Kamebakaurin Suppresses Antigen-Induced Mast Cell Activation by Inhibition of FcεRI Signaling Pathway.

INTRODUCTION: Kamebakaurin is an active constituent of both Rabdosia japonica and Rabdosia excisa, which are utilized in Chinese traditional medicine for improving symptoms in patients with allergies. We investigated the molecular mechanisms of the anti-allergic effects of kamebakaurin using BMMCs. METHODS: The degranulation ratio, histamine release, and the interleukin (IL)-4, leukotriene B4 (LTB4), and cysteinyl leukotriene productions on antigen-triggered BMMC were investigated. Additionally, the effects of kamebakaurin on signal transduction proteins were examined by Western blot and binding to the Syk and Lyn kinase domain was calculated. The effects of kamebakaurin on antigen-induced hyperpermeability were investigated using mouse model. RESULTS: At 10 µm, kamebakaurin partially inhibited degranulation, histamine release, and IL-4 production. At 30 µm, kamebakaurin partially reduced LTB4 and cysteinyl leukotriene productions and suppressed degranulation, histamine release, and IL-4 production. Phosphorylation of both Syk Y519/520 and its downstream protein, Gab2, was reduced by kamebakaurin, and complete inhibition was observed with 30 µm kamebakaurin. In contrast, phosphorylation of Erk was only partially inhibited, even in the presence of 30 µm kamebakaurin. Syk Y519/520 is known to be auto-phosphorylated via intramolecular ATP present in its own ATP-binding site, and this auto-phosphorylation triggers degranulation, histamine release, and IL-4 production. Docking simulation study indicated kamebakaurin blocked ATP binding to the ATP-binding site in Syk. Therefore, inhibition of Syk auto-phosphorylation by kamebakaurin binding to the Syk ATP-binding site appeared to cause a reduction of histamine release and IL-4 production. Kamebakaurin inhibited antigen-induced vascular hyperpermeability in a dose-dependent fashion but did not reduce histamine-induced vascular hyperpermeability. CONCLUSION: Kamebakaurin ameliorates allergic symptoms via inhibition of Syk phosphorylation; thus, kamebakaurin could be a lead compound for the new anti-allergic drug.

Synthesis of 1-O-acyl- and 1-oxo-kamebanin analogues and their cytotoxic activity.

A series of 1-O-acyl- and 1-oxo-kamebanin analogues were prepared from kamebanin, isolated from Rabdosia excisa and their cytotoxicity was assayed on HL60 promyelocytic leukemia cells and HCT116 human colon cancer cells. The structure-activity relationship study showed that the presence of 1-O-acyl groups of a C3-C5 carbon chain increased the cytotoxic activity.

Urine metabolic profiling of dementia rats with vital energy deficiency using ultra-high-performance liquid chromatography coupled with an orbitrap mass spectrometer.

Dementia is a chronic and multifactor-induced neurodegenerative disorder that occurs frequently in the elderly with weak constitution and insufficient vital energy. However, the relationship between vital energy deficiency and the occurrence and development of dementia is still unclear. In this study, a rat model of dementia with vital energy deficiency was established through intraperitoneal injection with d-galactose and AlCl3 and combined with exhaustive swimming. Changes in the dementia with vital energy deficiency rat model were assessed by examining behaviors, hippocampal histopathological and biochemical parameters, and serum biochemical parameters. Urine metabolomics based on ultra-high-performance liquid chromatography coupled with an orbitrap mass spectrometer was also used to discover endogenous metabolic profile and disease-related biomarkers and investigate the potential mechanism of dementia with vital energy deficiency. Among the 31 potential biomarkers that were identified, nine involved metabolic pathways. The four main types were phenylalanine, tyrosine and tryptophan metabolism, taurine and hypotaurine metabolism, and citrate cycle and pyrimidine metabolism. The pathogenesis of dementia with vital energy deficiency is mainly neurotoxin accumulation and body aging that leads to oxidative stress injury and loss of neuronal protective substances. Vital energy deficiency inhibits the body's energy metabolism and eventually leads to aggravate the dementia.

An efficient strategy based on two-stage chromatography and in vitro evaluation for rapid screening and isolation of acetylcholinesterase inhibitors from Scutellaria baicalensis Georgi.

