Evaluation of wound healing active principles in the transdermal patch formulated with crude bio wastes and plant extracts against GSK-3 beta - an in silico study.

The wound-healing process is accelerated by inhibiting proteins that decelerate the wound-healing pathway. One of the active proteins involved in enhancing healing at the nuclear level and in gene expression is catenin. Inhibition of Glycogen Synthase Kinase 3ß (GSK3 ß) phosphorylates and degrades catenin via the downstream Wnt signalling pathway, thereby stabilizing catenin. A medicated wound dressing transdermal patch designed with fusion of bio wastes, viz. physiologically clotted fibrin, fish scale collagen, and the ethanolic extract of Mangifera indica (L.) and spider web, was analysed against GSK3ß to enhance healing. In our earlier studies, the compounds present in the transdermal patch were identified using GC-MS analysis; 12 compounds exhibiting the wound healing mechanism were analyzed using PASS software and filtered out. From these 12 compounds, 6 compounds that possessed drug-likeness were screened by SwissADME and vNN-ADMET to dock against GSK3ß in the present work. The PyRx results confirmed the binding of the six ligands to the active site of the target protein. Though the remaining filtered ligands also exhibited inhibitory activity, Molecular dynamics simulation studies were carried out with 100 ns on a complex of 10,12 Tricosadiyonic acid, Nopyl acetate and 2 Methyl 4 Heptanol as they showed binding affinity of -6.2Kcal/mol, -5.7Kcal/mol and -5.1Kcal/mol respectively. The stability of the complex was validated using MD simulation parameters RMSD, RMSF, Rg, and Number of Hydrogen bonds. These results implied that the transdermal patch would be efficient in accelerating the wound healing process through the inactivation of GSK3ß.Communicated by Ramaswamy H. Sarma.

Carbon Dioxide Fractional Laser Treatment Induces Lgr5+ Stem Cell Activation and Hair Regrowth Through the Canonical Wnt/ß-Catenin Pathway.

BACKGROUND: Different types of alopecia have negative impacts on patients. Recently, some kinds of laser or light therapies have been reported to effectively alleviate hair loss. Carbon dioxide fractional laser (CO2FL) treatment is one of the most effective laser treatments, but its beneficial effects and exact mechanism in hair regrowth have not been reported in detail. The purpose of this study was to investigate the effect and molecular mechanism further. METHODS: C57 and Lgr5-Cre: Rosa-mTmG mouse models of hair regrowth were established by CO2FL treatment, and the parameters that induced the best effect were determined. Tissues were harvested on the day prior to the treatment day and on days 3, 5, 7, 10 and 14 after CO2FL. H&E and immunofluorescence staining, RNA sequencing (RNA-seq), quantitative real-time polymerase chain reaction (qPCR), Western blotting (WB) and related inhibitor were used to determine the molecular mechanism underlying the effect of CO2FL treatment on the hair cycle and hair regrowth. In clinical trial, five participants were treated three sessions at 1-month intervals to obverse the effects. RESULTS: Hair regrew and covered the treatment area on the tenth day after CO2FL treatment with the best parameters, while the control group showed signs of hair growth on the 14th day. H&E and immunofluorescence staining showed that the transition of hair follicles (HFs) from telogen to anagen was accelerated, and the rapid activation and proliferation of Lgr5+ hair follicle stem cells (HFSCs) were observed in the treatment group. The RNA-seq, qPCR and WB results indicated that the Wnt pathway was significantly activated after CO2FL treatment. Improvement achieved with CO2FL treatment in clinical trial. CONCLUSIONS: The results of this study suggest that CO2FL treatment can promote hair regrowth by activating Lgr5+ HFSCs and upregulating the Wnt/ß-catenin pathway. Clinical trial results demonstrated that CO2FL treatment will be a promising therapeutic regimen for alopecia. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Vitamin D inhibits bone loss in mice with thyrotoxicosis by activating the OPG/RANKL and Wnt/ß-catenin signaling pathways.

