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Objectives: Ameloblastoma (AM), a locally aggressive tumor with extensive growth capacity, causes significant damage to the jaw and affects facial appearance. Although the high prevalence of BRAF V600E mutation in AM is known, its specific impacts on patients with AM remain unclear. Thus, the present study investigated the role of BRAF V600E mutation, thereby focusing on its impact on AM invasion and growth. Materials and Methods: Immunohistochemical analysis was used to compare BRAF V600E, MMP2, MMP9, and Ki‐67 expressions in AM (n = 49), normal oral mucosa (NOM) (n = 10), and odontogenic keratocyst (OKC) (n = 15) tissues. AM was further classified according to the presence or absence of BRAF V600E. The relationship between BRAF V600E and invasion as well as growth was evaluated. In addition, correlation analysis was performed using immunohistochemistry and confirmed via double‐labeling immunofluorescence. Finally, comparative analyses using mass spectrometry, immunohistochemistry, and immunofluorescence were performed to explore and identify underlying mechanisms. Results: AM exhibited a higher incidence of BRAF V600E mutation than NOM and OKC. BRAF V600E expression was positively correlated with the invasion‐associated proteins MMP2 and MMP9 and the growth‐related protein Ki‐67. Proteomic data revealed that BRAF V600E primarily activates the MAPK signaling pathway in AM, particularly driving the phosphorylation of extracellular signal‐regulated kinase 1/2 (ERK1/2). Conclusions: In summary, the findings suggested that the BRAF V600E mutation enhances the invasion and growth abilities of AM via the MAPK/ERK signaling pathway. Thus, targeting BRAF V600E or the MAPK/ERK pathway may be a potential AM therapy. [ABSTRACT FROM AUTHOR]

Objective To study the improvement mechanism of astaxanthin in rats with polycystic ovary syndrome (PCOS) by regulating Klotho expression and Wnt/β-Catenin signaling pathway. Methods Thirty PCOS model rats were constructed by intragastric administration of letrozole, and rats were randomly grouped into 6 groups: the model group, the low-dose astaxanthin group (50 mg/kg), the middle-dose astaxanthin groupm (100 mg/kg), the high-dose astaxanthin group (200 mg/kg), the high-dose astaxanthin+no-load group and the high-dose astaxanthin+Klotho knockdown group, with 5 rats in each group. Another 5 SD rats were taken as the control group. After treatment, the body weight and ovarian weight of rats in each group were measured. Forty-five SD rats were modeled in the same way and randomly grouped into: the model group, the astaxanthin group (200 mg/kg), the astaxanthin+Klotho knockdown group, the astaxanthin+lithium chloride group and the astaxanthin+PD98059 (MEK inhibitor) group, with 9 rats in each group. Another 9 SD rats were taken as the control group. After treatment, data of body weight, ovarian weight and volume, the number of cystic follicles in ovarian tissue, levels of serum hormones including follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T) and levels of inflammatory factors prostaglandin 2 (PGE2), interleukin (IL) -17, tumor necrosis factor- α (TNF- α), and IL-18, the expression of Klotho protein and the expression of Wnt/β-Catenin and MEK/ERK signal-related proteins in ovarian tissue were detected in rats of each group. Results Compared with the control group, body weight and ovarian weight were obviously increased in the model group (P＜0.05). Compared with the model group, body weight and ovarian weight were all decreased in the low-dose astaxanthin group, the middle-dose astaxanthin group and the high-dose astaxanthin group in a dose-dependent manner (P＜0.05). Compared with the high-dose astaxanthin group, body mass and ovarian mass of rats were increased in the high-dose astaxanthin+Klotho knockdown group (P＜0.05). There was no significant change in each index of rats in the high dose of astaxanthin+empty load group (P＞0.05). Compared with the control group, serum level of FSH, and expression levels of Klotho, p-MEK, p-ERK1/2 proteins in ovarian tissue were obviously decreased in the model group (P＜0.05). Body weight, ovarian mass and volume, number of cystic follicles, serum levels of LH, T, PGE2, IL-17, TNF-α and IL-18, and expression levels of Wnt1 and β-Catenin proteins in ovarian tissue were obviously increased in the model group (P＜0.05). Compared with the model group, the level of FSH, the expression levels of Klotho, p-MEK and p- ERK1/2 proteins in ovarian tissue were increased in the astaxanthin group (P＜0.05). Body weight, ovarian mass and volume, number of cystic follicles, serum levels of LH, T, PGE2, IL-17, TNF-α and IL-18, and expression of Wnt1 and β-Catenin proteins in ovarian tissue were decreased in the astaxanthin group (P＜0.05). Knockdown of Klotho, lithium chloride and PD98059 can weaken the improvement effect of astaxanthin on PCOS rats. Conclusion Astaxanthin can down-regulate Wnt/β -Catenin signaling and activate MEK/ERK signaling by up-regulating Klotho, thereby preventing inflammation, improving hormone levels in PCOS rats, reducing number of cystic follicles, and ultimately alleviating the symptoms of polycystic ovaries. [ABSTRACT FROM AUTHOR]