The extraction of Scutellaria baicalensis Georgi was investigated using the response surface methodology-genetic algorithm mathematical regression model, and the extraction variables were optimized to maximize the flavonoid yield. Furthermore, a simple and efficient ultrafiltration-liquid chromatography-mass spectrometry and molecular docking methods were developed for the rapid screening and identification of acetylcholinesterase inhibitors present in Scutellaria baicalensis Georgi. Subsequently, four major chemical constituents, namely baicalein, norwogonin, wogonin, and oroxylin A, were identified as potent acetylcholinesterase inhibitors. This novel approach, involving the use of ultrafiltration-liquid chromatography-mass spectrometry and molecular docking methods combined with stepwise flow rate counter-current chromatography and semi-preparative high-performance liquid chromatography, could potentially provide a powerful tool for the screening and extraction of acetylcholinesterase inhibitors from complex matrices and be a useful platform for the production of bioactive and nutraceutical ingredients.

Hierarchical flower-like manganese oxide/polystyrene with enhanced oxidase-mimicking performance for sensitive colorimetric detection of glutathione.

Glutathione (GSH) is an important antioxidant and free radical scavenger that converts harmful toxins into harmless substances and excretes them out of the body. In this paper, 3D hierarchical flower-like nanozyme named MnO2/PS (polystyrene) was successfully prepared by template method for the first time. After the systematical studies, MnO2/PS nanozyme was evaluated to possess favorable oxidase activity and direct 3,3',5,5'-tetramethylbenzidine (TMB) catalytic ability in the near-neutral environment at room temperature. With the addition of different concentrations of GSH, oxidized TMB can be reduced to TMB with the whole process from blue to nearly colorless be observed by naked eyes. In addition, there is a good linear relationship in the range 1-50 µM and a detection limit of 0.08 µM. The method proposed can be successfully applied to the detection of reduced GSH in tablets and injections with good selectivity and high sensitivity. The analysis results exhibited good consistency with the results obtained by HPLC.

Single-Cell RNA Sequencing Analysis Reveals a Crucial Role for CTHRC1 (Collagen Triple Helix Repeat Containing 1) Cardiac Fibroblasts After Myocardial Infarction.

BACKGROUND: Cardiac fibroblasts (CFs) have a central role in the ventricular remodeling process associated with different types of fibrosis. Recent studies have shown that fibroblasts do not respond homogeneously to heart injury. Because of the limited set of bona fide fibroblast markers, a proper characterization of fibroblast population heterogeneity in response to cardiac damage is lacking. The purpose of this study was to define CF heterogeneity during ventricular remodeling and the underlying mechanisms that regulate CF function. METHODS: Collagen1α1-GFP (green fluorescent protein)-positive CFs were characterized after myocardial infarction (MI) by single-cell and bulk RNA sequencing, assay for transposase-accessible chromatin sequencing, and functional assays. Swine and patient samples were studied using bulk RNA sequencing. RESULTS: We identified and characterized a unique CF subpopulation that emerges after MI in mice. These activated fibroblasts exhibit a clear profibrotic signature, express high levels of Cthrc1 (collagen triple helix repeat containing 1), and localize into the scar. Noncanonical transforming growth factor-ß signaling and different transcription factors including SOX9 are important regulators mediating their response to cardiac injury. Absence of CTHRC1 results in pronounced lethality attributable to ventricular rupture. A population of CFs with a similar transcriptome was identified in a swine model of MI and in heart tissue from patients with MI and dilated cardiomyopathy. CONCLUSIONS: We report CF heterogeneity and their dynamics during the course of MI and redefine the CFs that respond to cardiac injury and participate in myocardial remodeling. Our study identifies CTHRC1 as a novel regulator of the healing scar process and a target for future translational studies.

Inhibitory activity of narirutin on RBL-2H3 cells degranulation.

