PI3K Signaling Pathway Research Articles

7,8-dihydroxyflavone as a Neuroprotective agent in Ischemic Stroke through the Regulation of HIF-1α Protein

Stroke is one of the leading causes of death worldwide, particulary ischemic stroke. Tissue hypoxia due to decreased blood flow to the brain causes loss of energy, failure of homeostasis, and cell death. Pharmacological treatment based of the Food and Drug Administration is recombinant tissue plasminogen activator given intravenously. In addition, neuroprotectant agents given to prevent the expansion of the infarct area. Screening of a new compound as a drug candidate with in silico simulation to predict an interaction between 7,8-dihydroxiflavone (DHF) as a neuroprotective agent by stimulating a protein kinase through PI3K signaling pathway and inhibiting the activity of prolyl hydroxylase enzyme. The protein target was obtained from Protein Data Bank using the structure of PI3K (1E8X) and prolyl hydroxylase 2 (5OX6). Ligand structure of 7,8 dihydroxyflavone was obtained from PubChem. Those structures are analyzed for the pharmacokinetic and protein-ligand interaction with the help of software such as PyRx, PyMol and BIOVIA Discovery Studio. 7,8 DHF has a much lower bond energy (-8.6 Kcal/mol) when it binds to PI3K compared to the native ligand (-7.5 Kcal/mol). The same bond energy results between 7,8-DHF and its native ligands (-7.5 kcl/mol) when binds to prolyl hydroxylase. As an adaptive response to hypoxia caused by ischemic stroke, the findings are likely to boost the downstream signaling pathway and enhance HIF-1α expression.

Pharmacologic Inhibition of SHP2 Blocks Both PI3K and MEK Signaling in Low-epiregulin HNSCC via GAB1.

Preclinical and clinical studies have evidenced that effective targeted therapy treatment against receptor tyrosine kinases (RTKs) in different solid tumor paradigms is predicated on simultaneous inhibition of both the PI3K and MEK intracellular signaling pathways. Indeed, re-activation of either pathway results in resistance to these therapies. Recently, oncogenic phosphatase SHP2 inhibitors have been developed with some now reaching clinical trials. To expand on possible indications for SHP099, we screened over 800 cancer cell lines covering over 25 subsets of cancer. We found HNSCC was the most sensitive adult subtype of cancer to SHP099. We found that, in addition to the MEK pathway, SHP2 inhibition blocks the PI3K pathway in sensitive HNSCC, resulting in downregulation of mTORC signaling and anti-tumor effects across several HNSCC mouse models, including an HPV+ patient-derived xenograft (PDX). Importantly, we found low levels of the RTK ligand epiregulin identified HNSCCs that were sensitive to SHP2 inhibitor, and, adding exogenous epiregulin mitigated SHP099 efficacy. Mechanistically, epiregulin maintained SHP2-GAB1 complexes in the presence of SHP2 inhibition, preventing downregulation of the MEK and PI3K pathways. We demonstrate HNSCCs were highly dependent on GAB1 for their survival and knockdown of GAB1 is sufficient to block the ability of epiregulin to rescue MEK and PI3K signaling. These data connect the sensitivity of HNSCC to SHP2 inhibitors and to a broad reliance on GAB1-SHP2, revealing an important and druggable signaling axis. Overall, SHP2 inhibitors are being heavily developed and may have activity in HNSCCs, and in particular those with low levels of epiregulin.

Oncodiabetology I. Metabolic and molecular relationships between cancer and diabetes

In the recent decades, numerous studies have investigated the metabolic and molecular links between carbohydrate metabolic disorders and cancer, raising potential anti-tumor therapies. Based on epidemiological, preclinical, and clinical studies, now we know that advanced diabetes is a distinct risk factor of the development of many tumors, and even prediabetes may lead to the increased risk of developing cancer. Nowadays we can also state that the relationship is also present vice versa. It is a well-known fact that malignancies cause metabolic and molecular changes in the host over time resulting in an insulin-resistant state, characteristic of early diabetes. The tumor-induced insulin resistance may lead to the development of secondary diabetes in some patients with cancer. Furthermore, the diabetogenic ef-fect of the present anticancer therapies may worsen the metabolic condition. In recent years, research exploring the molecular causes of the correlation between malignancies and type 2 diabetes mellitus has highlighted the central role of RAS and PI3K signaling pathways. The altered function of these pathways significantly effects cell cycle, cellular metabolism, cell growth and proliferation, thus modifying cell survival, leading to tumorigenesis and tumor progres-sion and to insulin resistance as well. Without understanding the correlations between IGF receptors, RAS and PI3K signaling pathways the underlying molecular mechanism cannot be understood. Therefore, here we focus on these molecular mechanisms after a brief description of the most important metabolic connections between cancer and diabetes.

