nanoparticles as a Micronutrient Fertilizer for Wheat.

Limited research has focused on nanoparticle (NP) applications' impact on edible wheat parts in a field environment. Here, we studied the nutritional quality of edible parts of wheat (Triticum aestivum L.) with a field experiment by spraying MnFe2O4 nanoparticles. Wheat was foliar sprayed with 0, 25, 50, and 100 mg/L composite manganese ferrite (MnFe2O4) NPs during 220 d of a growth period. Ionic controls were prepared using the conventional counterparts (MnSO4·H2O and FeSO4·7H2O) to compare with the 100 mg/L MnFe2O4 NPs. After three consecutive foliar applications, nanoparticles demonstrated a substantial elevation in grain yield and harvest index, exhibiting a noteworthy increase to 5.0 ± 0.12 t/ha and 0.46 ± 0.001 in the 100 mg/L NP dose, respectively, concomitant with a 14% enhancement in the grain number per spike. Fe, Mn, and Ca content in grain increased to 77 ± 2.7 mg/kg, 119 ± 2.8 mg/kg, and 0.32 ± 7.9 g/kg in the 100 mg/L NPs, respectively. Compared to the ion treatment, the 100 mg/L NP treatments notably boosts wheat grain crude protein content (from 13 ± 0.79% to 15 ± 0.58%) and effectively lowers PA/Fe levels (from 11 ± 0.7 to 9.3 ± 0.5), thereby improving Fe bioavailability. The VSM results exhibited a slight superparamagnetic behavior, whereas the grains and stems exhibited diamagnetic behavior. The results indicate that the nanomaterial did not accumulate in the grains, suggesting its suitability as an Fe and Mn-rich fertilizer in agriculture. Above all, the foliar application of nanocomposites increased the concentrations of Fe, Mn, and Ca in wheat grains, accompanied by a significant enhancement in grain yield. Therefore, the research results indicate that the foliar application of MnFe2O4 NPs can positively regulate wheat grains' nutritional quality and yield.

Varietal responses to a soil amendment: Balancing cadmium mitigation and mineral biofortification in wheat production.

The application of soil amendment (SA) and the cultivation of low Cd-accumulating varieties have been a widely favored strategy to enable the safe utilization of Cd-contaminated arable land. However, little has been reported on the reciprocal effects of SA on the Cd mitigation and nutritional quality of different wheat varieties. In this study, we evaluated the impact of an SA on agronomic traits, Cd accumulation, translocation and mineral nutrition of 12 wheat varieties in an acidic field with a Cd concentration of 0.46 mg/kg. The results showed that the SA significantly reduced soil DTPA Cd (42.3 %) and resulted in a slight decrease in wheat grain yield (4.24-9.72 %, average 7.62 %). Similarly, the SA significantly reduced grain Cd concentrations (average 61.65 %) while increased the concentrations of beneficial elements such as Mo and Se in all wheat varieties. However, this intervention also led to a reduction in the concentration of essential mineral elements (such as Ca, Fe, and Mn) in whole wheat grain and starchy endosperm, as well as a reduction in their proportion in the bran. Based on genotypic differences, Huaimai 33, Zhenmai 168, Sumai 188 and Yangmai 28 were considered to be the relatively most promising wheat varieties for achieving a balance among food safety, nutritional quality, and economic yield in this region. Taken together, this study highlights the varietal differences in Cd mitigation and mineral accumulation in different wheat varieties in response to the SA, offering new perspectives for phytoremediation and biofortification strategies for Cd-contaminated farmland.

Hyperbaric Oxygen Treatment for Long COVID: From Molecular Mechanism to Clinical Practice.