Context: It is an efficient strategy to apply inhibition of mast cell degranulation for evaluating anti-allergic effects of compounds. Previous works confirmed that narirutin had anti-allergic activity in OVA induced allergic asthma murine model. However, the mechanism is not clear. Objective: Here, inhibitory mechanism of narirutin on RBL-2H3 cells degranulation was investigated. Materials and methods: Cell viability was analyzed by CCK-8 kits, cell degranulation was analyzed by ELISA methods, morphology and ultrastructure of cells was observed by atomic force microscopy, intracellular Ca 2+ concentration was measured by fluorescence microscopre, mRNA expression were measured by PCR, and signaling pathways were measured by WB. Results: The results showed that narirutin have no direct effects on mRNA expression of FcεRI subunit. However, it inhibited Ca2+ influx by suppressing the phosphorylation of Syk, LAT and PLCγ1 signaling pathway transduction. Subsequently, the inhibition of Ca2+ influx directly leads to NF-κB signaling pathway transduction decreased. Narirutin can also suppress the phosphorylation of MAPK signaling pathways by decreasing the expression of P-p38, P-ERK and P-JNK, inhibit the synergistic effect for Ca2+ influx, and then reduce the release of IL-4, TNF-α, histamine and ß-HEX. Conclusion: Our study suggested that the inhibitory mechanism of narirutin on RBL-2H3 cells degranulation could be related to regulate MAPK, NF-κB and Tyrosine kinase signaling pathway.

Stem cell membrane-coated isotretinoin for acne treatment.

BACKGROUND: Topical isotretinoin is commonly used to treat acne. However, topical isotretinoin has side effects and can hardly permeate through the stratum corneum, the most important skin barrier. Therefore, this study aimed to demonstrate the efficacy of nanoparticles as stable carriers with great curative effects, low side effects, and strong transdermal ability. RESULTS: In a rabbit model of hyperkeratinization, STCM-ATRA-NPs showed significant therapeutic efficacy. By contrast, negative therapeutic efficacy was observed in a golden hamster model of hyper sebum production. Scanning electron microscopy and Fourier transform infrared spectral analyses showed that nanoparticles could penetrate the stratum corneum. Western blotting demonstrated that the nanoparticles could enhance the transdermal efficacy of isotretinoin by reducing the effect of keratin and tight junction proteins. Further, nanoparticles enhanced endocytosis, thereby promoting drug penetration and absorption into the skin. CONCLUSION: STCM-ATRA-NPs were demonstrated to control isotretinoin release, reducing its side effects, and efficiently permeating through the skin by reducing the effect of keratin and tight junction proteins and enhancing endocytosis.

Five New Triterpenoid Saponins from the Rhizomes of Panacis majoris and Their Antiplatelet Aggregation Activity.

Five new triterpenoid saponins (1-5) and four known triterpenoid saponins, ginsenoside Re5 (6), majonoside R1 (7), 24(R)-majonoside R1 (8), and ginsenoside Rf (9), were isolated from the rhizomes of Panacis majoris. The structures of new compounds were elucidated as (20S,24S,25R*)-6-O-[ß-D-glucopyranosyl-(1 → 2)-ß-D-glucopyranosyl]-dammar-20,24-epoxy-3ß,6α,12ß,25,26-pentaol (1), (20S,24R,25R)-6-O-[ß-D-glucopyranosyl-(1 → 2)-ß-D-glucopyranosyl]-dammar-20,24-epoxy-3ß,6α,12ß,25,26-pentaol (2), (20S)-6-O-[ß-D-glucopyranosyl-(1 → 2)-ß-D-glucopyranosyl]-dammar-20,25-epoxy-3ß,6α,12ß,24α-tetraol (3), 6-O-[ß-D-glucopyranosyl-(1 → 2)-ß-D-glucopyranosyl]-dammar-3ß,6α,12ß,20S,24R,25-hexaol (4), and 6-O-[ß-D-glucop-yranosyl-(1 → 2)-ß-D-glucopyranosyl]-dammar-25(26)-ene-3ß,6α,12ß,20S,24R-pentaol (5) on the basis of extensive spectral analysis and chemical methods. Ginsenoside Re5 was isolated from the plant for the first time. The similarities of the nine compounds lie in the fact that their aglycones are conjoined with the same glucopyranose moieties, the same linkage of the glycosyl chains, and the same glycosylation sites, while they have a varied C-17 side chain. Compounds 3 and 5 exhibited moderate antiplatelet aggregation activities induced by adenosine diphosphate with IC50 values of 23.24 and 18.43 µM, respectively. Compound 5 displayed moderate inhibition of arachidonic acid-induced platelet aggregation with an IC50 value of 30.11 µM.

Sensitive determination of three aconitum alkaloids and their metabolites in human plasma by matrix solid-phase dispersion with vortex-assisted dispersive liquid-liquid microextraction and HPLC with diode array detection.