Objective: Vitamin D and thyroid hormones have crucial roles in bone metabolism. This study aims to explore the effects of vitamin D on bone metabolism in mice with thyrotoxicosis and its mechanisms. Methods: 12-week-old mice were randomly divided into 6 groups (6 mice/group), the control (CON) group, vitamin D (VD) group, low-dose LT4 (Low LT4) group, low-dose LT4+VD (Low LT4+VD) group, high-dose LT4 (High LT4) group, high-dose LT4+VD (High LT4+VD) group, LT4 was provided every day and vitamin D3 every other day for 12 weeks. Thyroid function, 25-hydroxy vitamin D, type I collagen carboxy-terminal peptide (CTX), and type I procollagen amino-terminal peptide were determined. In addition, microcomputed tomography, bone histology and histomorphometry, a three-point bending test, and the mRNA expression of osteoprotegerin (OPG), receptor activator of nuclear factor-κB ligand (RANKL) and ß-catenin in bone were conducted. Results: The BMD of lumbar vertebrae and femur decreased and the bone microstructure was destroyed significantly in thyrotoxicosis mice. Addition of vitamin D improved the BMD and bone microstructure only in the low LT4+VD group. Mice with thyrotoxicosis had a significantly higher level of CTX (P<0.05), which was decreased by treatment with vitamin D (P<0.05). The eroded surface per bone surface (Er. S/BS) of the cancellous bone and elongated surface/endocortical perimeter (Er. S/E Pm) of the cortical bone significantly increased in the Low LT4 and High LT4 groups (P<0.05). Treatment with vitamin D significantly decreased the Er. S/BS and Er. S/E Pm. But, treatment with vitamin D did not significantly improve the toughness and rigidity of bones. The ratio of OPG to RANKL and mRNA expression of ß-catenin in the Low LT4+VD group were higher than that in the Low LT4 group (P<0.05). Conclusion: In mice with thyrotoxicosis, treatment with vitamin D can inhibit bone resorption and improve the BMD and trabecular bone architecture by increasing the ratio of OPG to RANKL and upregulating the expression of Wnt/ß-catenin.

Role of Neural Stem Cells and Vitamin D Receptor (VDR)-Mediated Cellular Signaling in the Mitigation of Neurological Diseases.

Specific stem cell-based therapies for treating Alzheimer's disease, Parkinson's disease, and schizophrenia are gaining importance in recent years. Accumulating data is providing further support by demonstrating the efficacy of neural stem cells in enhancing the neurogenesis in the aging brain. In addition to stem cells, recent studies have shown the efficacy of supplementing vitamin D in promoting neurogenesis and neuronal survival. Studies have also demonstrated the presence of mutational variants and single-nucleotide polymorphisms of the vitamin D receptor (VDR) in neurological disorders; however, implications of these mutations in the pathophysiology and response to drug treatment are yet to be explored. Hence, in this article, we have reviewed recent reports pertaining to the role of neural stem cells and VDR-mediated cellular signaling cascades that are involved in enhancing the neurogenesis through Wnt/ß-catenin and Sonic Hedgehog pathways. This review benefits neurobiologists and pharmaceutical industry experts to develop stem cell-based and vitamin D-based therapies to better treat the patients suffering from neurological diseases.

Therapeutic Effects of Curcumin on Osteoarthritis and Its Protection of Chondrocytes Through the Wnt/Β-Catenin Signaling Pathway.

Context: Osteoarthritis (OA) is a high-incidence, chronic condition, with an extremely high prevalence among older adults. OA seriously compromises the normal living of OA patients, and it's imperative to find a novel therapy as soon as possible to improve their prognosis and life quality. Objective: The study intended to investigate the therapeutic effects of Curcumin (Cur) on OA and to explore its preliminary mechanism of action, with the aim of offering more accurate guidance for use of OA therapy. Design: The research team designed a prospective non-randomized controlled trial. Setting: The study took place in the Department of Orthopedics at Sir Run Run Hospital at Nanjing Medical University in Nanjing, China. Participants: Participants were 107 OA patients treated at the hospital between March 2019 and January 2020. Intervention: Participants were divided into two groups, 51 in the Cur group and 56 in the ibuprofen group. Outcome Measures: The clinical efficacy and safety of the two groups were observed. In addition, the research team performed in-vitro studies. Chondrocytes HC-a and C28/I2 were purchased to evaluate the intracellular inflammatory response and apoptosis rate under the intervention of Cur and Wnt/ß-catenin pathway inhibitors. Results: No significant differences existed in the clinical-efficacy rate between the two groups (P > .05), but the Cur group show higher improvements in safety, joint mobility, and inhibition of inflammation (P < .05). In-vitro experiments showed that Cur inhibited the apoptosis rate of chondrocytes and the levels of inflammatory factors, while the Wnt/ß-catenin inhibitor did the opposite (P < .05). Conclusions: Cur can effectively decrease the pathological results of OA, with a remarkable safety profile; its mechanism may be the activation of the Wnt/ß-catenin signaling pathway to inhibit the inflammatory reaction and apoptosis in chondrocytes.