Objective To explore the effects of JNK and LIMK2 inhibitors on the erectile function of rats with cavernous nerve injury and mechanism of action. Methods The study sample selected 72 adult healthy male wistar rats, all of which established cavernous nerve injury models, and were randomly divided into 4 groups（control group, JNK group, LIMK2 group, combined group）, each with 18 rats, respectively, given placebo, JNK inhibitor, LIMK2 inhibitor and JNK inhibitor+LIMK2 inhibitor, observe the erectile function, LOX-1, NOX, NO, ET-1 expression, p-c-Jun positive apoptotic cell quantity, p-LIMK2 positive in each group of rats; The amount of fibroblasts and the relative expression of Bax, Bcl-2, Caspase-3, eNOS, c-Jun, Cofilin, and protein. Results The maximum ICP/MAP and AUC/MAP of the JNK, LIMK2, and the combination group were significantly higher than those of the control group, and the combination group was significantly higher than the JNK and LIMK2 group（P＜0.05）; The NO levels in the JNK, LIMK2, and the combination group significantly higher than the control group, the combined group was significantly higher than the JNK and LIMK2 group（P＜0.05）; the levels of LOX-1, NOX, ET-1 in the JNK, LIMK2 and combined group were significantly lower than those of the control group, and the combined group was significantly lower than JNK and LIMK2 group（P＜0.05）; JNK, LIMK2, and combined group’s p-c-Jun positive apoptotic cells, p-LIMK2 positive fibroblasts were significantly lower than the control group, the combination group was significantly lower than the JNK and LIMK2 group（P＜0.05）; JNK LIMK2 and combined group’s Bcl-2, eNOS protein relative expression was significantly higher than the control group, the combined group was significantly higher than the JNK and LIMK2 group（P＜0.05）; The relative expression of Bax and Caspase-3 protein in the JNK LIMK2 and the combination group was significantly lower than that of the control group, the combination group was significantly lower than the JNK and LIMK2 group（P＜0.05）; The JNK, LIMK2 and the combination group’s c-Jun, Cofilin relative protein expression was significantly lower than the control group, and the combination group was significantly lower than the JNK and LIMK2 group（P＜0.05）. Conclusion Combined inhibition of JNK and LIMK2 inhibitors can improve erectile function by regulating the c-Jun/Bcl-2/Bax and LIMK2/Cofilin pathways of rats with cavernous nerve injury to inhibit the apoptosis and fibrosis of cavernous cells. At present, in view of the limitations of penile rehabilitation after RP, the specific inhibition of JNK and LIMK2 may be used as one of the specific therapeutic targets for patients with erectile dysfunction induced by cavernous nerve injury. [ABSTRACT FROM AUTHOR]

Embryo implantation and fetal development are the process of mutual recognition and adaptation of mother and fetus. The molecular mechanisms of this process are complex. However, the exact mechanisms have not yet been elucidated. Implantation failure is one of the important causes of unexplained infertility, early miscarriage and repeated implantation failure. Embryo implantation is closely related to endometrial receptivity, and various cytokines secreted during implantation can regulate endometrial receptivity and effectively improve pregnancy outcomes. Current studies have found that the Notch, Janus kinase -signal transducer and activator of transcription, Wnt/β-catenin, mitogen activated protein kinase, nuclear factor κB and other signals are involved in embryo implantation. We review the research progress of the signaling pathways involved in embryo implantation, as a reference for exploring the mechanism of embryo implantation and improving pregnancy outcome. [ABSTRACT FROM AUTHOR]

• MIR4435-2HG is prognostic and predictive for triple-negative breast cancer. • MIR4435-2HG may reshape tumor microenvironment of triple-negative breast cancer. • Downregulation of MIR4435-2HG inhibits CAFs activation. • MIR4435-2HG promotes triple-negative breast cancer progression through EMT process. • Loss of MIR4435-2HG attenuates the JNK/c-Jun and p38 MAPK signaling pathway in TNBC cells. Breast cancer has the highest incidence rate and causes the most fatalities among all female cancers worldwide. Triple-negative breast cancer (TNBC) is known for its strong invasiveness and higher rates of recurrence. In this research, we aimed to identify MIR4435-2HG as a promising long non-coding RNA (lncRNA) biomarker and therapeutic target for TNBC. Utilizing clinicopathological information and transcriptome data from The Cancer Genome Atlas (TCGA) database, we assessed the clinical relevance of MIR4435-2HG in breast cancer through univariate and multivariate COX regression, receiver operating characteristic (ROC) analysis, as well as Kaplan-Meier survival analysis. To investigate the biological role of MIR4435-2HG in TNBC, we conducted gene set enrichment analysis (GSEA), as well as Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Additionally, we constructed and validated a nomogram to predict disease-free survival (DFS). Both the R package "pRRophetic" and the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm were employed to forecast the sensitivity to different therapeutics between the high- and low-MIR4435-2HG groups. We employed single-cell RNA sequencing analysis and tumor microenvironment infiltration analysis to investigate the potential involvement of MIR4435-2HG in the TNBC tumor microenvironment. Cellular biological behaviors were assessed utilizing CCK-8, transwell assays, and wound-healing assays. Furthermore, we performed RNA-seq, qRT-PCR, and western blotting analyses to elucidate and confirm the specific mechanisms underlying the role of MIR4435-2HG in TNBC. In our study, we have identified MIR4435-2HG as a significant diagnostic and prognostic factor for TNBC. We observed that MIR4435-2HG is widely expressed and might have a significant impact on the reshaping of the TNBC tumor microenvironment. Patients with TNBC in the high-MIR4435-2HG group may show reduced sensitivity to cisplatin, doxorubicin, and gemcitabine and have an increased propensity for immune escape. Knockdown of MIR4435-2HG inhibits cancer-associated fibroblasts (CAFs) activation. Notably, MIR4435-2HG predominantly enhances the migratory and invasive capabilities of TNBC cells through the epithelial-mesenchymal transition (EMT) process. Mechanistically, we validated that MIR4435-2HG activates the JNK/c-Jun and p38 non-classical MAPK signaling pathway in TNBC cells. Our findings highlight the significant potential of MIR4435-2HG as a highly promising biomarker for TNBC. Targeting MIR4435-2HG could represent an appealing therapeutic approach for TNBC. [ABSTRACT FROM AUTHOR]

