Natural antisense transcription of presenilin in sea urchin reveals a possible role for natural antisense transcription in the general control of gene expression during development

One presenilin gene (PSEN) is expressed in the sea urchin embryo, in the vegetal pole of the gastrula and then mainly in cilia cells located around the digestive system of the pluteus, as we recently have reported. PSEN expression must be accurately regulated for correct execution of these two steps of development. While investigating PSEN expression changes in embryos after expansion of endoderm with LiCl or of ectoderm with Zn2+ by whole-mount in situ hybridization (WISH) and quantitative PCR (qPCR), we detected natural antisense transcription of PSEN. We then found that Endo16 and Wnt5, markers of endo-mesoderm, and of Hnf6 and Gsc, markers of ectoderm, are also sense and antisense transcribed. We discuss that general gene expression could depend on both sense and antisense transcription. This mechanism, together with the PSEN gene, should be included in gene regulatory networks (GRNs) that theorize diverse processes in this species. We suggest that it would also be relevant to investigate natural antisense transcription of PSEN in the field of Alzheimer's disease (AD) where the role of human PSEN1 and PSEN2 is well known.

Flexible Aqueous Cr-Ion Hybrid Supercapacitors with Remarkable Electrochemical Properties in all Climates.

The integration of hostless battery-like metal anodes for hybrid supercapacitors is a realistic design method for energy storage devices with promising future applications. With significant Cr element deposits on Earth, exceptionally high theoretical capacity (1546 mAh g-1), and accessible redox potential (-0.74 V vs. reversible hydrogen electrode) of Cr metals, the design of Cr anodes has rightly come into our focus. This work presents a breakthrough design of a flexible Cr-ion hybrid supercapacitor (CHSC) based on a porous graphitized carbon fabric (PGCF) substrate prepared by K2FeO4 activation. In the CHSC device, PGCF acts as both a current collector and cathode material due to its high specific surface area and superior conductivity. The use of a highly concentrated LiCl-CrCl3 electrolyte with high Cr plating/stripping efficiency and excellent antifreeze properties enables the entire PGCF-based CHSC to achieve well-balanced performance in terms of energy density (up to 1.47 mWh cm-2), power characteristics (reaching 9.95 mW cm-2) and durability (95.4 % capacity retention after 30,000 cycles), while realizing it to work well under harsh conditions of -40 °C. This work introduces a new concept for low-temperature energy storage technology and confirms the potential application of Cr anodes in hybrid supercapacitors.

Involvement of Glycogen Synthase Kinase 3ß (GSK3ß) in Formation of Phosphorylated Tau and Death of Retinal Ganglion Cells of Rats Caused by Optic Nerve Crush.

Tauopathy is a neurodegenerative condition associated with oligomeric tau formation through abnormal phosphorylation. We previously showed that tauopathy is involved in death of retinal ganglion cells (RGCs) after optic nerve crush (ONC). It has been proposed that glycogen synthase kinase 3ß (GSK3ß) is involved in the hyperphosphorylation of tau in Alzheimer's disease. To determine the roles of GSK3ß in tauopathy-related death of RGCs, lithium chloride (LiCl), a GSK3ß inhibitor, was injected intravitreally just after ONC. The neuroprotective effects of LiCl were determined by counting Tuj-1-stained RGCs on day 7. Changes of phosphorylated (ser 396) tau in the retina were determined by Simple Western analysis (WES) on day 3. Retinal GSK3ß levels were determined by immunohistochemistry (IHC) and an ELISA. There was a 1.9- and 2.1-fold increase in the levels of phosphorylated tau monomers and dimers on day 3 after ONC. LiCl significantly suppressed the increase in the levels of phosphorylated tau induced by ONC. GSK3ß was mainly present in somas of RGCs, and ELISA showed that retinal levels increased to 2.0-fold on day 7. IHC showed that the GSK3ß expression increased over time and remained in RGCs that were poorly stained by Tuj-1. The GSK3ß and tau expression was colocalized in RGCs. The number of RGCs decreased from 1881 ± 188 (sham control) to 1150 ± 192 cells/mm2 on day 7, and LiCl preserved the levels at 1548 ± 173 cells/mm2. Accordingly, GSK3ß may be a promising target for some optic nerve injuries.