Interaction of NF-κB and Wnt/ß-catenin Signaling Pathways in Alzheimer's Disease and Potential Active Drug Treatments.

The most important neuropathological features of Alzheimer's disease (AD) are extracellular amyloid-ß protein (Aß) deposition, tau protein hyperphosphorylation and activation of neurometabolic reaction in the brain accompanied by neuronal and synaptic damage, and impaired learning and memory function. According to the amyloid cascade hypothesis, increased Aß deposits in the brain to form the core of the senile plaques that initiate cascade reactions, affecting the synapses and stimulating activation of microglia, resulting in neuroinflammation. A growing number of studies has shown that NF-κB and Wnt/ß-catenin pathways play important roles in neurodegenerative diseases, especially AD. In this review, we briefly introduce the connection between neuroinflammation-mediated synaptic dysfunction in AD and elaborated on the mechanism of these two signaling pathways in AD-related pathological changes, as well as their interaction. Based on our interest in natural compounds, we also briefly introduce and conduct preliminary screening of potential therapeutics for AD.

Pulsed Electromagnetic Fields Ameliorate Skeletal Deterioration in Bone Mass, Microarchitecture, and Strength by Enhancing Canonical Wnt Signaling-Mediated Bone Formation in Rats with Spinal Cord Injury.

Spinal cord injury (SCI) leads to extensive bone loss and high incidence of low-energy fractures. Pulsed electromagnetic fields (PEMF) treatment, as a non-invasive biophysical technique, has proven to be efficient in promoting osteogenesis. The potential osteoprotective effect and mechanism of PEMF on SCI-related bone deterioration, however, remain unknown. The spinal cord of rats was transected at vertebral level T12 to induce SCI. Thirty rats were assigned to the control, SCI, and SCI+PEMF groups (n = 10). One week after surgery, the SCI+PEMF rats were subjected to PEMF (2.0 mT, 15 Hz, 2 h/day) for eight weeks. Micro-computed tomography results showed that PEMF significantly ameliorated trabecular and cortical bone microarchitecture deterioration induced by SCI. Three-point bending and nanoindentation assays revealed that PEMF significantly improved bone mechanical properties in SCI rats. Serum biomarker and bone histomorphometric analyses demonstrated that PEMF enhanced bone formation, as evidenced by significant increase in serum osteocalcin and P1NP, mineral apposition rate, and osteoblast number on bone surface. The PEMF had no impact, however, on serum bone-resorbing cytokines (TRACP 5b and CTX-1) or osteoclast number on bone surface. The PEMF also attenuated SCI-induced negative changes in osteocyte morphology and osteocyte survival. Moreover, PEMF significantly increased skeletal expression of canonical Wnt ligands (Wnt1 and Wnt10b) and stimulated their downstream p-GSK3ß and ß-catenin expression in SCI rats. This study demonstrates that PEMF can mitigate the detrimental consequence of SCI on bone quantity/quality, which might be associated with canonical Wnt signaling-mediated bone formation, and reveals that PEMF may be a promising biophysical approach for resisting osteopenia/osteoporosis after SCI in clinics.

Promotive effects of tetrahydroxystilbene glucoside on the differentiation of neural stem cells from the mesencephalon into dopaminergic neurons.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of midbrain dopaminergic (DA) neurons. Neural stem cells (NSCs) are the most promising cells for cell-replacement therapy for PD. However, the poor differentiation and maturation of DA neurons and decreased cell survival after transplantation are a challenge. Tetrahydroxystilbene glucoside (2,3,5,4'-tetrahydroxystilbene-2-O-glucoside; TSG), an active component of the popular traditional Chinese medicinal plant Polygonum multiflorum Thunb, possesses multiple pharmacological actions. In this study, we determined whether TSG can induce neural stem cell (NSCs) differentiation into neurons, especially DA neurons, and the possible involvement of Wnt/ß-catenin signaling pathways. Results revealed that NSCs differentiated primarily into astrocytes when cultured in 2 % serum-containing medium. However, TSG treatment during NSC differentiation in vitro increased the number of Tuj-1-positive neurons, as well as the proportion of tyrosine hydroxylase(TH)-positive cells and dopamine- transporter- positive neurons, a late marker of mature DA neurons. We also found that TSG enhanced the expression of nuclear receptor related factor 1, a transcription factor specific for the development and maintenance of midbrain DA neurons in inducing NSC differentiation into TH -immunoreactive DA neurons. Moreover, TSG upregulated the expression of Wnt/ß-catenin signaling molecules (Wnt1, Wnt3a, Wnt5a, and ß-catenin). However, these promoting effects were significantly inhibited by the application of IWR1, a Wnt signaling-specific blocker in culture. Our findings suggested that TSG may have potential in inducing the DA neuronal differentiation of mouse NSCs mediated by triggering the Wnt/ß-catenin signaling pathway. These results indicated the possible role for TSG in the transplantation of NSCs for PD.