The MAPK signaling pathway can mediate a variety of cytokines to participate in the processes of inflammation, cancer, immune disorder, and neurodegenerative diseases, and it also plays an important role in the development and progression of hepatic echinococcosis. This article reviews the structure and regulation of the MAPK signaling pathway and elaborates on the role of the MAPK signaling pathway in hepatic echinococcosis. It is pointed out that the MAPK signaling pathway can activate both the cyst and the host in hepatic echinococcosis, participate in the development and progression of the disease, and exert an impact on its treatment. Drug therapy targeting the MAPK signaling pathway is expected to become a new strategy for the treatment of hepatic echinococcosis. [ABSTRACT FROM AUTHOR]

Objective To explore the mechanism of Shuanghuanglian（SHL）freeze-dried powder induced apoptosis of acute B lymphocytic leukemia cells (Nalm6). Methods SHL was used to treat acute lymphoblastic leukemia cell lines (Nalm6, Jurkat, Molt4 and KG1a) at 0, 0.025, 0.05, 0.1, 0.2, 0.4 and 0.8 g/L. The cell proliferation activity was detected by the CCK-8 method and the half inhibitory concentration (IC50) was calculated. Nalm6 cells were divided into the blank control group (RPMI 1640 medium containing 10% fetal bovine serum) and the SHL treatment groups (0.1, 0.2, and 0.4 g/L). Flow cytometry was used to detect cell cycle distribution and apoptosis in each group. The morphological changes of cell apoptosis were observed after Hoechst 33342 staining. Western blot assay was used to detect the expression levels of MEK-ERK-c-Myc signaling pathway proteins and apoptosis proteins in Nalm6 cells of each group. Results SHL had the lowest IC50 for Nalm6, which was (0.11±0.01) g/L. After treatment with 0.1-0.4 g/L SHL, flow cytometry analysis showed that the cell cycle distribution of Nalm6 cells had no obvious changes. However, with the SHL concentration increasing, the apoptotic cell number and the total apoptotic rate of Nalm6 increased. In addition, the expression levels of tBid, cleaved Caspase-9, cleaved Caspase-3 and cleaved PARP increased. While the expression levels of MEK/ERK pathway related proteins decreased, including p-MEK/MEK, p-ERK/ERK and c-Myc (all P＜0.05). After pretreatment with the apoptosis inhibitor Z-VAD-FMK, the pro-apoptotic effect of SHL on Nalm6 cells was inhibited. Conclusion SHL can induce Nalm6 cell apoptosis by inhibiting the MEK-ERK signaling pathway. [ABSTRACT FROM AUTHOR]

Background: This study investigated the effect of intrathecal Sec-O-glucosylhamaudol (SOG) on the p38/c-Jun N-terminal kinase (JNK) signaling pathways, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-related inflammatory responses, and autophagy in a spinal nerve ligation (SNL)-induced neuropathic pain model. Methods: The continuous administration of intrathecal SOG via an osmotic pump was performed on male Sprague-Dawley rats (n = 50) with SNL-induced neuropathic pain. Rats were randomized into four groups after the 7th day following SNL and treated for 2 weeks as follows (each n = 10): Group S, sham-operated; Group D, 70% dimethylsulfoxide; Group SOG96, SOG at 96 µg/day; and Group SOG192, SOG at 192 µg/day. The paw withdrawal threshold (PWT) test was performed to assess neuropathic pain. Western blotting of the spinal cord (L5) was performed to measure changes in the expression of signaling pathway components, cytokines, and autophagy. Additional studies with naloxone challenge (n = 10) and cells were carried out to evaluate the potential mechanisms underlying the effects of SOG. Results: Continuous intrathecal SOG administration increased the PWT with p38/JNK mitogen-activated protein kinase (MAPK) pathway and NF-κB signaling pathway inhibition, which induced a reduction in proinflammatory cytokines with the concomitant downregulation of autophagy. Conclusions: SOG alleviates mechanical allodynia, and its mechanism is thought to be related to the regulation of p38/JNK MAPK and NF-κB signaling pathways, associated with autophagy during neuroinflammatory processes after SNL. [ABSTRACT FROM AUTHOR]