A simple and sensitive method for determination of three aconitum alkaloids and their metabolites in human plasma was developed using matrix solid-phase dispersion combined with vortex-assisted dispersive liquid-liquid microextraction and high-performance liquid chromatography with diode array detection. The plasma sample was directly purified by matrix solid-phase dispersion and the eluate obtained was concentrated and further clarified by vortex-assisted dispersive liquid-liquid microextraction. Some important parameters affecting the extraction efficiency, such as type and amount of dispersing sorbent, type and volume of elution solvent, type and volume of extraction solvent, salt concentration as well as sample solution pH, were investigated in detail. Under optimal conditions, the proposed method has good repeatability and reproducibility with intraday and interday relative standard deviations lower than 5.44 and 5.75%, respectively. The recoveries of the aconitum alkaloids ranged from 73.81 to 101.82%, and the detection limits were achieved within the range of 1.6-2.1 ng/mL. The proposed method offered the advantages of good applicability, sensitivity, simplicity, and feasibility, which makes it suitable for the determination of trace amounts of aconitum alkaloids in human plasma samples.

Wnt9b-dependent FGF signaling is crucial for outgrowth of the nasal and maxillary processes during upper jaw and lip development.

Outgrowth and fusion of the lateral and medial nasal processes and of the maxillary process of the first branchial arch are integral to lip and primary palate development. Wnt9b mutations are associated with cleft lip and cleft palate in mice; however, the cause of these defects remains unknown. Here, we report that Wnt9b(-/-) mice show significantly retarded outgrowth of the nasal and maxillary processes due to reduced proliferation of mesenchymal cells, which subsequently results in a failure of physical contact between the facial processes that leads to cleft lip and cleft palate. These cellular defects in Wnt9b(-/-) mice are mainly caused by reduced FGF family gene expression and FGF signaling activity resulting from compromised canonical WNT/ß-catenin signaling. Our study has identified a previously unknown regulatory link between WNT9B and FGF signaling during lip and upper jaw development.

Graphene-encapsulated silica as matrix solid-phase dispersion extraction sorbents for the analysis of poly-methoxylated flavonoids in the leaves of Murraya panaculata (L.) Jack.

In this study, graphene-encapsulated silica was synthesized by a hydrothermal reduction strategy. The presence of silica in graphene was identified by Fourier-transform infrared spectrometry, X-ray diffraction and scanning electron microscopy. The graphene-encapsulated silica subsequently was used as adsorbent for matrix solid-phase dispersion extraction of poly-methoxylated flavonoids from the dried leaves of Murraya panaculata (L.) Jack. Compared with the other adsorbents (graphene, silica gel, C18 silica, neutral alumina, diatomaceous earth) and without any adsorbents, better results were obtained. Then a method for analysis of poly-methoxylated flavonoids was established by coupling matrix solid-phase dispersion extraction with ultra high performance liquid chromatography and UV detection. Compared with reflux extraction and ultrasonic extraction, the proposed method is quicker, more efficient and more environmental protection. Less than 10 min is needed from extraction to detection.

Ionic liquid and aqueous two-phase extraction based on salting-out coupled with high-performance liquid chromatography for the determination of seven rare ginsenosides in Xue-Sai-Tong injection.

A method of ionic liquid salt aqueous two-phase extraction coupled with high-performance liquid chromatography has been developed for the analysis of seven rare ginsenosides including Rg6 , F4 , 20(S)-Rg3 , 20(R)-Rg3 , Rk3 , Rk1 , and Rg5 in Xue-Sai-Tong injection. The injection was mixed with ionic liquid 1-butyl-3-methylimidazolium bromide aqueous solution, and a mixture was obtained. With the addition of sodium dodecyl sulfate and dipotassium phosphate into the mixture, the aqueous two-phase mixture was formed after ultrasonic treatment and centrifuged. Rare ginsenosides were extracted into the upper phase. To obtain a high extraction factors, various influences were considered systematically, such as the volume of ionic liquid, the category and amount of salts, the amount of sodium dodecyl sulfate, the pH value of system, and the time of ultrasonic treatment. Under the optimal condition, rare ginsenosides in Xue-Sai-Tong injection were enriched and detected, the recoveries of seven rare ginsenosides ranged from 90.05 to 112.55%, while relative standard deviations were lower than 2.50%. The developed method was reliable, rapid and sensitive for the determination of seven rare ginsenosides in the injections.

