Sulfenylation of ERK1/2: A novel mechanism for SO2-mediated inhibition of cardiac fibroblast proliferation.

Background: Endogenous sulfur dioxide (SO2) plays a crucial role in protecting heart from myocardial fibrosis by inhibiting the excessive growth of cardiac fibroblasts. This study aimed to investigate potential mechanisms by which SO2 suppressed myocardial fibrosis. Methods and results: Mouse model of angiotensin II (Ang II)-induced cardiac fibrosis and cell model of Ang II-stimulated cardiac fibroblast proliferation were employed. Our findings discovered that SO2 mitigated the aberrant phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) induced by Ang II, leading to a reduction of fibroblast proliferation. Mechanistically, for the first time, we found that SO2 sulfenylated ERK1/2, and inhibited ERK1/2 phosphorylation and cardiac fibroblast proliferation, while a sulfhydryl reducing agent dithiothreitol (DTT) reversed the above effects of SO2. Furthermore, mutant ERK1C183S (cysteine 183 to serine) abolished the sulfenylation of ERK by SO2, thereby preventing the inhibitory effects of SO2 on ERK1 phosphorylation and cardiac fibroblast proliferation. Conclusion: Our study suggested that SO2 inhibited cardiac fibroblast proliferation by sulfenylating ERK1/2 and subsequently suppressing ERK1/2 phosphorylation. These new findings might enhance the understanding of the mechanisms underlying myocardial fibrosis and emphasize the potential of SO2 as a novel therapeutic target for myocardial fibrosis.

CRH upregulates supervillin through ERK and AKT pathways to promote bladder cancer cell migration.

Corticotropin-releasing hormone (CRH) has been well documented playing a role in the regulation of cellular processes, immune responses, and inflammatory processes that can influence the occurrence and development of tumors. Supervillin (SVIL) is a membrane-associated and actin-binding protein, which is actively involved in the proliferation, spread, and migration of cancer cells. This work investigated CRH's influence on bladder cancer cells' migration and relevant mechanisms. By using human bladder cancer cells T24 and RT4 in wound healing experiments and transwell assay, we found that the migration ability of the T24 cells was significantly increased after CRH treatment. In vivo experiments showed that CRH significantly promoted the metastases of T24 cells in cell line-derived xenograft (CDX) mouse model. Interestingly, downregulation of SVIL by SVIL-specifc small hairpin RNAs significantly reduced the promoting effect of CRH on bladder cancer cell migration. Furthermore, CRH significantly increased SVIL messenger RNA and protein expression in T24 cells, accompanied with AKT and ERK phosphorylation in T24 cells. Pretreatment with AKT inhibitor (MK2206) blocked the CRH-induced SVIL expression and ERK phosphorylation. Also, inhibition of ERK signaling pathway by U0126 significantly reduced the CRH-induced SVIL expression and AKT phosphorylation. It suggested that cross-talking between AKT and ERK pathways was involved in the effect of CRH on SVIL. Taken together, we demonstrated that CRH induced migration of bladder cancer cells, in which AKT and ERK pathways -SVIL played a key role.

IL-1ß-activated PI3K/AKT and MEK/ERK pathways coordinately promote induction of partial epithelial-mesenchymal transition.

Epithelial-mesenchymal transition (EMT) is a cellular process in embryonic development, wound healing, organ fibrosis, and cancer metastasis. Previously, we and others have reported that proinflammatory cytokine interleukin-1ß (IL-1ß) induces EMT. However, the exact mechanisms, especially the signal transduction pathways, underlying IL-1ß-mediated EMT are not yet completely understood. Here, we found that IL-1ß stimulation leads to the partial EMT-like phenotype in human lung epithelial A549 cells, including the gain of mesenchymal marker (vimentin) and high migratory potential, without the complete loss of epithelial marker (E-cadherin). IL-1ß-mediated partial EMT induction was repressed by PI3K inhibitor LY294002, indicating that the PI3K/AKT pathway plays a significant role in the induction. In addition, ERK1/2 inhibitor FR180204 markedly inhibited the IL-1ß-mediated partial EMT induction, demonstrating that the MEK/ERK pathway was also involved in the induction. Furthermore, we found that the activation of the PI3K/AKT and MEK/ERK pathways occurred downstream of the epidermal growth factor receptor (EGFR) pathway and the IL-1 receptor (IL-1R) pathway, respectively. Our findings suggest that the PI3K/AKT and MEK/ERK pathways coordinately promote the IL-1ß-mediated partial EMT induction. The inhibition of not one but both pathways is expected yield clinical benefits by preventing partial EMT-related disorders such as organ fibrosis and cancer metastasis.