Apoptosis is proved responsible for renal damage during ischemia/reperfusion. The regulation for renal apoptosis induced by ischemia/reperfusion injury (IRI) has still been unclearly characterized to date. In the present study, we investigated the regulation of histone acetylation on IRI-induced renal apoptosis and the molecular mechanisms in rats with the application of curcumin possessing a variety of biological activities involving inhibition of apoptosis. Sprague-Dawley rats were randomized into four experimental groups (SHAM, IRI, curcumin, SP600125). Results showed that curcumin significantly decreased renal apoptosis and caspase-3/-9 expression and enhanced renal function in IRI rats. Treatment with curcumin in IRI rats also led to the decrease in expression of p300/cyclic AMP response element-binding protein (CBP) and activity of histone acetyltransferases (HATs). Reduced histone H3 lysine 9 (H3K9) acetylation was found near the promoter region of caspase-3/-9 after curcumin treatment. In a similar way, SP600125, an inhibitor of c-Jun N-terminal kinase (JNK), also attenuated renal apoptosis and enhanced renal function in IRI rats. In addition, SP600125 suppressed the binding level of p300/CBP and H3K9 acetylation near the promoter region of caspase-3/-9, and curcumin could inhibit JNK phosphorylation like SP600125. These results indicate that curcumin could attenuate renal IRI via JNK/p300/CBP-mediated anti-apoptosis signaling. [ABSTRACT FROM AUTHOR]

Depression is the most common psychiatric comorbidity of epilepsy. However, the molecular pathways underlying this association remain unclear. The NMDA receptor (NMDAR) may play a role in this association, as its downstream signaling has been shown to undergo long-term changes following excitotoxic neuronal damage. To study this pathway, we used an animal model of fluoxetine-resistant epilepsy-associated depression (EAD). We determined the molecular changes associated with the development of depressive symptoms and examined their response to various combinations of fluoxetine and a selective neuronal nitric oxide synthase inhibitor, 7-nitroindazole (NI). Depressive symptoms were determined using the forced swim test. Furthermore, expression and phosphorylation levels of markers in the ERK/CREB/ELK1/BDNF/cFOS pathway were measured to determine the molecular changes associated with these symptoms. Finally, oxidative stress markers were measured to more clearly determine the individual contributions of each treatment. While chronic fluoxetine (Flxc) and NI were ineffective alone, their combination had a statistically significant synergistic effect in reducing depressive symptoms. The development of depressive symptoms in epileptic rats was associated with the downregulation of ERK2 expression and ELK1 and CREB phosphorylation. These changes were exactly reversed upon Flxc + NI treatment, which led to increased BDNF and cFOS expression as well. Interestingly, ERK1 did not seem to play a role in these experiments. NI seemed to have augmented Flxc's antidepressant activity by reducing oxidative stress. Our findings suggest NMDAR signaling alterations are a major contributor to EAD development and a potential target for treating conditions associated with underlying excitotoxic neuronal damage. [ABSTRACT FROM AUTHOR]

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited chronic kidney disorder (CKD) that is characterized by the development of numerous fluid-filled cysts in kidneys. It is caused either due to the mutations in the PKD1 or PKD2 gene that encodes polycystin-1 and polycystin-2, respectively. This condition progresses into end-stage renal disorder if the renal or extra-renal clinical manifestations remain untreated. Several clinical trials with a variety of drugs have failed, and the only Food and Drugs Administration (FDA) approved drug to treat ADPKD to date is tolvaptan that works by antagonizing the vasopressin-2 receptor (V2R). The pathology of ADPKD is complex and involves the malfunction of different signaling pathways like cAMP, Hedgehog, and MAPK/ERK pathway owing to the mutated product that is polycystin-1 or 2. A measured yet substantial number of preclinical studies have found pioglitazone to decrease the cystic burden and improve the renal function in ADPKD. The peroxisome proliferator-activated receptor-gamma is found on the epithelial cells of renal collecting tubule and when it gets agonized by pioglitazone, confers efficacy in ADPKD treatment through multiple mechanisms. There is only one clinical trial (ongoing) wherein it is being assessed for its benefits and risk in patients with ADPKD, and is expected to get approval from the regulatory body owing to its promising therapeutic effects. This article would encompass the updated information on the epidemiology, pathophysiology of ADPKD, different mechanisms of action of pioglitazone in the treatment of ADPKD with preclinical and clinical shreds of evidence, and related safety updates. [ABSTRACT FROM AUTHOR]