Long COVID symptoms typically occur within 3 months of an initial COVID-19 infection, last for more than 2 months, and cannot be explained by other diagnoses. The most common symptoms include fatigue, dyspnea, coughing, and cognitive impairment. The mechanisms of long COVID are not fully understood, but several hypotheses have been put forth. These include coagulation and fibrosis pathway activation, inflammatory and autoimmune manifestations, persistent virus presence, and Epstein-Barr virus reactivation. Hyperbaric oxygen therapy (HBOT) is a therapeutic method in which a person inhales 100% oxygen under pressure greater than that of the atmosphere. HBOT has some therapeutic effects, including improvement of microcirculation, inhibition of cytokine release leading to a reduction in inflammatory responses, inhibition of autoimmune responses, and promotion of neurological repair. Several clinical trials have been carried out using HBOT to treat long COVID. The results suggest that HBOT helps to improve symptom severity, reduce symptom duration, and enhance patients' quality of life. It is believed that HBOT is an effective option for patients with long COVID, which is worth actively promoting.

Zinc glycerolate (Glyzinc): A novel foliar fertilizer for zinc biofortification and cadmium reduction in wheat (Triticum aestivum L.).

Sustainable strategies are essential for zinc (Zn) biofortification and cadmium (Cd) reduction in staple food crops. Herein, we evaluated the phytotoxicity of Glyzinc under foliar and root application (FA&RA) in a lab-scale experiment, and then investigated its Zn efficiency and Cd reduction through foliar application on wheat (Triticum aestivum L.) under field conditions. Compared to RA, FA of Glyzinc exhibited no adverse effect on wheat growth and oxidative stresses at all doses. In field conditions, FA of Glyzinc remarkably increased Zn (28.7 %), S (10.4 %), Cu (17.3 %) and crude protein (9.1 %) content in wheat grain at 100 mg/L without damaging wheat yield. Furthermore, FA of Glyzinc significantly reduced the grain phytic acid (PA) (23.7 %) and Cd level (19.5 %), as well as PA to Zn molar ratio (32.3 %). Overall, our results indicate that Glyzinc has great potential as a high-efficiency foliar fertilizer for Zn biofortification and safe crop production in nano-enabled agriculture.

Effects of straw return with N fertilizer reduction on crop yield, plant diseases and pests and potential heavy metal risk in a Chinese rice paddy: A field study of 2 consecutive wheat-rice cycles.

Understanding the comprehensive effect on crop production and quality, soil acidification, and Cd accumulation and distribution for wheat-rice rotation under N fertilization and continuous straw return is important for proper contaminated agricultural soil management. A 2-year paddy field experiment was conducted to study the effects of above factors change in the Zhejiang province, China. Fertilization treatments included: conventional N fertilizer application (N3), 20% reduction of N application (N2), 40% reduction of N application (N1), combined with three portions of straw incorporation: all straws retention (N3), half of the straws into the fields (S2), 20% straws retention(S1). The N1 treatments significantly decreased crop yields compared to N2 and N3 treatments. Except for C2-wheat, soil pH generally decreased with increasing N fertilizer input in the order of N1>N2>N3, regardless of how many straws was amended. Moreover, we found that straw addition plus N fertilization had a intersystem impacts on Cd accumulation, distribution and availability. Although total Cd had different trends among 4 experimental seasons, when the N reduced 20% applied, the DTPA-Cd contents were lowest among 3 out of four experimental seasons, except for that of C2-wheat, where N2 treatments ranked the second lower contents. For most seasons, Cd contents in straws were higher than soils and lowest in grains, and S2N2 treatment performed an intermediate value among all treatments. Furthermore, our study demonstrated that S2 or N2 treatments or S2N2 reduced the potential risk of plant diseases and pests with lower disease index, disease cluster rate. Notably, the relative outbreak of pests was remarkably suppressed under S2 treatments, especially S2N2. Thus, these findings demonstrated that in wheat-rice rotation reducing 20% N fertilization with 50% straw returning may be a win-win practice in this region for the equilibrium between agricultural productivity, quality and low Cd polluted risk.

Identification of wheat (Triticum aestivum L.) genotypes for food safety on two different cadmium contaminated soils.

