Protein Kinase Signal Transduction Pathway Research Articles

An infant who cannot open her eyes and does not smile: a case report

Noonan syndrome (NS) is a genetically heterogeneous disorder, with distinctive facial features, short stature, chest deformity, and congenital heart diseases. Germline mutations in the RAS-MAPK (mitogen-activated protein kinase) signal transduction pathway result in Noonan syndrome. It shares clinical features with other RASopathies like Costello syndrome, and cardio-facio-cutaneous syndrome. Ocular findings like hypertelorism, ptosis, refractive errors, strabismus, amblyopia, and external eye abnormalities. It is often difficult to differentiate from other syndromes. Molecular genetic testing can confirm the diagnosis in 70% of cases and plays an important role in genetic counselling and management.

RASopathies - what they reveal about RAS/MAPK signaling in skeletal muscle development.

RASopathies are rare developmental genetic syndromes caused by germline pathogenic variants in genes that encode components of the RAS/mitogen-activated protein kinase (MAPK) signal transduction pathway. Although the incidence of each RASopathy syndrome is rare, collectively, they represent one of the largest groups of multiple congenital anomaly syndromes and have severe developmental consequences. Here, we review our understanding of how RAS/MAPK dysregulation in RASopathies impacts skeletal muscle development and the importance of RAS/MAPK pathway regulation for embryonic myogenesis. We also discuss the complex interactions of this pathway with other intracellular signaling pathways in the regulation of skeletal muscle development and growth, and the opportunities that RASopathy animal models provide for exploring the use of pathway inhibitors, typically used for cancer treatment, to correct the unique skeletal myopathy caused by the dysregulation of this pathway.

A clinical and biologic review of congenital melanocytic nevi.

Congenital melanocytic nevi (CMN) are the result of aberrations in the mitogen-activated protein kinase signal transduction pathway caused by postzygotic somatic mutations. The estimated incidence of newborns with CMN is 1%-2%. The main complications of CMN include proliferative nodules, melanomas, and neurocutaneous melanosis, and the latter two are the most troublesome issues to address. Treatments are primarily taken into account for aesthetic purposes and the reduction of melanoma risk. Due to the much lower incidence of malignant transformation observed in recent studies than in previous data, clinical management paradigms for CMN patients have gradually shifted towards conservative observation and close monitoring. Surgery and lasers are still the main treatments, and targeted therapy may be a promising strategy to help manage complications. With the increase in awareness of mental health, increasing focus has been placed on the quality of life (QoL) and psychological issues of both CMN patients and their parents. Recent studies have revealed that families coping with CMN might endure intense pressure, a major loss in QoL, and psychological problems after diagnosis and during treatment. Here, we sought to present an overview of genetic basis, complications, treatments, and psychological issues related to CMN and hope to provide better management for patients with CMN.

Synthesis and Biological Properties of Pyranocoumarin Derivatives as Potent Anti-Inflammatory Agents.

This study aimed to synthesize 23 coumarin derivatives and analyze their anti-inflammatory effects on lipopolysaccharide (LPS)-induced inflammation in RAW264.7 macrophages. A cytotoxicity test performed on LPS-induced RAW264.7 macrophages revealed that none of the 23 coumarin derivatives were cytotoxic. Among the 23 coumarin derivatives, coumarin derivative 2 showed the highest anti-inflammatory activity by significantly reducing nitric oxide production in a concentration-dependent manner. Coumarin derivative 2 inhibited the production of proinflammatory cytokines, including tumor necrosis factor alpha and interleukin-6, and decreased the expression level of each mRNA. In addition, it inhibited the phosphorylation of extracellular signal-regulated kinase, p38, c-Jun NH2-terminal kinase, nuclear factor kappa-B p65 (NF-κB p65), and inducible nitric oxide synthase. These results indicated that coumarin derivative 2 inhibited LPS-induced mitogen-activated protein kinase and NF-κB p65 signal transduction pathways in RAW264.7 cells, as well as proinflammatory cytokines and enzymes related to inflammatory responses, to exert anti-inflammatory effects. Coumarin derivative 2 showed potential for further development as an anti-inflammatory drug for the treatment of acute and chronic inflammatory diseases.