Update on the Genetics of Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) is a heterogeneous heritable skeletal dysplasia characterized by bone fragility and deformity, growth deficiency, and other secondary connective tissue defects. OI is now understood as a collagen-related disorder caused by defects of genes whose protein products interact with collagen for folding, post-translational modification, processing and trafficking, affecting bone mineralization and osteoblast differentiation. This review provides the latest updates on genetics of OI, including new developments in both dominant and rare OI forms, as well as the signaling pathways involved in OI pathophysiology. There is a special emphasis on discoveries of recessive mutations in TENT5A, MESD, KDELR2 and CCDC134 whose causality of OI types XIX, XX, XXI and XXI, respectively, is now established and expends the complexity of mechanisms underlying OI to overlap LRP5/6 and MAPK/ERK pathways. We also review in detail new discoveries connecting the known OI types to each other, which may underlie an eventual understanding of a final common pathway in OI cellular and bone biology.

[Retracted] lncRNA­u50535 promotes the progression of lung cancer by activating CCL20/ERK signaling.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that certain of the western blotting data shown in Fig. 4B and C on p. 1952, and the Transwell invasion assay data in Fig. 2F and 4I, had already appeared in previously published articles written by different authors at different research institutes (a number of which have been retracted). Owing to the fact that the contentious data in the above article had already been published prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 42: 1946­1956, 2019; DOI: 10.3892/or.2019.7302].

Aquaporin-3 is down-regulated by LMP1 in nasopharyngeal carcinoma cells to regulate cell migration and affect EBV latent infection.

Epstein-Barr virus (EBV) infection has a strong correlation with the development of nasopharyngeal carcinoma (NPC). Aquaporin 3 (AQP3), a member of the aquaporin family, plays an important role in tumor development, especially in epithelial-mesenchymal transition. In this study, the expression of AQP3 in EBV-positive NPC cells was significantly lower than that in EBV-negative NPC cells. Western blot and qRT-PCR analysis showed that LMP1 down-regulated the expression of AQP3 by activating the ERK pathway. Cell biology experiments have confirmed that AQP3 affects the development of tumor by promoting cell migration and proliferation in NPC cells. In addition, AQP3 can promote the lysis of EBV in EBV-positive NPC cells. The inhibition of AQP3 expression by EBV through LMP1 may be one of the mechanisms by which EBV maintains latent infection-induced tumor progression.

Glypican-3 deficiency in liver cancer upregulates MAPK/ERK pathway but decreases cell proliferation.

Glypican-3 (GPC3) is overexpressed in hepatocellular carcinomas and hepatoblastomas and represents an important therapeutic target but the biologic importance of GPC3 in liver cancer is unclear. To date, there are limited data characterizing the biological implications of GPC3 knockout (KO) in liver cancers that intrinsically express this target. Here, we report on the development and characterization of GPC3-KO liver cancer cell lines and compare to them to parental lines. GPC3-KO variants were established in HepG2 and Hep3B liver cancer cell lines using a lentivirus-mediated CRISPR/Cas9 system. We assessed the effects of GPC3 deficiency on oncogenic properties in vitro and in murine xenograft models. Downstream cellular signaling pathway changes induced by GPC3 deficiency were examined by RNAseq and western blot. To confirm the usefulness of the models for GPC3-targeted drug development, we evaluated the target engagement of a GPC3-selective antibody, GC33, conjugated to the positron-emitting zirconium-89 (89Zr) in subcutaneous murine xenografts of wild type (WT) and KO liver cancer cell lines. Deletion of GPC3 significantly reduced liver cancer cell proliferation, migration, and invasion compared to the parental cell lines. Additionally, the tumor growth of GPC3-KO liver cancer xenografts was significantly slower compared with control xenografts. RNA sequencing analysis also showed GPC3-KO resulted in a reduction in the expression of genes associated with cell cycle regulation, invasion, and migration. Specifically, we observed the downregulation of components in the AKT/NFκB/WNT signaling pathways and of molecules related to cell cycle regulation with GPC3-KO. In contrast, pMAPK/ERK1/2 was upregulated, suggesting an adaptive compensatory response. KO lines demonstrated increased sensitivity to ERK (GDC09994), while AKT (MK2206) inhibition was more effective in WT lines. Using antibody-based positron emission tomography (immunoPET) imaging, we confirmed that 89Zr-GC33 accumulated exclusively in GPC3-expression xenografts but not in GPC3-KO xenografts with high tumor uptake and tumor-to-liver signal ratio. We show that GPC3-KO liver cancer cell lines exhibit decreased tumorigenicity and altered signaling pathways, including upregulated pMAPK/ERK1/2, compared to parental lines. Furthermore, we successfully distinguished between GPC3+ and GPC3- tumors using the GPC3-targeted immunoPET imaging agent, demonstrating the potential utility of these cell lines in facilitating GPC3-selective drug development.