S100A12 is a member of S100 calcium‐binding proteins with effect to promote inflammation in brain damage and stroke. However, the role of S100A12 in ischemia/reperfusion (I/R) remains to be clarified. This study aimed to explore the effect of S100A12 on I/R and discover the possible mechanism. Oxygen‐glucose deprivation and reperfusion (OGD/R) was used to induce I/R injury model in vitro. Knockdown or overexpression of S100A12 was utilized to explore the role of S100A12 in I/R‐induced inflammation and apoptosis. Results indicated that S100A12 expression was dramatically upregulated after OGD/R. Knockdown of S100A12 inhibited, while overexpression of S100A12 enhanced, the activation of ERK1/2 protein. OGD/R also triggered the occurrence of inflammation and oxidative stress, while these effects were blunted by S100A12 silencing and aggravated by S100A12 overexpression, and the presence of MAP kinase signaling system (ERK) inhibitor MK‐8353 counteracted the effect of S100A12 overexpression. Besides, S100A12 silencing abolished, while its overexpression restored, the OGD/R‐induced increased apoptosis rate and pro‐apoptotic proteins expression. Similarly, ERK inhibitor MK‐8353 reversed the effects of S100A12 overexpression. In conclusion, S100A12 promoted OGD/R‐induced inflammation, oxidative stress and apoptosis via activation of ERK signaling in vitro. [ABSTRACT FROM AUTHOR]

Background: Cardiac kinases play a critical role in the development of heart failure, and represent potential tractable therapeutic targets. However, only a very small fraction of the cardiac kinome has been investigated. To identify novel cardiac kinases involved in heart failure, we used an integrated transcriptomics and bioinformatics analysis and identified Homeodomain-Interacting Protein Kinase 2 (HIPK2) as a novel candidate kinase. The role of HIPK2 in cardiac biology is unknown.Methods: We used the Expression2Kinase algorithm for the screening of kinase targets. To determine the role of HIPK2 in the heart, we generated cardiomyocyte (CM)-specific HIPK2 knockout and heterozygous mice. Heart function was examined by echocardiography, and related cellular and molecular mechanisms were examined. Adeno-associated virus serotype 9 carrying cardiac-specific constitutively active MEK1 (TnT-MEK1-CA) was administrated to rescue cardiac dysfunction in CM-HIPK2 knockout mice.Results: To our knowledge, this is the first study to define the role of HIPK2 in cardiac biology. Using multiple HIPK2 loss-of-function mouse models, we demonstrated that reduction of HIPK2 in CMs leads to cardiac dysfunction, suggesting a causal role in heart failure. It is important to note that cardiac dysfunction in HIPK2 knockout mice developed with advancing age, but not during development. In addition, CM-HIPK2 knockout mice and CM-HIPK2 heterozygous mice exhibited a gene dose-response relationship of CM-HIPK2 on heart function. HIPK2 expression in the heart was significantly reduced in human end-stage ischemic cardiomyopathy in comparison to nonfailing myocardium, suggesting a clinical relevance of HIPK2 in cardiac biology. In vitro studies with neonatal rat ventricular CMscorroborated the in vivo findings. Specifically, adenovirus-mediated overexpression of HIPK2 suppressed the expression of heart failure markers, NPPA and NPPB, at basal condition and abolished phenylephrine-induced pathological gene expression. An array of mechanistic studies revealed impaired extracellular signal-regulated kinase 1/2 signaling in HIPK2-deficient hearts. An in vivo rescue experiment with adeno-associated virus serotype 9 TnT-MEK1-CA nearly abolished the detrimental phenotype of knockout mice, suggesting that impaired extracellular signal-regulated kinase signaling mediated apoptosis as the key factor driving the detrimental phenotype in CM-HIPK2 knockout mice hearts.Conclusions: Taken together, these findings suggest that CM-HIPK2 is required to maintain normal cardiac function via extracellular signal-regulated kinase signaling. [ABSTRACT FROM AUTHOR]

Abstract: WNT5A, a representative ligand of activating several non‐canonical WNT signal pathways, plays significant roles in oncogenesis and tumor inhibition. It has been shown that the non‐receptor tyrosine kinase SRC is required for WNT5A‐induced invasion of osteosarcoma cells. However, the precise molecular mechanism underlying WNT5A/SRC‐mediated osteosarcoma cells invasion remains poorly defined. The study was designed to explore the role of ERK1/2 in WNT5A/SRC‐induced osteosarcoma cells invasion and the downstream target of the SRC/ERK1/2 signalings. We found that WNT5A (100 ng/mL) remarkably stimulated migration and invasion of human osteosarcoma MG‐63 cells, whereas inhibiting either SRC kinase activity by siRNA‐mediated SRC silence or ERK1/2 phosphorylation by PD98059 treatment suppressed these effects, which suggested that the activation of SRC and ERK1/2 is essential for WNT5A‐induced MG‐63 cells migration and invasion. Furthermore, ERK1/2 phosphorylation induced by WNT5A was dramatically blocked by SRC siRNA. Additionally, our study further demonstrated that MMP‐14 was upregulated after exposure to WNT5A in MG‐63 cells, and the increased expression was blocked by SRC siRNA or PD98059. Collectively, these results indicate that WNT5A activates SRC/ERK1/2 signal pathway, leading to the upregulation of MMP‐14 expression and MG‐63 cells migration and invasion. [ABSTRACT FROM AUTHOR]