Over the last decade, human population has been facing great challenges in ensuring appropriate supply of food free from cadmium (Cd) contamination. Selection of genetically low-Cd wheat (Triticum aestivum L.) genotypes, with a large biomass and high accumulation of Cd in straw but low-Cd concentration in grains, is an inventive approach of phytoremediation while keeping agricultural production in moderately contaminated soils. In this study, variations in Cd uptake and translocation among the 30 wheat genotypes in two different sites were investigated in field experiments. Significant differences in grain Cd concentration were observed between the two sites, with averaged values of 0.048 and 0.053 mg kg-1 DW, respectively. Based on straw Cd accumulation, grain Cd concentration, and TFrs, Bainong207 and Aikang58 for site A and Huaimai23 and Yannong21 for site B are promising candidates of low-Cd genotypes, which have considerable potential in achieving phytoremediation while keeping agricultural production on moderately or slightly Cd-polluted soil. The results indicate that it is possible to select the optimal low-Cd genotypes of wheat for different soil types by taking consideration of the effect of soil-wheat genotype interaction on grain Cd concentration.

Ginkgetin attenuates cerebral ischemia-reperfusion induced autophagy and cell death via modulation of the NF-κB/p53 signaling pathway.

Background: Cerebral ischemia-reperfusion (I/R) injury is the key to fatality in cerebrovascular accident, hence further endeavor is warranted to delineate the mechanism underlying its lethal aggravation procedure. In the present study, we aimed to elucidate the anti-autophagy and anti-apoptosis effects of ginkgetin via nuclear factor κB (NF-κB)/p53 pathway in cerebral I/R rats. Methods: Rats were administrated 2-h occlusion of right middle cerebral artery before the 24-h reperfusion followed. There were three doses of ginkgetin (25, 50, 100 mg/kg) given intraperitoneally (i.p.) after the 2-h ischemia, and Pifithrin-α (PFT-α, p53 inhibitor), SN50 (NF-κB inhibitor) and 3-methyladenine (3-MA, autophagy inhibitor) was administered 20 min before the ischemia, respectively. Results: The neurological deficits decreased significantly with the administration of ginkgetin. The concentrations of microtubule-associated protein 1 light chain 3-II and p53 were significantly decreased by PFT-α, 3-MA and ginkgetin. The concentrations of Beclin 1, damage-regulated autophagy modulator, cathepsin B and cathepsin D were significantly decreased due to the administration of PFT-α, ginkgetin and SN50. Furthermore, the concentrations of Bax and p53-upregulated modulator of apoptosis were significantly decreased with that of Bcl-2 being significantly increased by administration of SN50, PFT-α and ginkgetin. Conclusion: Ginkgetin can alleviate cerebral ischemia/reperfusion induced autophagy and apoptosis by inhibiting the NF-κB/p53 signaling pathway.

Tumor Restrictive Suicide Gene Therapy for Glioma Controlled by the FOS Promoter.

Effective suicide gene delivery and expression are crucial to achieving successful effects in gene therapy. An ideal tumor-specific promoter expresses therapeutic genes in tumor cells with minimal normal tissue expression. We compared the activity of the FOS (FBJ murine osteosarcoma viral oncogene homolog) promoter with five alternative tumor-specific promoters in glioma cells and non-malignant astrocytes. The FOS promoter caused significantly higher transcriptional activity in glioma cell lines than all alternative promoters with the exception of CMV. The FOS promoter showed 13.9%, 32.4%, and 70.8% of the transcriptional activity of CMV in three glioma cell lines (U87, U251, and U373). Importantly, however, the FOS promoter showed only 1.6% of the transcriptional activity of CMV in normal astrocytes. We also tested the biologic activity of recombinant adenovirus containing the suicide gene herpes simplex virus thymidine kinase (HSV-tk) driven by the FOS promoter, including selective killing efficacy in vitro and tumor inhibition rate in vivo. Adenoviral-mediated delivery of the HSV-tk gene controlled by the FOS promoter conferred a cytotoxic effect on human glioma cells in vitro and in vivo. This study suggests that use of the FOS-tk adenovirus system is a promising strategy for glioma-specific gene therapy but still much left for improvement.