MAZ promotes thyroid cancer progression by driving transcriptional reprogram and enhancing ERK1/2 activation.

Papillary thyroid carcinoma (PTC) is the most common type of thyroid malignancies worldwide. Oncogenic transcription factors (TFs) drive transcriptional reprogramming and tumorigenesis. The myc-associated zinc finger protein (MAZ) is one of the Myc family TFs. The role of MAZ in PTC pathogenesis is still largely unknown. Here, we report that MAZ profoundly promotes proliferation of PTC cells ex vivo and in vivo through activating MAPK signaling. We firstly profiled gene expression of PTC cells after silencing of MAZ. BRAF, KRAS and LOC547 were identified as important target genes of TF MAZ. In particular, TF MAZ bound to the promoters of BRAF or KRAS and significantly increased their transcription and expression levels. Meanwhile, MAZ could noticeably elevate LOC547 transcription and expression as a TF. High levels of LOC547 relocated ACTN4 protein from the nucleus to the cytosol, improved protein-protein interactions between ACTN4 and EGFR in the cytosol, enhanced ERK1/2 phosphorylation, activated the MAPK signaling and, thus, promoted PTC progression. Our data identify a previously underappreciated MAZ-controlled transcriptional reprogram and ERK1/2 activation via BRAF, KRAS and LOC547. Our data illustrate that activation of the MAZ-controlled axis promotes thyroid tumorigenesis. These insights would advance our knowledge of the role of TFs in cancer development and highlight the potential of TFs as future targets for treatments against cancers.

Protective effect of irbesartan against hepatic ischemia-reperfusion injury in rats: role of ERK, STAT3, and PPAR-γ inflammatory pathways in rats.

This study aimed to elucidate the possible hepatocellular protective role of irbesartan during hepatic ischemia-reperfusion injury (HIRI) and the probable underlying mechanisms. Wistar rats were allocated into four groups: sham; HIRI (control); irbesartan (50 mg/kg) + HIRI; irbesartan (100 mg/kg) + HIRI; irbesartan + GW9662 (1 mg/kg, i.p.) + HIRI. Rats pretreated orally with irbesartan or vehicle for 14 days underwent 45-min hepatic ischemia followed by 60-min reperfusion. Irbesartan preconditioning diminished alanine transaminase (ALT) and aspartate transaminase (AST) serum levels, and reduced extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription 3 (STAT3). Irbesartan decreased proapoptotic BAX (bcl-2-like protein 4), increased anti-apoptotic B-cell lymphoma 2 (BCL2) hepatic content, and thereby reduced BAX/BCL2 ratio. Moreover, irbesartan preconditioning reduced autophagy-related proteins Beclin1 and LC3 II, and elevated p62 (protein responsible for autophagosome degradation). It elevated proliferator-activated receptor γ (PPAR-γ), and reduced tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) hepatic gene expression. Also, hepatic protein expressions of nuclear factor kappa-B p65 (NF-κB p65) and caspase-3 were lessoned by irbesartan pretreatment in HIRI rats. However, GW9662 abrogated irbesartan's effect on HIRI. The protective effect of irbesartan on HIRI may be mediated by alleviation of ERK, STAT3, and PPAR-γ inflammatory pathways, exerting anti-apoptotic and anti-autophagic effects in HIRI in rats.

Unveiling the protective potential of mirabegron against thioacetamide-induced hepatic encephalopathy in rats: Insights into cAMP/PPAR-γ/p-ERK1/2/p S536 NF-κB p 65 and p-CREB/BDNF/TrkB in parallel with oxidative and apoptotic trajectories.