Thyroid cancer is a frequent endocrine related malignancy with continuous increasing incidence. There has been moving development in understanding its molecular pathogenesis recently mainly through the explanation of the original role of several key signaling pathways and related molecular distributors. Central to these mechanisms are the genetic and epigenetic alterations in these pathways, such as mutation and DNA rearrangements. That does not mean, however, that all the somatic abnormalities here in a cancer genome have been involved in development of the cancer and just driver mutations are concerned in tumor initiation. By way of illustrations, MAPK pathway which is motivated by BRAFV600E and RAS and RET / PTC rearrangements are suggesting driver genetic alterations in follicular derived thyroid cancers which are considered in this review. [ABSTRACT FROM AUTHOR]

Peucedanum japonicum Thunberg are perennial herbaceous plants known to be cultivated for food and traditional medicinal purposes. P. japonicum has been used in traditional medicine to soothe coughs and colds, and to treat many other inflammatory diseases. However, there are no studies on the anti-inflammatory effects of the leaves. Inflammation plays an important role in our body as a defense response of biological tissues to certain stimuli. However, the excessive inflammatory response can lead to various diseases. This study aimed to investigate the anti-inflammatory effects of P. japonicum leaves extract (PJLE) in LPS-stimulated RAW 264.7 cells. Nitric Oxide (NO) production assay measured by NO assay. Inducible NO synthase (iNOS), COX-2, MAPKs, AKT, NF-κB, HO-1, Nrf-2 were examined by western blotting. PGE 2 , TNF-α, and IL-6 were analyzed by ELSIA. Nuclear translocation of NF-κB was detected by immunofluorescence staining. PJLE suppressed inducible nitric oxygen synthase (iNOS) and prostaglandin-endoperoxide synthase 2 (cyclooxygenase-2, COX-2) expression, increased heme oxygenase 1 (HO-1) expression, and decreased nitric oxide production. And PJLE inhibited the phosphorylation of AKT, MAPK, and NF-κB. Taken together, PJLE down-regulated inflammatory factors such as iNOS and COX-2 by inhibiting the phosphorylation of AKT, MAPK, and NF-κB. These results suggest that PJLE can be used as a therapeutic material to modulate inflammatory diseases. [Display omitted] • A review of anti-inflammatory properties of the traditional plant Peucedanum japonicum Leaves. • Extract of Peucedanum japonicum Leaves can inhibit inflammatory factors. • Extract of Peucedanum japonicum Leaves inhibits pro-inflammatory cytokines. • Extracts of Peucedanum japonicum Leaves inhibit inflammatory factors through MAPK, AKT/PI3K, and NF-κB signaling pathways. [ABSTRACT FROM AUTHOR]

Purpose We investigated the effects of laminin on the fraction of cells with self-renewing capacity in the estrogen-dependent, tamoxifen-sensitive LM05-E breast cancer cell line. We also determined whether laminin affected the response to tamoxifen. Materials and Methods The LM05-E breast cancer cell line was used as a model for all experiments. Aldehyde dehydrogenase (ALDH) activity, clonogenic and mammosphere assays were performed to measure the effects of laminin on modulation of the stem cell subpopulation. Pluripotent gene expression was analyzed by reverse transcriptase-polymerase chain reaction. The involvement of the mitogen-activated protein kinase (MAPK)/ERK pathway was determined using specific inhibitors. The effects of laminin on the response to tamoxifen were determined and the involvement of α6 integrin was investigated. Results We found that pretreatment with laminin leads to a decrease in cells with the ability to form mammospheres that was accompanied by a decrease in ALDH activity. Moreover, exposure of mammospheres to laminin reduced the capacity to form secondary mammospheres and decreased the expression of Sox-2, Nanog, and Oct-4. We previously reported that 4-OHtamoxifen leads to an increase in the expression of these genes in LM05-E cells. Treatment with signaling pathway inhibitors revealed that the MAPK/ERK pathway mediates the effects of laminin. Finally, laminin induced tamoxifen resistance in LM05-E cells through α6 integrin. Conclusion Our results suggest that the final number of cells with self-renewing capacity in estrogendependent breast tumors may result from the combined effects of endocrine treatment and microenvironmental cues. [ABSTRACT FROM AUTHOR]

Abnormal activation of the mitogen-activated protein kinase (MAPK) signaling pathway is closely associated with the development, progression, and metastasis of liver cancer. This article introduces the expression of MAPK proteins in liver cancer and its role in the proliferation, differentiation, and metastasis of liver cancer, and elaborates on the value of the MAPK signaling pathway in the treatment and prognostic evaluation of liver cancer. It is pointed out that the MAPK signaling pathway plays an important role in the development/progression and treatment of liver cancer and is a potential molecular target for the treatment and prognostic evaluation of liver cancer. [ABSTRACT FROM AUTHOR]