Poly(3,4-ethylenedioxythiophene)/poly(styrenesulfonate)-poly(vinyl alcohol)/poly(acrylic acid) interpenetrating polymer networks for improving optrode-neural tissue interface in optogenetics.

The field of optogenetics has been successfully used to understand the mechanisms of neuropsychiatric diseases through the precise spatial and temporal control of specific groups of neurons in a neural circuitry. However, it remains a great challenge to integrate optogenetic modulation with electrophysiological and behavioral read out methods as a means to explore the causal, temporally precise, and behaviorally relevant interactions of neurons in the specific circuits of freely behaving animals. In this study, an eight-channel chronically implantable optrode array was fabricated and modified with poly(3,4-ethylenedioxythiophene)/poly(styrenesulfonate)-poly(vinyl alcohol)/poly(acrylic acid) interpenetrating polymer networks (PEDOT/PSS-PVA/PAA IPNs) for improving the optrode-neural tissue interface. The conducting polymer-hydrogel IPN films exhibited a significantly higher capacitance and lower electrochemical impedance at 1 kHz as compared to unmodified optrode sites and showed significantly improved mechanical and electrochemical stability as compared to pure conducting polymer films. The cell attachment and neurite outgrowth of rat pheochromocytoma (PC12) cells on the IPN films were clearly observed through calcein-AM staining. Furthermore, the optrode arrays were chronically implanted into the hippocampus of SD rats after the lentiviral expression of synapsin-ChR2-EYFP, and light-evoked, frequency-dependant action potentials were obtained in freely moving animals. The electrical recording results suggested that the modified optrode arrays showed significantly reduced impedance and RMS noise and an improved SNR as compared to unmodified sites, which may have benefited from the improved electrochemical performance and biocompatibility of the deposited IPN films. All these characteristics are greatly desired in optogenetic applications, and the fabrication method of conducting polymer-hydrogel IPNs can be easily integrated with other modification methods to build a more advanced optrode-neural tissue interface.

Nicotinic acetylcholine receptor agonists may be a novel therapy for endometriosis.

Endometriosis (EMs) is defined as the presence of tissue which somewhat resembles endometrial glands and stroma outside the uterus, and elicit an inflammatory response. This response is accompanied by angiogenesis, adhesions, fibrosis, scarring, neuronal infiltration, and anatomical distortion, resulting in pain and infertility. Owing to the side effects of the present medical treatment and the 10% incidence of recurrence after surgery, EMs is difficult to cure completely so far, that have given impetus to consider novel therapy. Since 1980s, cigarette smoking was found inversely related to the risk of having EMs and it is generally considered that nicotine may play a beneficial role in the pathological process of EMs. Recently, the anti-inflammatory and anti-nociceptive functions of nicotinic acetylcholine receptors (nAChRs) as well as the related mechanisms have become a research hotspot. Based on the above-mentioned, it suggests that the nicotinic acetylcholine receptor agonists may be applied for the treatment of EMs.

Recombinant adeno-associated virus encoding Epstein-Barr virus latent membrane proteins fused with heat shock protein as a potential vaccine for nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a common cancer in Southern China and EBV is the most important pathogenesis. In this study, we explore the potential that a recombinant adeno-associated virus (rAAV) carrying a fusing gene containing heat shock protein as an adjuvant, EBV latent membrane proteins (LMP1 and LMP2) CTL epitope DNA as a vaccine prevents NPC. The tumor vaccine was devised by constructing a chimeric gene which contained EBV LMPs CTL epitope DNA fused with the heat shock protein gene as a tumor vaccine delivered via rAAV. Our results show that this vaccine can eliminate tumors in syngeneic animals and induce CTL activity in vitro. Taken together, the data suggest that this chimeric gene delivered by rAAV has potential as a NPC vaccine for prevention and therapy.