Effect on MAPK Signal Path of Lead, Nickel, Mercury, Cadmium and Chromium in Breast Cancer Cell Line

The harms of heavy metals such as cadmium and lead on human health have been identified in the literature. However, genetic mechanisms that show the relationship between heavy metals and cancer have not been identified up to now. In the proposed project, the effects of lead, nickel, mercury, cadmium, and chrome on the expression levels of mitogen-activated protein kinase signal transduction pathways in breast cancer cell lines will be quantified by the Real Time-Polymerase Chain Reaction method, comparatively. Mitogen-activated protein kinase signal transduction pathway, found in eukaryotic organisms, plays a significant role in information transfer from the cell membrane to the nucleus. Genes in this signal transfer regulate embryogenesis, reproduction, diversification, survival, and apoptosis functions. Most of these genes are well-known oncogenes and each of these is an important subject in cancer treatment. The changes of gene expression levels in this transduction pathway can be the reason of breast and some other cancer types. According to the findings, when the heavy metal-treated cells were compared with the heavy metal-untreated cells, significant changes were observed in the level of expression of 47 genes in the signal pathway. It has been determined that heavy metals cause changes in the expression level of genes in the signaling pathway according to the obtained data.

Transcriptome and metabolome profiling of interspecific CSSLs reveals general and specific mechanisms of drought resistance in cotton.

In order to understand the molecular mechanism of cotton's response to drought during the flowering and boll stage, transcriptomics and metabolomics were carried out for two introgression lines (drought-tolerant line: T307; drought-sensitive line: S48) which were screened from Gossypium hirsutum cv. 'Emian22' with some gene fragments imported from Gossypium barbadense acc. 3-79, under drought stress by withdrawing water at flowering and boll stage. Results showed that the basic drought response in cotton included a series of broad-spectrum responses, such as amino acid synthesis, hormone (abscisic acid, ABA) signal transduction, and mitogen-activated protein kinases signal transduction pathway, which activated in both drought-tolerant and drought-sensitive lines. However, the difference of their imported fragments and diminished sequences triggers endoplasmic reticulum (ER) protein processing, photosynthetic-related pathways (in leaves), and membrane solute transport (in roots) in drought-tolerant line T307, while these are missed or not activated in drought-sensitive line S48, reflecting the different drought tolerance of the two genotypes. Virus-induced gene silencing assay of drought-tolerant differentially expressed heat shock protein (HSP) genes (mainly in leaf) and ATP-binding cassette (ABC) transporter genes (mainly in roots) indicated that those genes play important role in cotton drought tolerant. Combined analysis of transcriptomics and metabolomics highlighted the important roles of ER-stress-related HSP genes and root-specific ABC transporter genes in plants drought tolerance. These results provide new insights into the molecular mechanisms underlying the drought stress adaptation in cotton.

A curcumin-induced assembly of a transferrin nanocarrier system and its antitumor effect

To increase the solubility and targeting efficiency of curcumin (CCM) to tumors, transferrin (Tf)-CCM nanoparticles (NPs-CCM) with a CCM loading capacity of 5.2% were fabricated by Tf denaturation with hydrochloric acid, a denaturing agent, to open the hydrophobic cavity of Tf. The NPs-CCM were approximately 160 nm in size with a spherical shape. The solubility of the CCM in the nanoparticles was approximately 100,000 times greater than that of CCM alone (11 ng mL−1 vs 1.11 mg mL−1, respectively). The changes in the fluorescence spectra of Tf and 1-(anilinon)-aphthalene-8-sulfonic acid (ANS) in the NP-CCM preparation indicated that the polarity of certain hydrophobic and hydrophilic groups of Tf changed. CCM treatment of A549 cells resulted in a decrease in the mitochondrial membrane potential (MMP) and induced apoptosis through mitochondrial dependence. CCM increased the expression of phosphorylated c-Jun N-terminal kinase (JNK), P38, and extracellular signal-regulated kinase (ERK) but had a weak effect on the expression of nonphosphorylated JNK, P38, and ERK, which showed that the mitogen-activated protein kinase signaling (MAPK) transduction pathway is involved in CCM-mediated apoptosis. The half maximal inhibitory concentration (IC50) of NPs-CCM was higher than that of free CCM in A549 (16.41 ± 0.86 vs 12.51 ± 3.9 (μg mL−1), p = 0.036) and MCF-7 (9.31 ± 0.11 vs 2.44 ± 3.76 (μg mL−1), p < 0.0037) tumor cells, however the former had a greater tumor-targeting in vivo. Without the side effects of polyoxyethylene castor oil/ethanol as solvent, the hemolysis effect of NPs-CCM (0.05–1 mg mL−1) was notably lower than that of free CCM (p < 0.05). It was estimated that the half maximal lethal dose (LD50) of NPs-CCM was approximately two times that of CCM (100 mg kg−1 vs 50 mg kg−1), and the former had many advantages over that of free CCM in terms of lower toxicity and better targeting; thus, NPs-CCM can be administered at higher doses to acquire better antitumor effects than CCM alone, indicating that NPs-CCM are an effective and safe carrier for CCM delivery.