Advancements of compounds targeting Wnt and Notch signalling pathways in the treatment of inflammatory bowel disease and colon cancer.

The Wnt and Notch signalling pathways are important for maintenance of intestinal epithelial barrier integrity by intestinal stem cells (ISCs). Dysfunction of these pathways is implicated in inflammatory bowel disease (IBD) and colon cancer. The objective of this review is to summarise advancements of drugs that regulate Wnt and Notch in the treatment of IBD and colon cancer. The compositions and biological effects of Wnt and Notch modulators in both ISCs and non-ISCs are discussed. The drugs, including phytochemicals, plant extracts, probiotics and synthetic compounds, have been found to regulate Wnt and Notch signalling pathways by targeting regulatory factors (including secreted frizzled-related proteins or pathway proteins such as ß-catenin and γ-secretase) to alleviate IBD and colon cancer. This review highlights the potential for targeting Wnt and Notch pathways to treat IBD and colon cancer.

Capsaicin suppresses breast cancer cell viability by regulating the CDK8/PI3K/Akt/Wnt/ß­catenin signaling pathway.

Breast cancer displays high morbidity and mortality. Despite exerting certain effects, traditional treatments cannot eliminate every cancer cell and may kill normal cells due to inaccurate targeting. However, as a traditional Chinese medicine, capsaicin, an active compound extracted from chili peppers, has displayed potent anticarcinogenic activities in vitro and in vivo, but the underlying mechanism is not completely understood. The pharmacological effects of capsaicin on tumors was evaluated in MDA MB 231 breast cancer cells. The MTT, cell scratch assay, cell cycle analysis, cell transfection, reverse transcription­quantitative PCR and western blotting were performed to investigate the potential antitumor mechanisms of capsaicin. In the present study, the potential anticancer mechanism underlying capsaicin in MDA­MB­231 cells in vitro was investigated. Capsaicin significantly inhibited MDA­MB­231 breast cancer cell viability and migration compared with the control group. The flow cytometry results indicated that capsaicin induced G2/M cell cycle arrest in MDA­MB­231 cells. In addition, capsaicin significantly reduced the expression of cyclin­dependent kinase 8 (CDK8) in breast cancer cells compared with the control group. Moreover, LV­CDK8 small interfering RNA­transduced MDA­MB­231 cells displayed lower CDK8 mRNA and protein expression levels compared with LV­negative control­shRNA­transduced cells. Furthermore, capsaicin significantly reduced the expression levels of phosphorylated (p)­PI3K, p­Akt, Wnt and ß­catenin in vitro compared with the control group. Collectively, the results of the present study suggested that capsaicin inhibited breast cancer cell viability, induced G2/M cell cycle arrest, reduced CDK8 expression levels, decreased the phosphorylation of PI3K and Akt and downregulated Wnt and ß­catenin expression levels in MDA­MB­231 cells.

Wnt/PCP signalling cascade disruption by JNK inhibition as a potential mechanism underlying the teratogenic effects of potato glycoalkaloids.

It is hypothesised that the inhibition of the non-canonical Wnt/PCP intracellular signalling cascade by potato glycoalkaloids, [Formula: see text]-solanine and [Formula: see text]-chaconine, results in an increased risk of neural tube defects (NTDs). One very prominent intracellular signalling pathway with substantial implications in the development and closure of the neural tube is the Wnt/PCP pathway. Experimental inhibition of this results in NTDs. A vital element of this signalling cascade is JNK, which controls the transcription of DNA, which controls cell polarity and directional cell migration. JNK inhibition also results in NTDs experimentally. Through their use in cancer research, [Formula: see text]-solanine and [Formula: see text]-chaconine were found to inhibit metastasis by inhibiting JNK, among other intracellular signalling molecules. Thus, this shows that potato glycoalkaloids increase the likelihood of causing NTDs by inhibiting the proper functioning of JNK in the Wnt/PCP pathway, resulting in defective neural tube closure.