Hepatic encephalopathy (HE) is one of the most prevalent and severe hepatic and brain disorders in which escalation of the oxidative, inflammatory and apoptotic trajectories pathologically connects acute liver injury with neurological impairment. Mirabegron (Mira) is a beta3 adrenergic receptor agonist with proven antioxidant and anti-inflammatory activities. The current research pointed to exploring Mira's hepato-and neuroprotective impacts against thioacetamide (TAA)-induced HE in rats. Rats were distributed into three experimental groups: the normal control group, the TAA group, received TAA (200 mg/kg/day for three consecutive days) and the Mira-treated group received Mira (10 mg/kg/day; oral gavage) for 15 consecutive days and intoxicated with TAA from the 13th to the 15th day of the experimental period. Mira counteracted hyperammonemia, enhanced rats' locomotor capability and motor coordination. It attenuated hepatic/neurological injuries by its antioxidant, anti-apoptotic as well as anti-inflammatory potentials. Mira predominantly targeted cyclic adenosine monophosphate (cAMP)/phosphorylated extracellular signal-regulated kinase (p-Erk1/2)/peroxisome proliferator-activated receptor gamma (PPARγ) dependent pathways via downregulation of p S536-nuclear factor kappa B p65 (p S536 NF-κB p 65)/tumor necrosis alpha (TNF-α) axis. Meanwhile, it attenuated nuclear factor erythroid 2-related factor (Nrf2) depletion in parallel with restoring of the neuroprotective defensive pathway by upregulation of cerebral cAMP/PPAR-γ/p-ERK1/2 and p-CREB/BDNF/TrkB besides reduction of GFAP immunoreactivity. Mira showed anti-apoptotic activity through inhibition of Bax immunoreactivity and elevation of Bcl2. To summarize, Mira exhibited a hepato-and neuroprotective effect against TAA-induced HE in rats via shielding antioxidant defense and mitigation of the pathological inflammatory and apoptotic axis besides upregulation of neuroprotective signaling pathways.

PRSS50-mediated inhibition of MKP3/ERK signaling is crucial for meiotic progression and sperm quality.

Serine protease 50 (PRSS50/TSP50) is highly expressed in spermatocytes. Our study investigated its role in testicular development and spermatogenesis. Initially, PRSS50 knockdown was observed to impair DNA synthesis in spermatocytes. To further explore this, we generated PRSS50 knockout ( Prss50 -/- ) mice ( Mus musculus), which exhibited abnormal spermatid nuclear compression and reduced male fertility. Furthermore, dysplastic seminiferous tubules and decreased sex hormones were observed in 4-week-old Prss50 -/- mice, accompanied by meiotic progression defects and increased apoptosis of spermatogenic cells. Mechanistic analysis indicated that PRSS50 deletion resulted in increased phosphorylation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and elevated levels of MAP kinase phosphatase 3 (MKP3), a specific ERK antagonist, potentially accounting for testicular dysplasia in adolescent Prss50 -/- mice. Taken together, these findings suggest that PRSS50 plays an important role in testicular development and spermatogenesis, with the MKP3/ERK signaling pathway playing a significant role in this process.

Novel analgesic peptide derived from Cinobufacini injection suppressing inflammation and pain via ERK1/2/COX-2 pathway.

Inflammatory pain is a chronic pain caused by peripheral tissue inflammation, seriously impacting the patient's life quality. Cinobufacini injection, as a traditional Chinese medicine injection preparation, shows excellent efficacy in anti-inflammatory and analgesic treatment in patients with advanced tumors. In this study, a novel analgesic peptide CI5 with anti-inflammatory and analgesic bio-functions that naturally presents in Cinobufacini injection and its regulatory mechanism are reported. Our results showed that the administration of CI5 significantly relieved the pain of mice in the acetic acid twisting analgesic model and formalin inflammatory pain model. Furthermore, CI5 effectively reduced the inflammatory cytokines (IL-6, TNF-α and IL-1ß) and inflammatory mediator (PGE2) expressions, and prevented the carrageenan-induced paw edema in mice. Further LC-MS/MS results showed the anti-inflammatory and analgesic bio-functions of CI5 depended on its interaction with the Rac-2 protein upstream of ERK1/2 and the inflammatory signaling pathway (ERK1/2/COX-2 axis). In summary, CI5, as a novel natural candidate identified from Cinobufacini injection, showed substantial clinical promise for inflammatory pain treatments.