Cytomegalovirus infection induces Alzheimer's disease-associated alterations in tau.

Alzheimer's disease (AD) manifests with loss of neurons correlated with intercellular deposition of amyloid (amyloid plaques) and intracellular neurofibrillary tangles of hyperphosphorylated tau. However, targeting AD hallmarks has not as yet led to development of an effective treatment despite numerous clinical trials. A better understanding of the early stages of neurodegeneration may lead to development of more effective treatments. One underexplored area is the clinical correlation between infection with herpesviruses and increased risk of AD. We hypothesized that similar to work performed with herpes simplex virus 1 (HSV1), infection with the cytomegalovirus (CMV) herpesvirus increases levels and phosphorylation of tau, similar to AD tauopathy. We used murine CMV (MCMV) to infect mouse fibroblasts and rat neuronal cells to test our hypothesis. MCMV infection increased steady-state levels of primarily high molecular weight forms of tau and altered the patterns of tau phosphorylation. Both changes required viral late gene products. Glycogen synthase kinase 3 beta (GSK3ß) was upregulated in the HSVI model, but inhibition with lithium chloride suggested that this enzyme is unlikely to be involved in MCMV infection mediated tau phosphorylation. Thus, we confirm that MCMV, a beta herpes virus, like alpha herpes viruses (e.g., HSV1), can promote tau pathology. This suggests that CMV infection can be useful as another model system to study mechanisms leading to neurodegeneration. Since MCMV infects both mice and rats as permissive hosts, our findings from tissue culture can likely be applied to a variety of AD models to study development of abnormal tau pathology.

A simple green method for in-situ selective extraction of Li from spent LiFePO4 batteries by synergistic effect of deep-eutectic solvent and ozone.

Efficient and clean extraction lithium (Li) from spent LiFePO4 batteries (LIBs) still remains a challenge. In this paper, a green deep eutectic solvent (DES) based on ethylene glycol (EG) and choline chloride (CC), combined with ozone (O3) from air source, realized highly selective leaching Li from LiFePO4 in situ for the first time. The influence of experimental parameters on Li and Fe leaching efficiencies (ηLi, ηFe) were studied by orthogonal and single-factor tests, and ηLi ≥ 92.2% while ηFe ≤ 1.6% were obtained under the optimal conditions (6 h, 20 g/L, 8EG:1CC, 40 °C). The impurity Fe in the filtrate was completely precipitated as amorphous FePO4·3H2O after heating (150 °C, 0.5 h), achieving a pure Li-solution. The leaching mechanism elucidated that the synergistic effect (acidification, replacement and oxidation reaction) between the DES and O3 determined the phase transition of Li and Fe, promoting the efficient selective extraction of Li and in-situ separation of Fe (FePO4). The average ηLi and ηFe were separately 85.4% and 2.0% after ten cycles of the 8EG:1CC, indicative of its' excellent reusability. Meanwhile, LiCl was recovered from the filtrate. This process avoided the use of strong acid/alkali and discharge of waste water, providing fresh perspectives on the green recovery of spent LiFePO4 batteries.

Lithium chloride inhibits infectious bronchitis virus-induced apoptosis and inflammation.

Avian infectious bronchitis (IB) was caused by infectious bronchitis virus (IBV), a coronavirus, which leads to enormous economic losses in the poultry industry. Studies have shown that lithium chloride (LiCl) is a good virus inhibitor. Through cell culture, virus infection, and RT-qPCR, we found that LiCl could down-regulate the apoptosis-related genes Caspase-3 and Bax, up-regulate Bcl-2, and down-regulate the inflammatory-related genes (NF-κB, NLRP3, TNF-α, and IL-1ß) via inhibiting virus replication. Finally, clinical trials showed that LiCl could inhibit IBV-induced apoptosis and inflammatory in chicken embryos as well as reduce the mortality and deformity rate of chicken embryos. The results showed that LiCl has antiviral activity against IBV and clinical effects. Further studies are required to explore the exact action mechanism of LiCl on IBV-induced apoptosis and inflammation.

Aquaporins: Important players in the cardiovascular pathophysiology.