Pharmacological Effects of Cisplatin Combination with Natural Products in Cancer Chemotherapy.

Cisplatin and other platinum-based drugs, such as carboplatin, ormaplatin, and oxaliplatin, have been widely used to treat a multitude of human cancers. However, a considerable proportion of patients often relapse due to drug resistance and/or toxicity to multiple organs including the liver, kidneys, gastrointestinal tract, and the cardiovascular, hematologic, and nervous systems. In this study, we sought to provide a comprehensive review of the current state of the science highlighting the use of cisplatin in cancer therapy, with a special emphasis on its molecular mechanisms of action, and treatment modalities including the combination therapy with natural products. Hence, we searched the literature using various scientific databases., such as MEDLINE, PubMed, Google Scholar, and relevant sources, to collect and review relevant publications on cisplatin, natural products, combination therapy, uses in cancer treatment, modes of action, and therapeutic strategies. Our search results revealed that new strategic approaches for cancer treatment, including the combination therapy of cisplatin and natural products, have been evaluated with some degree of success. Scientific evidence from both in vitro and in vivo studies demonstrates that many medicinal plants contain bioactive compounds that are promising candidates for the treatment of human diseases, and therefore represent an excellent source for drug discovery. In preclinical studies, it has been demonstrated that natural products not only enhance the therapeutic activity of cisplatin but also attenuate its chemotherapy-induced toxicity. Many experimental studies have also reported that natural products exert their therapeutic action by triggering apoptosis through modulation of mitogen-activated protein kinase (MAPK) and p53 signal transduction pathways and enhancement of cisplatin chemosensitivity. Furthermore, natural products protect against cisplatin-induced organ toxicity by modulating several gene transcription factors and inducing cell death through apoptosis and/or necrosis. In addition, formulations of cisplatin with polymeric, lipid, inorganic, and carbon-based nano-drug delivery systems have been found to delay drug release, prolong half-life, and reduce systemic toxicity while other formulations, such as nanocapsules, nanogels, and hydrogels, have been reported to enhance cell penetration, target cancer cells, and inhibit tumor progression.

Combinational Anti-tumor Effects of Chemicals from Paeonia lutea Leaf Extract in Oral Squamous Cell Carcinoma Cells.

We identified chemical components that exhibited antitumor activity against oral squamous cell carcinoma (OSCC) cells and examined their effective concentrations and additive and/or synergistic effects in combinational usage on the proliferation, apoptosis and cell cycle of OSCC cells. Using high-performance liquid chromatography, nuclear magnetic resonance spectroscopy and electrospray ionization-mass spectrometry, we identified the main chemical components of the methanol extracts from Paeonia lutea. We investigated the pharmaceutical effects of those components on the proliferation, apoptosis, and cell cycle of an OSCC cell line, SAS, using the tetrazolium salt 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and caspase assays, as well as flow cytometry cell cycle analysis. We also examined the effects of those components on the mitogen-activated protein kinase signal transduction pathway by western blotting. Finally, the effects on normal human epidermal keratinocyte cells were also examined in similar experiments. Three chemicals have been identified in P. lutea leaves using high performance liquid chromatography: gallic acid methyl ester (GAME), pentagalloyl glucose (PGG) and paeoniflorin (PF). Both GAME and PGG significantly suppressed cell proliferation, and their combined effects were synergistic, while the effect of PF was minimal. However, those chemicals did not induce apoptosis. Cell cycle and western blotting analysis showed that the suppressive effects on cell proliferation resulted from G2 arrest and the suppression of phosphorylation of Akt/PKB. No effect was identified on normal human epidermal keratinocyte cells. These results indicate that GAME and PGG are the main chemical components of P. lutea leaves that have potential anti-cancer therapeutic effects.