The canonical Wnt signaling activator, R-spondin2, regulates craniofacial patterning and morphogenesis within the branchial arch through ectodermal-mesenchymal interaction.

R-spondins are a recently characterized family of secreted proteins that activate Wnt/ß-catenin signaling. Herein, we determine R-spondin2 (Rspo2) function in craniofacial development in mice. Mice lacking a functional Rspo2 gene exhibit craniofacial abnormalities such as mandibular hypoplasia, maxillary and mandibular skeletal deformation, and cleft palate. We found that loss of the mouse Rspo2 gene significantly disrupted Wnt/ß-catenin signaling and gene expression within the first branchial arch (BA1). Rspo2, which is normally expressed in BA1 mesenchymal cells, regulates gene expression through a unique ectoderm-mesenchyme interaction loop. The Rspo2 protein, potentially in combination with ectoderm-derived Wnt ligands, up-regulates Msx1 and Msx2 expression within mesenchymal cells. In contrast, Rspo2 regulates expression of the Dlx5, Dlx6, and Hand2 genes in mesenchymal cells via inducing expression of their upstream activator, Endothelin1 (Edn1), within ectodermal cells. Loss of Rspo2 also causes increased cell apoptosis, especially within the aboral (or caudal) domain of the BA1, resulting in hypoplasia of the BA1. Severely reduced expression of Fgf8, a survival factor for mesenchymal cells, in the ectoderm of Rspo2(-/-) embryos is likely responsible for increased cell apoptosis. Additionally, we found that the cleft palate in Rspo2(-/-) mice is not associated with defects intrinsic to the palatal shelves. A possible cause of cleft palate is a delay of proper palatal shelf elevation that may result from the small mandible and a failure of lowering the tongue. Thus, our study identifies Rspo2 as a mesenchyme-derived factor that plays critical roles in regulating BA1 patterning and morphogenesis through ectodermal-mesenchymal interaction and a novel genetic factor for cleft palate.

A WNT/beta-catenin signaling activator, R-spondin, plays positive regulatory roles during skeletal myogenesis.

R-spondins (RSPOs) are a recently characterized family of secreted proteins that activate WNT/ß-catenin signaling. In this study, we investigated the potential roles of the RSPO proteins during myogenic differentiation. Overexpression of the Rspo1 gene or administration of recombinant RSPO2 protein enhanced mRNA and protein expression of a basic helix-loop-helix (bHLH) class myogenic determination factor, MYF5, in both C2C12 myoblasts and primary satellite cells, whereas MYOD or PAX7 expression was not affected. RSPOs also promoted myogenic differentiation and induced hypertrophic myotube formation in C2C12 cells. In addition, Rspo2 and Rspo3 gene knockdown by RNA interference significantly compromised MYF5 expression, myogenic differentiation, and myotube formation. Furthermore, Myf5 expression was reduced in the developing limbs of mouse embryos lacking the Rspo2 gene. Finally, we demonstrated that blocking of WNT/ß-catenin signaling by DKK1 or a dominant-negative form of TCF4 reversed MYF5 expression, myogenic differentiation, and hypertrophic myotube formation induced by RSPO2, indicating that RSPO2 exerts its activity through the WNT/ß-catenin signaling pathway. Our results provide strong evidence that RSPOs are key positive regulators of skeletal myogenesis acting through the WNT/ß-catenin signaling pathway.

Ursolic acid enhances mouse liver regeneration after partial hepatectomy.