ß2-microglobulin induced apoptosis of tumor cells via the ERK signaling pathway by directly interacting with HFE in HER2-overexpressing breast cancer.

BACKGROUND: Our previous study demonstrated that ß2-microglobulin (ß2M) promoted ER+/HER2- breast cancer survival via the SGK1/Bcl-2 signaling pathway. However, the role of ß2M has not been investigated in ER-/HER2+ breast cancer. Here, we aimed to determine the role of ß2M in ER-/HER2+ breast cancer. METHODS: The interaction between ß2M and HFE was confirmed by co-immunoprecipitation, mass spectrometry, yeast two-hybrid screening, and His pull-down. The knockdown and overexpression of ß2M or HFE were performed in MDA-MB-453 cells, and ERK signaling pathway was subsequently analyzed via western blotting. Apoptotic cells were detected using flow cytometer. ß2M, HFE, and p-ERK1/2 were examined in tumor and paired adjacent tissues via immunohistochemistry. RESULTS: HFE was found to be an interacting protein of ß2M in ER-/HER2+ breast cancer cells MDA-MB-453 by co-immunoprecipitation and mass spectrometry. A yeast two-hybrid system and His-pull down experiments verified that ß2M directly interacted with HFE. ß2M and HFE as a complex were mainly located in the cytoplasm, with some on the cytomembrane of MDA-MB-453 cells. In addition to breast cancer cells BT474, endogenous ß2M directly interacted with HFE in breast cancer cells MDA-MB-453, MDA-MB-231, and MCF-7. ß2M activated the ERK signaling pathway by interacting with HFE and induced apoptosis of MDA-MB-453 cells. The expression of HFE and p-ERK1/2 showed significantly high levels in HER2-overexpressing breast cancer tumor tissue compared with adjacent normal tissue, consistent with the results obtained from the cell experiments. CONCLUSIONS: ß2M induced apoptosis of tumor cells via activation of the ERK signal pathway by directly interacting with HFE in HER2-overexpressing breast cancer.

Pyrocurzerenone suppresses human oral cancer cell metastasis by inhibiting the expression of ERK1/2 and cathepsin S proteins.

Pyrocurzerenone is a natural compound found in Curcuma zedoaria and Chloranthus serratus. However, the anticancer effect of pyrocurzerenone in oral cancer remains unclear. Using the MTT assay, wound healing assay, transwell assay and western blot analysis, we investigated the impact of pyrocurzerenone on antimetastatic activity, as well as the critical signalling pathways that underlie the processes of oral cancer cell lines SCC-9, SCC-1 and SAS in this work. Our findings suggested that pyrocurzerenone inhibits cell migration and invasion ability in oral cancer cell lines. Furthermore, phosphorylation of ERK1/2 had significant inhibitory effects in SCC-9 and SCC-1 cell lines. Combining ERK1/2 inhibitors with pyrocurzerenone decreased the migration and invasion activity of SCC-9 and SCC-1 cell lines. We also found that the expressed level of cathepsin S decreased under pyrocurzerenone treatment. This study showed that pyrocurzerenone reduced ERK1/2 expression of the proteins and cathepsin S, suggesting that it could be a valuable treatment to inhibit human oral cancer cell metastasis.

The use of matrine to inhibit osteosarcoma cell proliferation via the regulation of the MAPK/ERK signaling pathway.

Background: Matrine is an alkaloid extracted from Sophorus beans of the legume family, and it has significant effects and a variety of pharmacological activities. Osteosarcoma(OS) is a common malignant bone tumor that is characterized by high incidence and rapid progression. There have been some preliminary studies on the therapeutic effect of matrine on OS, but the specific mechanism remains unclear. Objective: The aim of this study was to investigate the antitumor effect of matrine on HOS cells and the underlying molecular mechanism. Methods: The effects of matrine on the proliferation, apoptosis and cell cycle progression of HOS cells were determined by CCK-8 assay, TUNEL assay and flow cytometry in vitro. Wound healing and Transwell invasion assays were used to observe the effect of matrine on the migration and invasion of HOS cells. The mechanism underlying the antitumor effect of matrine on HOS cells was investigated by Western blotting. Results: Matrine significantly inhibited HOS cell proliferation, promoted HOS cell apoptosis, and arrested HOS cells in the G1 phase of the cell cycle. Both wound healing and Transwell invasion assays showed that matrine inhibited HOS cell migration and invasion. Western blotting results showed that matrine inhibited the activation of the MAPK/ERK signaling pathway. We found that matrine also downregulated Bcl-2 expression, which may be related to protein synthesis inhibition. Conclusion: Matrine can inhibit the proliferation of HOS cells, arrest HOS cells in the G1 phase, and promote HOS cell apoptosis through the MAPK/ERK signaling pathway.