Exploring the Biological and Molecular Characteristics of Resistance to Fludioxonil in Sclerotinia sclerotiorum From Soybean in China.

Sclerotinia sclerotiorum is one of the most damaging and economically important necrotrophic plant pathogens, infecting more than 400 plant species globally. Although the phenylpyrrole fungicide fludioxonil has high activity against S. sclerotiorum, reports indicate that there is also substantial potential for the development of fungicide resistance. However, the current study investigating five fludioxonil-resistant laboratory mutants found a significant fitness cost associated with fludioxonil resistance resulting in significantly (P < 0.05) reduced mycelial growth and sclerotia formation on potato dextrose agar as well as significantly (P < 0.05) lower pathogenicity on detached tomato leaves, with one mutant, LK-1R, completely losing the capacity to cause infection. In addition, all of the fludioxonil-resistant mutants had significantly (P < 0.05) increased sensitivity to osmotic stress (0.5 M of potassium chloride and 1.0 M of glucose), which is consistent with the proposed fludioxonil target sites within the high osmolarity glycerol stress response mitogen-activated protein kinase (HOG1-MAPK) signaling transduction pathway. Sequence analysis of six genes from this two-component pathway, including SsHk, SsYpd, SsSk1, SsSk2, SsPbs, and SsHog, revealed several mutations that may be associated with fludioxonil resistance. For example, six separate point mutations were found in SsHk that led to changes in the predicted amino acid sequence, including A136G, F249V, G353A, E560K, M610K, and K727R. Similarly, SsPbs had three mutations (D34G, S46L, and L337E), SsSk1 and SsYpd had two (S53G and A795V for SsSk1, and E67G and Y141H for SsYpd), and SsHog and SsSk2 had one each (V220A and S763P, respectively). To our knowledge, these constitute the first reports of amino acid changes in proteins of the HOG1-MAPK pathway being associated with fludioxonil resistance in S. sclerotiorum. This study also showed a positive cross-resistance between fludioxonil and dimethachlone and procymidone, but none with tebuconazole or carbendazim, indicating that the inclusion of tebuconazole within an integrated pest management program could reduce the risk of fludioxonil resistance developing in field populations of S. sclerotiorum and ensure the sustainable production of soybeans in China into the future.

PtP38 May Increase the Immune Ability of Portunus trituberculatus Stimulated by LPS Imitating a Gram-Negative Bacterial Infection

The P38 mitogen-activated protein kinase (MAPK) signal transduction pathway is widespread in organisms and plays important roles in immune activities. The infection mechanism of environmental gram-negative bacteria on crustaceans is an important scientific problem. In this study, the cDNA full-length sequence ofPortunus trituberculatusP38 (PtP38) was cloned and its structure was analyzed by bioinformatics methods. To study the function of the PtP38 gene after a Gram-negative bacterial infection, we injectedP. trituberculatuswith LPS to activate the immune response instead of directly infecting with Gram-negative bacteria. With LPS stimulation, the expression of the PtP38 gene in different tissues increased significantly. At the same time, the expression of immune-related genes (ALF and crustin) in the hepatopancreas, activities of antioxidant enzymes [superoxide dismutase (SOD), catalase (CAT), and inducible nitric oxide synthase (iNOS) enzymes], and expression of apoptosis-related genes (caspase2 and caspase3) were increased significantly. To further conform the function of PtP38 in the immune response, we injectedP. trituberculatuswith P38 inhibitor and subsequently injected with LPS. The results showed that the expression of immune-related genes was inhibited, the activity of antioxidant enzymes was decreased, and the expression of apoptosis-related genes were inhibited. Thus, we speculated that PtP38 may increase the immune ability by improving the expression of antimicrobial peptides, increasing the activity of oxidative stress-related enzymes, and promoting cell apoptosis in infectedP. trituberculatus. This study also laid the foundation for further study of the P38 MAPK signaling pathway and immune mechanism ofP. trituberculatus.

Malvidin and its derivatives exhibit antioxidant properties by inhibiting MAPK signaling pathways to reduce endoplasmic reticulum stress in ARPE-19 cells.