CONTEXT: Ursolic acid is a pentacyclic triterpenoid which has hepatoprotective and antihepatotoxic activities. OBJECTIVE: This study investigated whether ursolic acid is able to stimulate liver regeneration in partially hepatectomized mice. MATERIALS AND METHODS: Ursolic acid or the vehicle solution was orally administered to the experimental, sham-operated and vehicle-treated group mice for 7 days, positive control animal (mice) was treated with recombinant human hepatocyte growth factor (rhHGF), and then the 70% liver partial hepatectomy was performed. The liver mass recovery rate was estimated by measuring the ratios of mice liver weight to body weight. The liver cells undergoing DNA synthesis were identified by immunohistochemistry analysis using monoclonal anti-BrdU antibodies. The expression levels of cyclin D1, cyclin E and C/EBP proteins (C/EBPα and C/EBPß) were detected by the Western blotting technique. RESULTS: Our results showed administration of ursolic acid significantly increased the ratio of the liver to body weight and BrdU labeling index at 36 and 48 h after partial hepatectomy, and the potency of UA is similar to rhHGF treated positive control mice. In addition, ursolic acid treatment significantly increased cyclin D1, cyclin E and C/EBPß protein expression levels at 36 h after liver PHx compared with the vehicle-treated control mice. DISCUSSION AND CONCLUSION: All these results suggest that ursolic acid stimulates liver proliferation after partial hepatectomy, and this effect may be associated with the stimulation of C/EBPß expression.

Studies on the mechanism of Panax Ginseng in the treatment of deficiency of vital energy dementia rats based on urine metabolomics.

Panax Ginseng (PG) has been used to strengthen memory and physique for thousands of years, because its main components ginsenosides (GS) and ginseng polysaccharides (GP) play a major role, but its mechanism is not clear. In this study, a rat model of dementia with vital energy deficiency (DED) was established through intraperitoneal injection with D-galactose and AlCl3 and combined with exhaustive swimming. Pharmacological studies and the urine metabolomics based on ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) were employed for evaluation the efficacy of PG and exploring this treatment mechanism. Through urine metabolic profiling, it can be seen that DED rats after PG administration are close to normal group (NG) rats, and PG can regulate the in vivo status of DED rats which tend to NG. The results of behavioral, biochemical indicators and immunohistochemistry further verified the above results, and the mechanism of action of each component is refined. Ultimately, we believe that the mechanism of PG in the treatment of DED is that ginsenosides (GS) intervenes in phenylalanine tryptophan and tyrosine metabolism, stimulates dopamine production, inhibits Aß deposition and neuroinflammation; and that ginseng polysaccharides (GP) provides energy to strengthen the TCA cycle and improve immune capacity.

Oral Intervention of Narirutin Ameliorates the Allergic Response of Ovalbumin Allergy.

A new intervention was investigated for the induction of oral tolerance (OT) of OVA using narirutin by in vivo and in vitro experiments combined with network pharmacology and structural analysis of molecular docking. Narirutin (and its metabolism naringenin) has effects on OT by affecting B cell function, DCs, and T cell response by prediction. It was verified that narirutin could affect B cell function of secreting antibodies, thereby reducing the ability of DCs to absorb antigens by affecting GATA3, CCR7, STAT5, and MHCII expression and regulating T cell response by suppressing Th2 and improving Treg cells in vivo. Molecular docking showed that steric hindrance effects may be the reason for weaker binding energy with targets of narirutin. However, this does not mean that it has no bioactivity, for it can inhibit mast cell degranulation. This finding is interesting because it offers the possibility of using natural compounds to promote oral tolerance.

Enzyme-Assisted Extraction of Narirutin from Citri Reticulatae Pericarpium and Anti-allergic Asthma Activity.

BACKGROUND: Asthma is a heterogeneous disorder of the airways related to inflammation; it affects millions of people worldwide. Due to the side effects of inhaled corticosteroids, researchers focused on the therapeutic effects of compounds derived from natural products. OBJECTIVE: To investigate the therapeutic benefits of Narirutin a valuable flavonoid in Citri Reticulatae Pericarpium for asthma. METHODS: Narirutin was extracted using the enzyme-assisted method with the L9 (34) orthogonal array to optimize the temperatures, pH, and reaction time. The mechanism of action of Narirutin was investigated via ELISA, flow cytometry, and Western blot analysis in vivo. RESULTS: Narirutin suppressed inflammatory cell infiltration in the lung tissue and decreased IgE and IgG1 levels in serum in vivo. It can also alleviate interleukin (IL)-4, IL-5, and interferon-γ concentrations in bronchoalveolar lavage fluid in mice. Moreover, it increased the ratio of CD4+/CD8+ T cells. Additionally, Narirutin significantly suppressed p-ERK1/2 and p-JNK expression in the MAPK signaling pathway. CONCLUSION: Narirutin affects the Th1/Th2 imbalance through the p-ERK and p-JNK suppression in the MAPK signaling pathway.