To evaluate the influence of high-intensity interval training (HIIT) on cardiac structural and functional characteristics and myocardial mitogen-activated protein kinase (MAPK) signaling in hypertensive rats. Male rats (12 months old) were divided into three groups: Wistar Kyoto rats (WKY, n = 8); sedentary spontaneously hypertensive rats (SED-SHR, n = 10), and trained spontaneously hypertensive rats (HIIT-SHR, n = 10). Systolic blood pressure (SBP), functional capacity, echocardiography, isolated papillary muscle, and gene expression of MAPK gene-encoding proteins associated with Elk1, cJun, ATF2, MEF2 were analyzed. HIIT decreased SBP and increased functional capacity, left ventricular diastolic diameter, posterior wall thickness-left ventricle, relative wall thickness-left ventricle, and resting tension of the papillary muscle. In hypertensive rats, we observed a decrease in the gene-encoding ATF2 protein; this decrease was reversed by HIIT. The influence of HIIT in the SHR model in the compensated hypertension phase generated an increase in cardiac hypertrophy, attenuated myocardial diastolic dysfunction, lowered blood pressure, improved functional capacity, and reversed the alteration in gene-encoding ATF2 protein. [ABSTRACT FROM AUTHOR]

Angiopoietin-like protein 4 (Angptl4), also known as fasting-induced adiopogenic factor (FIAF), has recently been reported to influence bone metabolism. However, there have been few studies on regulatory factors other than hypoxia for Angptl4 in bone, and particularly in osteoblasts. Expression of interleukin-1β (IL-1β), a proinflammatory cytokine, is increased in serum or bone microenvironments in inflammatory bone diseases or estrogen deficient-conditions. The present study was conducted to determine whether Angptl4 expression in osteoblasts is affected by IL-1β and investigate its involvement in MAP kinase signaling pathways. Angptl4 RNA levels were increased by IL-1β treatment in murine MC3T3-E1 osteoblastic cells. Western blotting and immunofluorescent staining showed a corresponding increase in Angptl4 protein. IL-1β treatment of osteoblasts induced phosphorylation of mitogen-activated protein kinases (MAPKs) including extracellular regulated kinases (ERKs), p38, and c-Jun N-terminal kinase (JNK). Furthermore, SP600125, an inhibitor of JNK, significantly blocked the upregulation of Angptl4 by IL-1β. In contrast, treatment with an inhibitor of p38 MAP kinase (SB203580) or an ERK inhibitor (PD98059) produced responses similar to those seen with the DMSO control. Taken together, these results suggest that IL-1β increases Angptl4 expression through a mechanism dependent on the JNKMAPK signaling pathway in MC3T3-E1 cells. [ABSTRACT FROM AUTHOR]

We investigated the influence of bone marrow cells upon activation of ERK ½ in an animal model of 90% PH. Phosphorylated ERK 1/2 was evaluated by western blot. No differences were found between the groups. Thus, increased survival does not appear to be mediated by ERK 1/2 activation. [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to determine whether cirrhosis could be reversed after treated with hepatocyte nuclear factor 4α ( HNF4α), a key transcriptional regulator of hepatocyte differentiation and function. Methods Early and advanced stages of liver cirrhosis were induced by thioacetamide (TAA) administration. The adenovirus carrying HNF4α gene was injected into cirrhotic rats via the tail vein. The effect of HNF4α on cirrhosis was evaluated by histological and immunohistochemical examination. Results Early stage of cirrhosis was remarkably resolved by HNF4α to a nearly-normal extent and advanced cirrhosis was partially ameliorated in vivo. The enforced expression of HNF4α downregulated profibrogenic factors remarkably including α-smooth muscle actin (α-SMA), transforming growth factor (TGF)-β1, fibroblast-specific protein (FSP)-1, collagen I and III. In vivo and in vitro studies revealed that HNF4α administration inhibited extracellular signal-regulated kinase ( ERK) signaling pathway through the downregulation of phosphorated ERK and phosphorated JunD. In addition, HNF4α readjusted the balance between extracellular matrix deposition and degradation through the upregulation of matrix metalloproteinase and downregulation of its inhibitors. Moreover, HNF4α treatment inhibited angiogenesis as determined by CD31 and CD34 immunostaining. Conclusions Our findings broaden the knowledge on the reversibility of different stages of cirrhosis as HNF4α could present a promising alternative for the treatment of liver cirrhosis. [ABSTRACT FROM AUTHOR]

• Administration of imipramine prevents STZ-induced spatial learning and memory impairment. • The memory loss was associated with activation of hippocampal JNK MAPKs, however, P38 and ERK activity did not show such significant change. • The memory loss was accompanied with partial disruption in insulin signaling and activation of apoptotic pathway shown by caspase-3 activation. • Imipramine treatment reverses the effect of STZ on hippocampal JNK and capase-3 activity. • Chronic administration of imipramine could potentiate ERK activity. Alzheimer's disease (AD) is the most common age-related neurodegenerative disease, associated with several pathophysiological complaints. Impaired insulin signaling in the brain, is one of the important characteristic features of AD which is accompanied by cognitive deficits. According to the multifactorial and complicated pathology of AD, no modifying therapy has been approved yet. Imipramine is a kind of tricyclic antidepressant with reported anti-inflammatory and anti-oxidant effects in the brain. There are controversial studies about the effect of this drug on spatial memory. This study investigates the effect of imipramine on streptozotocin (STZ) induced memory impairment in rats. Pursuing this objective, rats were treated with imipramine 10 or 20 mg/kg i.p. once a day for 14 days. 24 h after the last injection, memory function was evaluated by the Morris water maze (MWM) test in 4 consecutive days. Then, hippocampi were removed and the activity of caspase-3, mitogen activated protein kinases (MAPKs) family and inhibitory phosphorylation of insulin receptor substrate-1 (IRS-1 ser307) were analyzed using Western blotting. Results showed that imipramine prevents memory impairment in STZ induced rats and this improvement was accompanied with an increase in ERK activity, reduction of caspase-3 and JNK activity, as well as partial restoration of P38 and IRS-1 activity. In conclusion, our study demonstrated that at least some members of the MAPK family are involved in the neuroprotective effect of imipramine. [ABSTRACT FROM AUTHOR]