Malvidin (MV) and its derivatives, such as malvidin-3-O-guaiacol (Mv3C) and malvidin-3-O-6-(acrylic acid-(2-hydroxy,4-carboxy-cyclohexanol)ester)-guaiacol (Mv3ACEC), are natural compounds with antioxidant properties. However, the basic mechanisms underlying their functional activities are unclear. In this study, we show that MV, Mv3C, and Mv3ACEC inhibit reactive oxygen species production and malondialdehyde content, promote glutathione peroxidase activity, and increase superoxide dismutase levels in ARPE-19 cells treated with H2O2. Western blotting and immunofluorescence analysis revealed that MV, Mv3C, and Mv3ACEC regulate mitogen-activated protein kinase signal transduction pathways related to endoplasmic reticulum stress. Interestingly, Mv3C and Mv3ACEC showed greater beneficial properties than MV. Our results show that MV and its derivatives have potential as therapeutic compounds for ocular diseases associated with oxidative stress, such as age-related macular degeneration.

Enhanced Spinal Therapy: Extracorporeal Shock Wave Therapy for the Spine.

Extracorporeal shock wave therapy (ESWT) is a non-invasive therapeutic method used for pain management and muscle strength improvement through the use of shock waves. In vitro studies have demonstrated that shockwave therapy induces fluctuation in redox reaction regulation and increases in Mitogen-Activated Protein Kinase (MAPK) signal transduction pathways, stimulating increased gene expression in the nucleus. ESWT has also been shown to upregulate angiogenesis and growth factors through activation of endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF). The use of ESWT in the treatment of various musculoskeletal disorders was widely adopted throughout Europe, South America, and Asia before being introduced in the United States in 2000. Within the past 20 years, the clinical application of ESWT in the treatment of musculoskeletal and bone disorders has grown. This paper provides a comprehensive narrative review of applications and outcomes of ESWT in clinical spinal pathology and assesses reported efficacy as it relates to the pathology. A review of the literature yielded studies describing the use of ESWT in degenerative osteoporotic neuro-spinal pathology, heterotopic ossification due to spinal cord injury, cervical spondylosis, scoliosis, sacroiliitis, and coccydynia. The efficacy of ESWT as an adjunct treatment in patients with spinal cord pathologies varied with the specific pathology, however, all pathologies discussed in this review provided evidence of potential benefits with minimal adverse effects. While the use of ESWT for pain management has widely been established, further literature should aim to identify the long-term benefits of ESWT.

Different MAPK signal transduction pathways play different roles in the impairment of glucose‑stimulated insulin secretion in response to IL‑1β.

Mitogen‑activated protein kinase (MAPK) signal transduction pathways may be involved in the destruction of pancreatic islet β cells induced by inflammatory cytokines. The present study aimed to investigate the role of different MAPK signal transduction pathways in the interleukin‑1β (IL‑1β)‑induced inhibition of glucose‑stimulated insulin secretion (GSIS) in Min6 mouse pancreatic cells. Min6 cells were stimulated with different concentrations of glucose (0.0, 5.5, 11.1 and 22.2mmol/l), or different concentrations of IL‑1β (0.00, 0.25 and 2.50ng/ml) in combination with high glucose (22.2mmol/l) and the culture supernatant was collected. The concentration of insulin was measured by enzyme‑linked immunosorbent assay and the activation of different MAPK pathways was assessed by measuring the phosphorylation levels of extracellular signal‑regulated kinase 1/2 (ERK1/2), p38 and c‑jun N‑terminal kinase (JNK) via western blotting. The production of reactive oxygen species (ROS) was determined via flow cytometry, and cell viability was detected by Cell Counting Kit‑8 assay. Reverse transcription‑quantitative PCR was used to detect the insulin 1 gene. The results revealed that glucose activated ERK1/2 phosphorylation, but inhibited JNK and p38 phosphorylation in a concentration‑dependent manner. Furthermore, IL‑1β inhibited glucose‑stimulated insulin secretion in a dose‑dependent manner. Western blotting revealed that IL‑1β inhibited the activation of ERK1/2 phosphorylation and attenuated the inhibition of p38 phosphorylation induced by glucose stimulation. JNK was neither activated nor inhibited by IL‑1β. These results suggest that MAPK signal transduction pathways participated in the IL‑1β‑induced GSIS inhibition in Min6 cells, with the ERK1/2, JNK and p38 signaling pathways playing different roles.