Vitamin D deficiency as a potential risk factor for accelerated aging, impaired hippocampal neurogenesis and cognitive decline: a role for Wnt/ß-catenin signaling.

Vitamin D is an essential fat-soluble vitamin that participates in several homeostatic functions in mammalian organisms. Lower levels of vitamin D are produced in the older population, vitamin D deficiency being an accelerating factor for the progression of the aging process. In this review, we focus on the effect that vitamin D exerts in the aged brain paying special attention to the neurogenic process. Neurogenesis occurs in the adult brain in neurogenic regions, such as the dentate gyrus of the hippocampus (DG). This region generates new neurons that participate in cognitive tasks. The neurogenic rate in the DG is reduced in the aged brain because of a reduction in the number of neural stem cells (NSC). Homeostatic mechanisms controlled by the Wnt signaling pathway protect this pool of NSC from being depleted. We discuss in here the crosstalk between Wnt signaling and vitamin D, and hypothesize that hypovitaminosis might cause failure in the control of the neurogenic homeostatic mechanisms in the old brain leading to cognitive impairment. Understanding the relationship between vitamin D, neurogenesis and cognitive performance in the aged brain may facilitate prevention of cognitive decline and it can open a door into new therapeutic fields by perspectives in the elderly.

Enhancing WNT Signaling Restores Cortical Neuronal Spine Maturation and Synaptogenesis in Tbr1 Mutants.

Tbr1 is a high-confidence autism spectrum disorder (ASD) gene encoding a transcription factor with distinct pre- and postnatal functions. Postnatally, Tbr1 conditional knockout (CKO) mutants and constitutive heterozygotes have immature dendritic spines and reduced synaptic density. Tbr1 regulates expression of several genes that underlie synaptic defects, including a kinesin (Kif1a) and a WNT-signaling ligand (Wnt7b). Furthermore, Tbr1 mutant corticothalamic neurons have reduced thalamic axonal arborization. LiCl and a GSK3ß inhibitor, two WNT-signaling agonists, robustly rescue the dendritic spines and the synaptic and axonal defects, suggesting that this could have relevance for therapeutic approaches in some forms of ASD.

Huaier extract restrains pancreatic cancer by suppressing Wnt/ß-catenin pathway.

Pancreatic cancer is a lethal disease, and new treatments need to be explored. Huaier extract is a traditional Chinese medicine that has been found to exert antitumor properties in some cancers. However, the role of Huaier extract in pancreatic cancer has not been examined. In this study, we found that the proliferation, migration, invasion and EMT (epithelial-mesenchymal transition) of pancreatic cancer cells were suppressed by treatment with Huaier extract and that apoptosis increased. We also observed that expression of ß-catenin was inhibited by Huaier extract. Furthermore, an animal study showed that Huaier extract slowed tumor growth in pancreatic cancer. Our results reveal that Huaier extract suppresses pancreatic cancer by inhibiting Wnt/ß-catenin pathway both in vitro and in vivo.

ZNRF3 Regulates Collagen-Induced Arthritis Through NF-kB and Wnt Pathways.

Although the E3 ubiquitin ligase Zinc and ring finger 3 (ZNRF3) negatively regulates the Wnt signaling pathway, its function in rheumatoid arthritis (RA) is elusive. Here, the effects and the mechanism of ZNRF3 on a mouse model of collagen-induced arthritis (CIA) and human fibroblast-like synoviocytes (FLS) obtained from RA patients were determined. Our results showed that ZNRF3 was highly expressed in tissues and FLSs compared to trauma patients. Lentivirus-mediated silencing of ZNRF3 induced apoptosis decreased cell viability and significantly attenuated inflammation in RA-FLSs via tumor necrosis-α (TNF-α). Additionally, silencing of ZNRF3 reduced knee joint damage and also decreased the level of TNF-α, IL-1ß, and IL-6 in the CIA mouse model. These effects were mediated by the crosstalk between Wnt and NF-κB pathways in RA-FLS.

Electroacupuncture pretreatment prevents ischemic stroke and inhibits Wnt signaling-mediated autophagy through the regulation of GSK-3ß phosphorylation.