Aquaporin is a membrane channel protein widely expressed in body tissues, which can control the input and output of water in cells. AQPs are differentially expressed in different cardiovascular tissues and participate in water transmembrane transport, cell migration, metabolism, inflammatory response, etc. The aberrant expression of AQPs highly correlates with the onset of ischemic heart disease, myocardial ischemia-reperfusion injury, heart failure, etc. Despite much attention to the regulatory role of AQPs in the cardiovascular system, the translation of AQPs into clinical application still faces many challenges, including clarification of the localization of AQPs in the cardiovascular system and mechanisms mediating cardiovascular pathophysiology, as well as the development of cardiovascular-specific AQPs modulators.Therefore, in this study, we comprehensively reviewed the critical roles of AQP family proteins in maintaining cardiovascular homeostasis and described the underlying mechanisms by which AQPs mediated the outcomes of cardiovascular diseases. Meanwhile, AQPs serve as important therapeutic targets, which provide a wide range of opportunities to investigate the mechanisms of cardiovascular diseases and the treatment of those diseases.

Enhancing osteoblast differentiation through small molecule-incorporated engineered nanofibrous scaffold.

OBJECTIVE: This study aimed to investigate the effect of small molecules incorporated into the engineered nanofibrous scaffold to enhance the osteoblast differentiation MATERIALS AND METHODS: Poly-ε-caprolactone (PCL) nanofiber matrices with lithium chloride (LiCl) were fabricated using the electrospinning technique. Scaffolds were characterized using scanning electron microscopy (SEM) and energy-dispersive X-ray (EDX). Scaffolds were seeded with MC3T3-E1 cells and assessed using Western blots (ß-catenin), alamarBlue assay (proliferation), qPCR (osteoblast differentiation), and mineralization (Alizarin Red staining). RESULTS: We observed LiCl nanofiber scaffolds induced concentration-dependent cell proliferation that correlated with an increased ß-catenin expression indicating sustained Wnt signaling. Next, we examined osteoblast differentiation markers such as osteocalcin (OCN) and Runt-related transcription factor 2 (Runx2) and noted increased expression in LiCl nanofiber scaffolds. We also noted increased bone morphogenetic protein (BMP-2, 4, and 7) expressions suggesting activated Wnt can promote cures to further osteogenic differentiation. Finally, Alizarin Red staining demonstrated increased mineral deposition in LiCl-incorporated nanofiber scaffolds. CONCLUSIONS: Together, these results indicated that LiCl-incorporated nanofiber scaffolds enhance osteoblast differentiation. CLINICAL RELEVANCE: Small molecule-incorporated nanofibrous scaffolds are an innovative clinical tool for bone tissue engineering.

An overview of solutions for airborne viral transmission reduction related to HVAC systems including liquid desiccant air-scrubbing.

The spread of the coronavirus SARS-CoV-2 affects the health of people and the economy worldwide. As air transmits the virus, heating, ventilation and air-conditioning (HVAC) systems in buildings, enclosed spaces and public transport play a significant role in limiting the transmission of airborne pathogens at the expenses of increased energy consumption and possibly reduced thermal comfort. On the other hand, liquid desiccant technology could be adopted as an air scrubber to increase indoor air quality and inactivate pathogens through temperature and humidity control, making them less favourable to the growth, proliferation and infectivity of microorganisms. The objectives of this study are to review the role of HVAC in airborne viral transmission, estimate its energy penalty associated with the adoption of HVAC for transmission reduction and understand the potential of liquid desiccant technology. Factors affecting the inactivation of pathogens by liquid desiccant solutions and possible modifications to increase their heat and mass transfer and sanitising characteristics are also described, followed by an economic evaluation. It is concluded that the liquid desiccant technology could be beneficial in buildings (requiring humidity control or moisture removal in particular when viruses are likely to present) or in high-footfall enclosed spaces (during virus outbreaks).

Adenosine Kinase Isoforms in the Developing Rat Hippocampus after LiCl/Pilocarpine Status Epilepticus.