BAP1-mediated MAFF deubiquitylation regulates tumor growth and is associated with adverse outcomes in colorectal cancer.

BACKGROUND: Despite improvements in colorectal cancer (CRC) treatment, the prognosis for advanced CRC patients remains poor. Disruption of protein stability is one of the important factors in cancer development and progression. In this study, we aim to identify and analyze novel dysregulated proteins in CRC, assessing their significance and the mechanisms. METHODS: Using quantitative proteomics, expression pattern analysis, and gain-of-function/loss-of-function experiments, we identify novel functional protein dysregulated by ubiquitin-proteasome axis in CRC. Prognostic significance was evaluated in a training cohort of 546 patients and externally validated in 794 patients. Mechanistic insights are gained through molecular biology experiments, deubiquitinating enzymes (DUBs) expression library screening, and RNA sequencing. RESULTS: MAFF protein emerged as the top novel candidate substrate regulated by ubiquitin-proteasome in CRC. MAFF protein was preferentially downregulated in CRC compared to adjacent normal tissues. More importantly, multicenter cohort study identified reduced MAFF protein expression as an independent predictor of overall and disease-free survival in CRC patients. The in vitro and vivo assays showed that MAFF overexpression inhibited CRC growth, while its knockdown had the opposite effect. Intriguingly, we found the abnormal expression of MAFF protein was predominantly regulated via ubiquitination of MAFF, with K48-ubiquitin being dominant. BAP1 as a nuclear deubiquitinating enzyme (DUB), bound to and deubiquitinated MAFF, thereby stabilizing it. Such stabilization upregulated DUSP5 expression, resulting in the inhibition of ERK phosphorylation. CONCLUSIONS: This study describes a novel BAP1-MAFF signaling axis which is crucial for CRC growth, potentially serving as a therapeutic target and a promising prognostic biomarker for CRC.

Combined swimming with melatonin protects against behavioural deficit in cerebral ischemia-reperfusion injury induced rats associated with modulation of Mst1- MAPK -ERK signalling pathway.

BACKGROUND: The inconvenience of social and behavioural deficits after cerebral ischaemia reperfusion (I/R) injury is still not well documented. AIM: We aimed to study the protective effect of preconditioning swimming exercise combined with melatonin against cerebral I/R induced injury. METHODOLOGY: Sixty rats were allocated into 6 groups; groups I and II served as control. Groups 3,4,5,6 subjected to bilateral carotid ligation for 30 minutes (min.) followed by reperfusion. Group 3 left untreated while groups 4 and 6; underwent swimming exercise 30 min/day, five days a week for three weeks before the surgery. Groups 5 and 6 treated with melatonin 30 minutes before the operation, then, all rats in groups 4, 5,6 were subjected to I/R. After that, groups 5 and 6 treated with 2nd dose of melatonin 30 minutes after reperfusion. RESULTS: Combined strategy exhibited the most neuroprotective effect through prevention of cerebral I/R induced inflammation, oxidative stress and apoptosis with subsequent improvement in socio behaviour deficits and enhanced Glial cell proliferative capacity. CONCLUSION: The protective contribution of combined strategy is associated with modulation in Macrophage-stimulating 1/mitogen-activated protein kinase/extracellular signal-regulated kinase (MST1/MAPK/ERK) pathway which may explain, at least in part, its protective potential.

Preconditioning swimming exercise combined with melatonin protected against cerebral I/R induced socio-behavioural deficit.Cerebral I/R induced pathophysiological alterations in Prefrontal cortical neurons (PFC) are prevented by combined Preconditioning swimming exercise and melatoninCombined Preconditioning swimming exercise/melatonin in cerebral I/R modulates MST1/MAPK/ERK signalling pathwayCombined Preconditioning swimming exercise/melatonin inhibit inflammation, oxidative stress and apoptosis, thus enhance Glial cell proliferative capacity in I/R induced injury in PFC neurons.

Therapeutic Potential of siRNAs in Tongue Squamous Cell Carcinoma by Modulating The PI3K/AKT and ERK Signaling Pathways: A Systematic Review.