Electroacupuncture (EA), a traditional Chinese replacement therapy, is widely accepted to treat ischemic stroke. Increasing evidence show that autophagy is involved in the process of cerebral ischemia injury and the Wnt/GSK3ß pathway, playing an important role in protecting central nervous system. In this study, rats were treated with EA prior to focal ischemia by middle cerebral artery occlusion (MCAO). Deficit score, infarct volumes and levels of autophagy markers, such as LC3I, LC3II and p62, were assessed with either PI3K inhibitor wortmannin or a GSK-3ß inhibitor LiCl. Oxygen-glucose deprivation/re-oxygenation (OGD/R) was made in the primitive neuron in vitro, and was respectively treated with autophagy inhibitors 3-MA, LiCl, GSK3ß siRNA, or mTOR inhibitor rapamycin. The results indicated that EA pretreatment increased the levels of autophagy marker LC3-II and reduced the levels of p62. Meanwhile, deficit outcome was improved, and infarct volumes were reduced by EA pretreatment. Furthermore, the beneficial effects of EA pretreatment were reversed by wortmannin. LiCl and GSK3ß siRNA can mimic the neuroprotective effects of EA pretreatment by downregulating autophagy, and increasing protein levels of p-mTOR, p-GSK3ß and ß-catenin in OGD/R neurons. However, the protective effects of GSK3ß siRNA were blocked by rapamycin. These results suggest that EA pretreatment induces tolerance to cerebral ischemia by inhibiting autophagy via the Wnt pathway through the inhibition of GSK3ß.

Inflammation both increases and causes resistance to FGF23 in normal and uremic rats.

Fibroblast growth factor 23 (FGF23) increases phosphorus excretion and decreases calcitriol (1,25(OH)2D) levels. FGF23 increases from early stages of renal failure. We evaluated whether strict control of phosphorus intake in renal failure prevents the increase in FGF23 and to what extent inflammation impairs regulation of FGF23. The study was performed in 5/6 nephrectomized (Nx) Wistar rats fed diets containing 0.2-1.2% phosphorus for 3 or 15 days. FGF23 levels significantly increased in all Nx groups in the short-term (3-day) experiment. However, at 15 days, FGF23 increased in all Nx rats except in those fed 0.2% phosphorus. In a second experiment, Nx rats fed low phosphorus diets (0.2 and 0.4%) for 15 days received daily intraperitoneal lipopolysaccharide (LPS) injections to induce inflammation. In these rats, FGF23 increased despite the low phosphorus diets. Thus, higher FGF23 levels were needed to maintain phosphaturia and normal serum phosphorus values. Renal Klotho expression was preserved in Nx rats on a 0.2% phosphorus diet, reduced on a 0.4% phosphorus diet, and markedly reduced in Nx rats receiving LPS. In ex vivo experiments, high phosphorus and LPS increased nuclear ß-catenin and p65-NFκB and decreased Klotho. Inhibition of inflammation and Wnt signaling activation resulted in decreased FGF23 levels and increased renal Klotho. In conclusion, strict control of phosphorus intake prevented the increase in FGF23 in renal failure, whereas inflammation independently increased FGF23 values. Decreased Klotho may explain the renal resistance to FGF23 in inflammation. These effects are likely mediated by the activation of NFkB and Wnt/ß-catenin signaling.

Identification of Prognostic Biomarkers and Drugs Targeting Them in Colon Adenocarcinoma: A Bioinformatic Analysis.

Objective: To identify prognostic biomarkers and drugs that target them in colon adenocarcinoma (COAD) based on the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases. Methods: The TCGA dataset was used to identify the top 50 upregulated differentially expressed genes (DEGs), and Gene Expression Omnibus profiles were used for validation. Survival analyses were conducted with the TCGA dataset using the RTCGAToolbox package in the R software environment. Drugs targeting the candidate prognostic biomarkers were searched in the DrugBank and herbal databases. Results: Among the top 50 upregulated DEGs in patients with COAD in the TCGA dataset, the Wnt signaling pathway and cytokine-cytokine receptor interactions and pathways in cancer Kyoto Encyclopedia of Genes and Genomes pathway analysis were enriched in DEGs. Tissue development and regulation of cell proliferation were the main Gene Ontology biological processes associated with upregulated DEGs. MYC and KLK6 were overexpressed in tumors validated in the TCGA, GSE41328, and GSE113513 databases (all P < .001) and were significantly associated with overall survival in patients with COAD (P = .021 and P = .047). Nadroparin and benzamidine were identified as inhibitors of MYC and KLK6 in DrugBank, and 8 herbs targeting MYC, including Da Huang (Radix Rhei Et Rhizome), Hu Zhang (Polygoni Cuspidati Rhizoma Et Radix), Huang Lian (Coptidis Rhizoma), Ban Xia (Arum Ternatum Thunb), Tu Fu Ling (Smilacis Glabrae Rhixoma), Lei Gong Teng (Tripterygii Radix), Er Cha (Catechu), and Guang Zao (Choerospondiatis Fructus), were identified. Conclusion: MYC and KLK6 may serve as candidate prognostic predictors and therapeutic targets in patients with COAD.