LiCl/pilocarpine status epilepticus (SE) induced in immature rats leads, after a latent period, to hippocampal hyperexcitability. The excitability may be influenced by adenosine, which exhibits anticonvulsant activity. The concentration of adenosine is regulated by adenosine kinase (ADK) present in two isoforms-ADK-L and ADK-S. The main goal of the study is to elucidate the changes in ADK isoform expression after LiCl/pilocarpine SE and whether potential changes, as well as inhibition of ADK by 5-iodotubercidin (5-ITU), may contribute to changes in hippocampal excitability during brain development. LiCl/pilocarpine SE was elicited in 12-day-old rats. Hippocampal excitability in immature rats was studied by the model of hippocampal afterdischarges (ADs), in which we demonstrated the potential inhibitory effect of 5-ITU. ADs demonstrated significantly decreased hippocampal excitability 3 days after SE induction, whereas significant hyperexcitability after 20 days compared to controls was shown. 5-ITU administration showed its inhibitory effect on the ADs in 32-day-old SE rats compared to SE rats without 5-ITU. Moreover, both ADK isoforms were examined in the immature rat hippocampus. The ADK-L isoform demonstrated significantly decreased expression in 12-day-old SE rats compared to the appropriate naïve rats, whereas increased ADK-S isoform expression was revealed. A decreasing ADK-L/-S ratio showed the declining dominance of ADK-L isoform during early brain development. LiCl/pilocarpine SE increased the excitability of the hippocampus 20 days after SE induction. The ADK inhibitor 5-ITU exhibited anticonvulsant activity at the same age. Age-related differences in hippocampal excitability after SE might correspond to the development of ADK isoform levels in the hippocampus.

Anchoring LiCl in the Nanopores of Metal-Organic Frameworks for Ultra-High Uptake and Selective Separation of Ammonia.

Ammonia (NH3 ) is an important chemical raw material and a unique carbon-free fuel with high hydrogen energy density. Thus, NH3 capture, storage, and desorption are of significant importance. However, high capacity capture, low energy desorption, and selective separation of NH3 are still challengs so far. Here, we report high-performance hybrid sorbents by anchoring LiCl in the nanopores of MIL-53-(OH)2 metal-organic frameworks (MOFs). It is found that the optimal composite shows a capture capacity of 33.9 mmol g-1 NH3 at 1.0 bar and 25 °C, which far exceeds the current record among the reported porous materials. Notably, the excellent capture capacity at low pressure and high temperature makes it possible to selectively capture NH3 from NH3 /N2 , NH3 /CO2 , and NH3 /H2 O. It is revealed that synergistic action of NH3 coordination to the highly dispersed Li+ in the MOF nanopores and hydrogen bonding of NH3 with Cl- account for such an excellent capture and selectivity performance.

LiCl attenuates impaired learning and memory of APP/PS1 mice, which in mechanism involves α7 nAChRs and Wnt/ß-catenin pathway.

We examined the mechanism by which lithium chloride (LiCl) attenuates the impaired learning capability and memory function of dual-transgenic APP/PS1 mice. Six- or 12-month-old APP/PS1 and wild-type (WT) mice were randomized into four groups, namely WT, WT+Li (100 mg LiCl/kg body weight, gavage once daily), APP/PS1 and APP/PS1+Li. Primary rat hippocampal neurons were exposed to ß-amyloid peptide oligomers (AßOs), LiCl and/or XAV939 (inhibitor of Wnt/ß-catenin) or transfected with small interfering RNA against the ß-catenin gene. In the cerebral zone of APP/PS1 mice, the level of Aß was increased and those of α7 nicotinic acetylcholine receptors (nAChR), phosphor-GSK3ß (ser9), ß-catenin and cyclin D1 (protein and/or mRNA levels) reduced. Two-month treatment with LiCl at ages of 4 or 10 months weakened all of these effects. Similar expression variations were observed for these proteins in primary neurons exposed to AßOs, and these effects were attenuated by LiCl and aggravated by XAV939. Inhibition of ß-catenin expression lowered the level of α7 nAChR protein in these cells. LiCl attenuates the impaired learning capability and memory function of APP/PS1 mice via a mechanism that might involve elevation of the level of α7 nAChR as a result of altered Wnt/ß-catenin signalling.

Investigation for GSK3ß expression in diabetic osteoporosis and negative osteogenic effects of GSK3ß on bone marrow mesenchymal stem cells under a high glucose microenvironment.