The Activation of Extracellular Signal-Regulated Kinase (ERK)/Mitogen-Activated Protein Kinase (MAPK) Signal Transduction Pathway on Invasive Growth of Breast Cancer

ERK/MAPK signal transduction pathway participates in occurrence and progression of breast cancer. This study utilized epidermal growth factor (EGF) and ERK antagonist PD98059 to analyze ERK/MAPK signal's role in breast cancer cells. Breast cancer MCF-7 cell line was separated into control group, EGF group, PD98059 group and EGF+ PD98059 group. Cell proliferation activity was assessed by MTT, whilst TUNEL was to describe cell apoptosis. Transwell assay was employed for cell invasion and migration. Protein expression of ERK1/2 and p-ERK1/2. Compared to control group, EGF treatment elevated cell proliferation or invasion/migration and decreased apoptosis at 6 h, 12 h and 24 h. PD98059 treatment decreased proliferation activity or cell invasion/migration, and enhanced apoptosis. Treatment of EGF plus PD98059 further decreased proliferation and invasion/migration compared to EGF group, but with higher level than PD98059 group (p &lt; 0 05). EGF treatment elevated ERK1/2 and pERK1/2, PD98059 group had lower ERK1/2 or pERK1/2 expression, whilst EGF plus PD98059 treatment further decreased ERK1/2 and pERK1/2 expression (p &lt; 0 05). EGF can regulate proliferation and invasion of breast cancer MCF-7 cells via ERK/MAPK signaling.

Transcriptome Profiling of Haloxylon persicum (Bunge ex Boiss and Buhse) an Endangered Plant Species under PEG-Induced Drought Stress.

Haloxylon persicum is an endangered western Asiatic desert plant species, which survives under extreme environmental conditions. In this study, we focused on transcriptome analysis of H. persicum to understand the molecular mechanisms associated with drought tolerance. Two different periods of polyethylene glycol (PEG)-induced drought stress (48 h and 72 h) were imposed on H. persicum under in vitro conditions, which resulted in 18 million reads, subsequently assembled by de novo method with more than 8000 transcripts in each treatment. The N50 values were 1437, 1467, and 1524 for the control sample, 48 h samples, and 72 h samples, respectively. The gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis resulted in enrichment of mitogen-activated protein kinase (MAPK) and plant hormone signal transduction pathways under PEG-induced drought conditions. The differential gene expression analysis (DGEs) revealed significant changes in the expression pattern between the control and the treated samples. The KEGG analysis resulted in mapping transcripts with 138 different pathways reported in plants. The differential expression of drought-responsive transcription factors depicts the possible signaling cascades involved in drought tolerance. The present study provides greater insight into the fundamental transcriptome reprogramming of desert plants under drought.

Comparative transcriptomics analysis of Zygosaccharomyces mellis under high-glucose stress

The high-glucose tolerance of yeast is the main factor determining the efficiency of high-density alcohol fermentation. Zygosaccharomyces mellis LGL-1 isolated from honey could survive under 700 g/L high-glucose stress and its tolerant characteristics were identified in our previous study. This study was performed to explore and clarify the high-glucose tolerance mechanism of Z. mellis LGL-1. Comparative transcriptomic analysis was used to analyze the genes with differential expression in Z. mellis under high-glucose conditions of 300, 500 and 700 g/L. With 300 g/L samples as reference, there were 937 and 2380 differentially expressed genes (DEGs) in the 500 and 700 g/L samples, respectively. Meanwhile, there was 825 significant DEGs in the 700 g/L samples compared with that of the 500 g/L samples. The result revealed that transcriptional changes in multiple metabolic pathways occur in response to high-glucose stress. q-RT PCR analysis further confirmed that several stress response pathways, such as the high osmolarity glycerol mitogen-activated protein kinase (HOG-MAPK) signal transduction pathway, trehalose synthesis pathway and oxidative stress response are closely related to high-glucose tolerance in Z. mellis. This study clarifies mechanisms of Z. mellis in response to high-glucose osmotic stress, providing theoretical basis for the process control of high-density alcohol fermentation.