High lithium levels in tobacco may account for reduced incidences of both Parkinson's disease and melanoma in smokers through enhanced ß-catenin-mediated activity.

Parkinson's disease (PD) patients have higher rates of melanoma and vice versa, observations suggesting that the two conditions may share common pathogenic pathways. ß-Catenin is a transcriptional cofactor that, when concentrated in the nucleus, upregulates the expression of canonical Wnt target genes, such as Nurr1, many of which are important for neuronal survival. ß-Catenin-mediated activity is decreased in sporadic PD as well as in leucine-rich repeat kinase 2 (LRRK2) and ß-glucosidase (GBA) mutation cellular models of PD, which is the most common genetic cause of and risk for PD, respectively. In addition, ß-catenin expression is significantly decreased in more aggressive and metastatic melanoma. Multiple observational studies have shown smokers to have significantly lower rates of PD as well as melanoma implying that tobacco may contain one or more elements that protect against both conditions. In support, smoker's brains have significantly reduced levels of α-synuclein, a pathological intracellular protein found in PD brain and melanoma cells. Tobacco contains very high lithium levels compared to other plants. Lithium has a broad array of neuroprotective actions, including enhancing autophagy and reducing intracellular α-synuclein levels, and is effective in both neurotoxin and transgenic preclinical PD models. One of lithium's neuroprotective actions is enhancement of ß-catenin-mediated activity leading to increased Nurr1 expression through its ability to inhibit glycogen synthase kinase-3 ß (GSK-3ß). Lithium also has anti-proliferative effects on melanoma cells and the clinical use of lithium is associated with a reduced incidence of melanoma as well as reduced melanoma-associated mortality. This is the first known report hypothesizing that inhaled lithium from smoking may account for the associated reduced rates of both PD and melanoma and that this protection may be mediated, in part, through lithium-induced GSK-3ß inhibition and consequent enhanced ß-catenin-mediated activity. This hypothesis could be directly tested in clinical trials assessing lithium therapy's ability to affect ß-catenin-mediated activity and slow disease progression in patients with PD or melanoma.

YY1-induced upregulation of lncRNA NEAT1 contributes to OGD/R injury-induced inflammatory response in cerebral microglial cells via Wnt/ß-catenin signaling pathway.

Stroke can lead to the serious long-term neurological disability. The dysregulation of long non-coding RNAs (lncRNAs) has been proven to be a pivotal factor for the progression of ischemic stroke. However, it is largely unknown whether lncRNAs regulated the OGD/R injury of cerebral microglial cells. In this study, we designed experiments to reveal the role of lncRNA Nuclear Enriched Abundant Transcript 1 (NEAT1) in the OGD/R injury of microglial cells. We found that NEAT1 contributed to the OGD/R injury and neuroinflammation damage in microglial cells. Moreover, the molecular mechanism involved in the NEAT1-mediated OGD/R injury. Mechanism investigation revealed that NEAT1 was upregulated by the transcription factor YY1. Moreover, Western blot analysis suggested that NEAT1 enhance the protein levels of core factors of Wnt/ß-catenin signaling pathway, indicating that NEAT1 contributed to the activation of Wnt/ß-catenin signaling pathway. Rescue assays were carried out in the microglial cells treated with OGD/R. The results showed that NEAT1 regulated the OGD/R injury and neuroinflammation damage via Wnt/ß-catenin signaling pathway. In conclusion, our findings suggested that YY1-induced upregulation of NEAT1 contributed to the OGD/R injury and neuroinflammation damage of microglial cells via Wnt/ß-catenin signaling pathway.