Osteoporosis is a common skeletal complication of diabetes mellitus (DM). The mechanisms underlying the pathophysiology of diabetic osteoporosis are complex. Glycogen synthase kinase-3ß (GSK-3ß) is a widely expressed serine/threonine kinase and associated with both DM and bone metabolism, which arouse our concern. In this study, we established the diabetic mouse model by high-fat diet combined with streptozotocin injection. Decreased bone mass and reduced osteogenesis were observed in femurs of the mice. Besides, we identified that there is an activated expression of GSK3ß in the bone marrow mesenchymal stem cells (BMSCs) of diabetic mice. To explore the link between GSK3ß and diabetic osteoporosis, we exposed BMSCs to a high glucose microenvironment in vitro and discovered that the glucose-induced GSK3ß activation has negative osteogenic effects on BMSCs by suppressing ß-catenin/Tcf7/Ccn4 signaling axis. Inhibition of GSK3ß by specific concentrations of LiCl could reverse the impaired osteogenesis of BMSCs and increase expression of ß-catenin, Tcf7 and Ccn4. Our research indicated that abnormal activation of GSK3ß plays a role in diabetic osteoporosis and might be a potential target to treat diabetic osteoporosis.

LiCl induces apoptosis via CHOP/NOXA/Mcl-1 axis in human choroidal melanoma cells.

BACKGROUND: Choroidal melanoma is the most common primary intraocular malignancy that occurs in adults. Lithium Chloride Promotes Apoptosis in Human Leukemia NB4 Cells by Inhibiting Glycogen Synthase Kinase-3 Beta. In this study, we aimed to understand whether LiCl exerts anticancer effects on choroidal melanoma cells and elucidate the underlying molecular mechanisms. METHODS: Human choroidal melanoma cells were treated with LiCl, and cell survival was assessed with MTT assays. Cell reproductive viability was measured by plate colony formation assays. Cell apoptosis was evaluated using flow cytometry, and proteins were detected using western blotting. A human choroidal melanoma xenograft model was established to demonstrate the effect of LiCl on human choroidal melanoma in vivo. RESULTS: We found that LiCl inhibited cell survival and clonogenic potential and induced apoptosis in human choroidal melanoma cells. LiCl also reduced the proliferation of choroidal melanoma cells in vivo. Moreover, the upregulation of NOXA and downregulation of Mcl-1 were responsible for LiCl-induced apoptosis. Mcl-1 overexpression obviously impaired LiCl-induced apoptosis and cleavage of caspase8, caspase9, caspase3 and PARP. Moreover, the protein expression of endoplasmic reticulum stress markers, including IRE1α, Bip, p-eIF2α, ATF4 and CHOP, were upregulated following treatment with LiCl. When CHOP expression was knocked down and cells were treated with LiCl, the protein level of NOXA was partially increased, and Mcl-1 expression was increased, while the cleavage of caspase8, caspase9, caspase3 and PARP that was induced by the LiCl was reduced compared with the vehicle treated group. Prolonged ER stress results in the activation of the apoptotic pathway. CONCLUSIONS: In summary, LiCl induced an endoplasmic reticulum stress response while activating intrinsic apoptosis. Furthermore, the CHOP/NOXA/Mcl-1 axis contributed to LiCl-induced apoptosis both in vitro and in vivo. The present study provides important mechanistic insight into potential cancer treatments involving LiCl and enhances the understanding of human choroidal melanoma.

External modulation of Rotimer exudate secretion in monogonant rotifers.

The Rotimer, a rotifer-specific biopolymer, is an exogenic bioactive exudate secreted by different monogonant species (e.g. Euchlanis dilatata or Lecane bulla). The production of this viscoelastic biomolecule is induced by different micro-particles, thereby forming a special Rotimer-Inductor Conglomerate (RIC) in a web format. In this case, the water insoluble Carmine crystals, filtered to size (max. diameter was 50 µm), functioned as an inductor. The RIC production is an adequate empirical indicator to follow up this filamentous biopolymer secretion experientially; moreover, this procedure is very sensitive to the environmental factors (temperature, pH, metals and possible natural pollutant agents). The above mentioned species show completely different reactions to these factors, except to the presence of calcium and to the modulating effects of different drugs. One of the novelties of this work is that the Rotimer secretion and consequently, the RIC-formation is a mutually obligatory and evolutionary calcium-dependent process in the concerned monogonants. This in vivo procedure needs calcium, both for the physiology of animals and for fiber formation, particularly in the latter case. The conglomerate covered area (%) and the detection of the longest filament (mm) of the given RIC were the generally and simultaneously applied methods in the current modulating experiments. Exploring the regulatory (e.g. calcium-dependency) and stimulating (e.g. Lucidril effect) possibilities of biopolymer secretion are the basis for optimizing the RIC-production capacities of these micro-metazoans.