TDCPP mimics thyroid hormones associated with the activation of integrin αvβ3 and ERK1/2

Tri(1,3-dichloropropyl) phosphate (TDCPP) potentially damages the thyroid system in humans and animals. However, knowledge of its toxic effects and underlying mechanisms is limited. The present study was conducted to determine the thyroid hormone-disrupting effects of TDCPP and its major metabolite, bis(1,3-dichloro-2-propyl) phosphate (BDCPP) in rat pituitary cell lines (GH3). TDCPP and BDCPP, that mimic the thyroid hormone (TH), promoted GH3 cell proliferation and modulated the progression of the cell cycle at 20 and 200 μmol/L, respectively. Similar to T3, TDCPP and BDCPP also significantly upregulated c-fos and downregulated Tshβ gene expression. Although the binding affinity of these chemicals for thyroid receptor β (TRβ) was not measured, significant competition between these chemicals to bind to the membrane thyroid hormone receptor (integrin αvβ3) was found, suggesting that TDCPP and BDCPP were strongly bound to integrin αvβ3. Results from a molecular docking analysis provided further evidence of strong binding affinities of TDCPP and BDCPP for integrin αvβ3, and the ligand binding site of Arg-Gly-Asp (RGD) was identified. Real-time PCR also supported the supposition that, after binding to integrin αvβ3, TDCPP and BDCPP may induce the activation of the extracellular signal-regulated protein kinase (ERK1/2) signal transduction pathway. Taken together, our data suggest that TDCPP and BDCPP have the ability to mimic THs and that the underlying mechanism might be associated with their interactions with integrin αvβ3 and the activation of the ERK1/2 pathway, providing new insight into the mechanism of TDCPP- and BDCPP-induced cytotoxicity.

The Mechanism of MAPK Signal Transduction Pathway Involved with Electroacupuncture Treatment for Different Diseases.

The mitogen-activated protein kinase (MAPK) signal transduction pathway plays an important role in the regulation of various diseases, such as cardiovascular and cerebrovascular diseases, and takes part in anti-inflammatory effects, analgesic effects, protection against injury, and maintenance of gastrointestinal functions. Electroacupuncture therapy is an external therapy used in traditional Chinese medicine. By adding external electrical stimulation to traditional acupuncture, the stimulus gets doubled and the therapeutic efficacy gets enhanced accordingly. It combines the benefits of both acupuncture and electrical stimulation. In recent years, some studies have explored the molecular mechanisms of MAPK signal pathways involved with electroacupuncture treatment. Based on these recent studies, this article summarizes the mechanisms of MAPK signal transduction pathways involved with electroacupuncture treatment. This adds great value to the studies of molecular mechanisms of electroacupuncture treatment and also provides an effective reference for its clinical use.

Levetiracetam Protects Against Cognitive Impairment of Subthreshold Convulsant Discharge Model Rats by Activating Protein Kinase C (PKC)-Growth-Associated Protein 43 (GAP-43)-Calmodulin-Dependent Protein Kinase (CaMK) Signal Transduction Pathway.

BackgroundSubclinical epileptiform discharges (SEDs) are defined as epileptiform electroencephalographic (EEG) discharges without clinical signs of seizure in patients. The subthreshold convulsant discharge (SCD) is a frequently used model for SEDs. This study aimed to investigate the effect of levetiracetam (LEV), an anti-convulsant drug, on cognitive impairment of SCD model rats and to assess the associated mechanisms.Material/MethodsA SCD rat model was established. Rats were divided into an SCD group, an SCD+ sodium valproate (VPA) group, and an SCD+ levetiracetam (LEV) group. The Morris water maze was used to evaluate the capacity of positioning navigation and space exploration. The field excitatory post-synaptic potentials (fEPSPs) were evaluated using a bipolar stimulation electrode. NCAM, GAP43, PS95, and CaMK II levels were detected using Western blot and RT-PCR, respectively. PKC activity was examined by a non-radioactive method.ResultsLEV shortens the latency of platform seeking in SCD rats in positioning navigation. fEPSP slopes were significantly lower in the SCD group, and LEV treatment significantly enhanced the fEPSP slopes compared to the SCD group (P<0.05). The NCAM and GAP-43 levels were increased and PSD-95 levels were increased in SCD rats (P<0.05), which were improved by LEV treatment. The PKC activity and CaMK II levels were decreased in SCD rats and LEV treatment significantly enhanced PKC activity and increased CaMK II levels.ConclusionsCognitive impairment in of SCD model rats may be caused by decreased PKC activity, low expression of CaMK II, and inhibition of LTP formation. LEV can improve cognitive function by activating the PKC-GAP-43-CaMK signal transduction pathway.