Among the various manifestations of oral cavity cancer, tongue squamous cell carcinoma (TSCC), is the most common form of this condition. TSCC represents a major challenge in the field of cancer treatment. The emergence of small interfering RNAs (siRNAs) has opened new avenues for therapeutic intervention in TSCC. This research provides an overview of siRNA-mediated mechanisms and emphasizes their complex involvement in modulating key signaling pathways associated with TSCC progression. Relevant articles from 2004 to 2023 were conducted by using different keywords, such as "Interfering RNA " and "Small Interfering ". The search was following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines based on inclusion and exclusion criteria. The quality of the studies was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. The selected studies (n=17) were subjected to perform comprehensive analysis. We concluded that the PI3K/AKT and ERK pathways, one of oncogenic signaling cascades in TSCC is notable. siRNAs and their role in targeting specific signaling pathways help us understand the molecular mechanisms underlying TSCC that may lead to the development promising therapies for TSCC. These therapies have the advantage of personalization and precision, targeted delivery, and the potential to overcome drug resistance. Therefore, the study enhances our comprehension of siRNA-based interventions' clinical potential in TSCC.

ERK5 mediates pro-tumorigenic phenotype in non-small lung cancer cells induced by PGE2.

Lung cancer is the leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) constituting approximately 84 % of all lung cancer cases. The role of inflammation in the initiation and progression of NSCLC tumors has been the focus of extensive research. Among the various inflammatory mediators, prostaglandin E2 (PGE2) plays a pivotal role in promoting the aggressiveness of epithelial tumors through multiple mechanisms, including the stimulation of growth, evasion of apoptosis, invasion, and induction of angiogenesis. The Extracellular signal-Regulated Kinase 5 (ERK5), the last discovered member among conventional mitogen-activated protein kinases (MAPK), is implicated in cancer-associated inflammation. In this study, we explored whether ERK5 is involved in the process of tumorigenesis induced by PGE2. Using A549 and PC9 NSCLC cell lines, we found that PGE2 triggers the activation of ERK5 via the EP1 receptor. Moreover, both genetic and pharmacological inhibition of ERK5 reduced PGE2-induced proliferation, migration, invasion and stemness of A549 and PC9 cells, indicating that ERK5 plays a critical role in PGE2-induced tumorigenesis. In summary, our study underscores the pivotal role of the PGE2/EP1/ERK5 axis in driving the malignancy of NSCLC cells in vitro. Targeting this axis holds promise as a potential avenue for developing novel therapeutic strategies aimed at controlling the advancement of NSCLC.

Development of Functional Foods: A Comparative Study on the Polyphenols and Anthocyanins Content in Chokeberry and Blueberry Pomace Extracts and Their Antitumor Properties.

Developing of functional foods is a promising strategy to reduce the increasing burden of colorectal cancer worldwide. Fruit pomace, particularly polyphenol and anthocyanin-rich chokeberry and blueberry, is a valuable ingredient for functional foods and nutraceuticals. Our study aimed to evaluate the anti-inflammatory and antiproliferative effects of chokeberry and blueberry pomace extracts on C2BBe1 colorectal carcinoma cells and explore the underlying signaling pathways. We analyzed both pomace extracts for total polyphenols and anthocyanins using Folin-Ciocalteu method and ultra-performance liquid chromatography, while antioxidative activity was assessed via the 2,2-diphenyl-1-picrylhydrazyl radical scavenging method. We evaluated the in vitro anti-inflammatory and antiproliferative effects using trypan blue exclusion, MTT and LDH assays, and assessed protein levels of p-Erk1/2, Akt-1, STAT1, STAT3, occludin, oxidized proteins, and MDA-protein adducts through western blotting, as well as analysis of a 37-plex panel of inflammatory markers. Chokeberry extracts exhibited higher total polyphenol content, anthocyanin levels, and antioxidative activity compared to blueberry extracts, however, blueberry extracts effects on cell viability and proliferation in C2BBe1 cells were stronger. Both fruit pomaces induced non-inflammatory cell death characterized by membrane integrity loss, beneficial in cancer therapy. Our data suggests chokeberry's cytotoxicity may be mediated by Erk signaling and Akt-1 inhibition, while blueberry uniquely decreased occludin levels. These berries pomaces' potential to mitigate cancer risks and enhance treatment efficacy is promising, warranting further investigation for functional foods development.