Prolonged Heat Stress of Lactobacillus paracasei GCRL163 Improves Binding to Human Colorectal Adenocarcinoma HT-29 Cells and Modulates the Relative Abundance of Secreted and Cell Surface-Located Proteins.

Lactobacillus casei group bacteria improve cheese ripening and may interact with host intestinal cells as probiotics, where surface proteins play a key role. Three complementary methods [trypsin shaving (TS), LiCl-sucrose (LS) extraction, and extracellular culture fluid precipitation] were used to analyze cell surface proteins of Lactobacillus paracasei GCRL163 by label-free quantitative proteomics after culture to the mid-exponential phase in bioreactors at pH 6.5 and temperatures of 30-45 °C. A total of 416 proteins, including 300 with transmembrane, cell wall anchoring, and secretory motifs and 116 cytoplasmic proteins, were quantified as surface proteins. Although LS caused significantly greater cell lysis as growth temperature increased, higher numbers of extracytoplasmic proteins were exclusively obtained by LS treatment. Together with the increased positive surface charge of cells cultured at supra-optimal temperatures, proteins including cell wall hydrolases Msp1/p75 and Msp2/p40, α-fucosidase AlfB, SecA, and a PspC-domain putative adhesin were upregulated in surface or secreted protein fractions, suggesting that cell adhesion may be altered. Prolonged heat stress (PHS) increased binding of L. paracasei GCRL163 to human colorectal adenocarcinoma HT-29 cells, relative to acid-stressed cells. This study demonstrates that PHS influences cell adhesion and relative abundance of proteins located on the surface, which may impact probiotic functionality, and the detected novel surface proteins likely linked to the cell cycle and envelope stress.

Modified chemical method for efficient transformation and diagnosis in Pichia pastoris.

In the present study, green fluorescence protein (GFP) was used as a candidate protein to test and optimize a robust chemical transformation procedure in P. pastoris. Towards this, it was adjudged that pretreatment of P. pastoris cells with lithium chloride (LiCl) and its optimal concentration is critical for efficient transformation. Using three different methods (M1: 100 mM LiCl, 10 min, M2: 1 M LiCl, 10 min and M3: 1 M LiCl, 1 h), it was found that concentration and incubation time for LiCl treatment significantly affects the transformation efficiency. The transformation efficiency (transformants/µg DNA) was observed to be 1.01 × 102, 5.07 × 103 and 6.52 × 103 using methods M1, M2 and M3, respectively, indicating the superiority of M3. Moreover, presence of the GFP gene in the positive transformants was confirmed using a novel colony PCR method where the colonies were treated with LiCl prior to GFP specific amplification. Also, it was established using fluorescence microscopy and western blot analysis that increasing zeocin concentration as a post transformational vector amplification (PTVA) strategy increased the fluorescence and gene expression, respectively. Further, RT-qPCR revealed that the gene copy number using methods M1, M2 and M3 were 2.97, 5.26 and 7.19, respectively, when 500 µg/ml zecocin was used for selection, thus corroborating western blot results. In conclusion, we demonstrate a cheap and robust chemical method for achieving higher transformation efficiency in P. pastoris and a simple procedure for colony-PCR based-diagnosis alleviating the need for enzymatic treatment.

Lithium chloride reduced the level of oxidative stress in brains and serums of APP/PS1 double transgenic mice via the regulation of GSK3ß/Nrf2/HO-1 pathway.