Intracellular signalling pathways have been extensively studied as therapeutic targets for the treatment of mental diseases. Our attention has been caught by two kinases potentially involved in anxiety, ERK1/2 and CaMKII. The study aimed to examine changes in the activation of ERK1/2 and CaMKII concerning anxiolytic-like behaviours in mice. To evaluate anxiety-related response in mice, we used the open field test and the elevated plus maze test. Behavioural studies were complemented with the immunoblotting analysis to identify proteins of interest in the cortex, hippocampus, and striatum. We analysed the phosphorylation status of ERK1/2 and CaMKII in mice treated with a well-known anxiolytic drug – diazepam. Next, the blockade of ERK1/2 pathway by SL-327, a selective MEK1/2 inhibitor, was checked for anxiolytic action. Finally, the co-administration of subeffective doses of diazepam and SL-327 was investigated for a potential synergistic anxiolytic effect. Anxiolytic effects of acute diazepam are accompanied by decreased p-ERK1/2 and upregulation of p-CaMKII. Subchronic treatment with SL-327 leads to the manifestation of anxiolytic-like behaviours and changes in the phosphorylation status of both kinases in a diazepam-like manner. Co-administration of subeffective doses of SL-327 and diazepam induces anxiolysis, which is CaMKII-independent and correlates to selectively decreased phosphoactive ERK1/2 in the hippocampus. The MEK-ERK pathway is significantly involved in anxiolytic action of diazepam and its prolonged inhibition produces anxiolytic-like phenotype in mice. ERK inhibition could be used to manage anxiety symptoms in a benzodiazepine-sparing regimen for treatment of anxiety. Subchronic SL-327 and acute diazepam induce anxiolytic-like behaviours in mice in the elevated plus maze and the open field test. Anxiolytic-like behaviours were accompanied by decreased levels of pERK1/2 in the prefrontal cortex, hippocampus and striatum. Co-administration of subeffective SL-327 and diazepam expresses their synergistic effect on anxiety-related behaviours presumably in a hippocampus-dependent manner. The graphical abstract was created with BioRender.com. Image 1 • SL-327- and diazepam-induced anxiolytic-like behaviours correlate with ↓ p-ERK1/2 and ↑ p-CaMKII. • SL-327 and diazepam have a synergistic effect on anxiety, correlated with hippocampal ↓ p-ERK1/2. • Targeting the MEK-ERK pathway may be beneficial in the treatment of anxiety disorders. • MEK inhibitors could play the role of adjuvants in diazepam-sparing therapy of anxiety. [ABSTRACT FROM AUTHOR]

• IFN-γ and IL-15 inhibit HCV replication in Huh7.5 cells. • IL-15 and IFN-γ do not induce anti-HCV effects via the type I IFN signaling pathway. • IL-15 and IFN-γ do not induce anti-HCV effects via nitric oxide production. • IL-15 and IFN-γ may provide protection against HCV via the ERK pathway. • Treatment of Huh7.5 cells with a MEK/ERK inhibitor abrogated the anti HCV effects of IL-15 and IFN-γ. Despite effective new treatments for Hepatitis C virus (HCV) infection, development of drug resistance, safety concerns and cost are remaining challenges. More importantly, there is no vaccine available against hepatitis C infection. Recent data suggest that there is a strong correlation between spontaneous HCV clearance and human NK cell function, particularly IFN-γ production. Further, IL-15 has innate antiviral activity and is also one of the main factors that activates NK cells to produce IFN-γ. To examine whether IL-15 and IFN-γ have direct antiviral activity against HCV, Huh7.5 cells were treated with either IFN-γ or IL-15 prior to HCV infection. Our data demonstrate that IFN-γ and IL-15 block HCV replication in vitro. Additionally, we show that IL-15 and IFN-γ do not induce anti-HCV effects through the type I interferon signaling pathway or nitric oxide (NO) production. Instead, IL-15 and IFN-γ provide protection against HCV via the ERK pathway. Treatment of Huh7.5 cells with a MEK/ERK inhibitor abrogated the anti-HCV effects of IL-15 and IFN-γ and overexpression of ERK1 prevented HCV replication compared to control transfection. Our in vitro data support the hypothesis that early production of IL-15 and activation of NK cells in the liver lead to control of HCV replication. [ABSTRACT FROM AUTHOR]