Aim: The aim of this study is to investigate whether lithium chloride (LiCl) can regulate glycogen synthase kinase-3ß (GSK3ß)/nuclear factor E2 related factor（Nrf2）/heme oxygenase-1 (HO-1) pathway to reduce the injury of oxidative stress in APP/PS1 double transgenic mice.Materials and Methods: The APP/PS1 double transgenic and wild-type (WT) mice were divided randomly into four groups, i.e. WT, WT + LiCl (LiCl 100 mg/kg by gavage once daily), the transgenic + LiCl and the transgenic groups. The expressions of phosphor-GSK3ß (ser9), Nrf2 and HO-1 at protein levels were detected by Western blotting. The activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and the content of malondialdehyde (MDA) were measured by related detection kits. Nissl bodies in different brain regions were examined by Nissl staining.Results: The decreased protein levels of phosphor-GSK3ß (ser9), Nrf2 and HO-1, the declined activities of SOD and GSH-Px, the increased content of MDA and the decreased Nissl bodies in neurons were observed in the brains or serums of APP/PS1 mice as compared with WT. The treatment with LiCl attenuated these changes in the levels of GSK3ß/Nrf2/HO-1 pathway and oxidative stress as well as Nissl bodies induced by APP/PS1 mutation.Conclusion: LiCl reversed the declined activities of SOD and GSH-Px and the increased content of MDA as well as the decreased Nissl bodies in neurons in the brains or serums of APP/PS1 mice, the mechanism of which may be involved in the down-regulation of the activity of GSK3ß and consequently enhances the expressions of Nrf2 and HO-1.

GANT61 and Lithium Chloride Inhibit the Growth of Head and Neck Cancer Cell Lines Through the Regulation of GLI3 Processing by GSK3ß.

Several signaling pathways are aberrantly activated in head and neck squamous cell carcinoma (HNSCC), including the Hedgehog-Gli (HH-GLI), WNT, EGFR, and NOTCH pathways. The HH-GLI pathway has mostly been investigated in the context of canonical signal transduction and the inhibition of the membrane components of the pathway. In this work we investigated the role of downstream inhibitors GANT61 and lithium chloride (LiCl) on cell viability, wound closure, and colony forming ability of HNSCC cell lines. Five HNSCC cell lines were treated with HH-GLI pathway inhibitors affecting different levels of signal transduction. GANT61 and LiCl reduce the proliferation and colony formation capabilities of HNSCC cell lines, and LiCl has an additional effect on wound closure. The major effector of the HH-GLI signaling pathway in HNSCC is the GLI3 protein, which is expressed in its full-length form and is functionally regulated by GSK3ß. LiCl treatment increases the inhibitory Ser9 phosphorylation of the GSK3ß protein, leading to increased processing of GLI3 from full-length to repressor form, thus inhibiting HH-GLI pathway activity. Therefore, downstream inhibition of HH-GLI signaling may be a promising therapeutic strategy for HNSCC.

High Dosage Lithium Treatment Induces DNA Damage and p57Kip2 Decrease.

Lithium salt is the first-line therapeutic option for bipolar disorder and has been proposed as a potential antitumoral drug. The effects of LiCl treatment were investigated in SH-SY5Y, a human neuroblastoma cell line and an in vitro model of dopaminergic neuronal differentiation. LiCl, at the dosage used in psychiatric treatment, does not affect cell proliferation, while at higher doses it delays the SH-SY5Y cell division cycle and for prolonged usage reduces cell viability. Moreover, the ion treatment affects DNA integrity as demonstrated by accumulation of p53 and γH2AX (the phosphorylated form of H2AX histone), two important markers of genome damage. p57Kip2, a CIP/Kip protein, is required for proper neuronal maturation and represents a main factor of response to stress including genotoxicity. We evaluated the effect of lithium on p57Kip2 levels. Unexpectedly, we found that lithium downregulates the level of p57Kip2 in a dose-dependent manner, mainly acting at the transcriptional level. A number of different approaches, mostly based on p57Kip2 content handling, confirmed that the CKI/Kip reduction plays a key role in the DNA damage activated by lithium and suggests the unanticipated view that p57Kip2 might be involved in DNA double-strand break responses. In conclusion, our study identified novel roles for p57Kip2 in the molecular mechanism of lithium at high concentration and, more in general, in the process of DNA repair.