Ovatodiolide and antrocin synergistically inhibit the stemness and metastatic potential of hepatocellular carcinoma via impairing ribosome biogenesis and modulating ERK/Akt-mTOR signaling axis

Activation of mitogen-activated protein kinase (MAPK) and PI3K signaling confers resistance against sorafenib, a mainstay treatment for advanced hepatocellular carcinoma (HCC). Antrocin and ovatodiolide constitute as the most potent secondary metabolites isolated from Antrodia camphorata and Anisomeles indica, respectively. Both natural compounds have recently gained a lot of attention due to their putative inhibition of MAPK and PI3K signaling in various solid cancers. However, whether their combination is effective in HCC remains unknown. Here, we investigated their effect, alone or in various combinations, on MAPK and PI3K signaling pathways in HCC cells. An array of in vitro study were used to investigate anticancer and stemness effects to treat HCC, such as cytotoxicity, drug combination index, migration, invasion, colony formation, and tumor sphere formation. Drug effect in vivo was evaluated using mouse xenograft models. In this study, antrocin and ovatodiolide synergistically inhibited the SNU387, Hep3B, Mahlavu, and Huh7 cell lines. Sequential combination treatment of Huh7 and Mahlavu with ovatodiolide followed by antrocin resulted stronger cytotoxic effect than did treatment with antrocin followed by ovatodiolide, their simultaneous administration, antrocin alone, or ovatodiolide alone. In the Huh7 and Mahlavu cell lines, ovatodiolide→antrocin significantly suppressed colony formation and proliferation as well as markedly downregulated ERK1/2, Akt, and mTOR expression. Inhibition of ERK1/2 and Akt/mTOR signaling by ovatodiolide→antrocin suppressed ribosomal biogenesis, autophagy, and cancer stem cell-like phenotypes and promoted apoptosis in Huh7 and Mahlavu cells. The sorafenib-resistant clone of Huh7 was effectively inhibited by synergistic combination of both compound in vitro. Eventually, the ovatodiolide→antrocin combination synergistically suppressed the growth of HCC xenografts. Taken together, our findings suggested that ovatodiolide→antrocin combination may represent potential therapeutic approach for patients with advanced HCC.

Pendimethalin exposure induces bovine mammary epithelial cell death through excessive ROS production and alterations in the PI3K and MAPK signaling pathways

Herbicides are chemicals that have been established to have adverse impacts. However, they are still widely used in agriculture. Pendimethalin (PDM) is an herbicide that is widely used in many countries to control annual grasses. The possibility of livestock being exposed to PDM is relatively high, considering the half-life of PDM and its residues in water, soil and crops. However, the toxicity of PDM in cattle, especially in the mammary glands, has not been reported. Therefore, we investigated whether PDM has toxic effects in the mammary epithelial cells (MAC-T) of cattle. MAC-T cells were treated with various doses (0, 2.5, 5 and 10 μM) of PDM. We found that PDM affected cell viability and cell proliferation and causes cell cycle arrest. Furthermore, PDM triggered cell apoptosis, induced excessive ROS production and mitochondrial membrane potential (MMP) loss, and disrupted calcium homeostasis. In addition, PDM altered the activation of proteins associated with the endoplasmic reticulum (ER) stress response and modified PI3K and MAPK signaling cascades. In conclusion, our current study unveiled the mechanism of PDM in MAC-T cells and we suggest that PDM might be harmful to the mammary gland system of cattle, possibly affecting milk production.

Differential proteomic of plasma provides a new perspective on scientific diagnosis and drug screening for dampness heat diarrhea in calves.

Dampness heat diarrhea (DHD) is one of the most common syndromes of calf diarrhea. Its complex etiology and lack of objective diagnostic criteria bring great challenges to the diagnosis and treatment of this disease. This study aims to screen some prospective diagnostic biomarkers or therapeutic targets for calves with DHD by investigating the differential protein profiles of plasma between DHD calves and clinically healthy calves by mass spectrometry-based proteomic. A total of 120 DHD calves and 90 clinically healthy calves were divided into two groups randomly, 30 DHD calves and 30 clinically healthy calves in the test group, and 90 DHD calves and 60 clinically healthy calves in the validation group. In the test group, a total of 52 proteins were differentially expressed between calves with DHD and clinically healthy calves, 13 proteins were significantly increased and 39 proteins were significantly decreased. The differentially expressed proteins were associated with the intestinal immune network of IgA production, caffeine metabolism, purine metabolism, and PI3K signaling pathway. In the validation group, 13 proteins were selected from 52 differential expression proteins for parallel reaction monitoring validation to verify their associations with DHD calves. The targeted proteomic results showed that fibronectin precursor (FN1) and apolipoprotein C-IV precursor (APOC4) were significantly associated with DHD in calves, and they were downregulated in sick calves. In conclusion, the differential expression of plasma proteins was associated with DHD pathogenesis in calves, and the FN1 and APOC4 might be the potential clinical biomarkers for diagnosis of DHD in calves, and the intestinal immune network of IgA production, caffeine metabolism, purine metabolism, and PI3K signaling pathway are the candidate targets to treat DHD in calves. Our finding provides a reference for further investigating the pathogenesis, developing techniques of diagnosis, and screening treatment drugs for DHD in calves.

Knockdown of miR-372-3p Inhibits the Development of Diabetic Cardiomyopathy by Accelerating Angiogenesis via Activating the PI3K/AKT/mTOR/HIF-1α Signaling Pathway and Suppressing Oxidative Stress.

Background DCM is the most common and malignant complication of diabetes. It is characterized by myocardial dilatation, hypertrophy, fibrosis, ventricular remodeling, and contractile dysfunction. Although many studies have demonstrated the function of miRNAs in the progression of DCM, but the specific role of miR-372-3p in DCM remains unknown. Methods C57/BL6J mice were used to construct mouse models of DCM by intraperitoneal injection of STZ (50 mg/kg/d) for 5 consecutive days. Then the mice were randomly divided into model group (intramyocardial injection of empty lentivirus) and miR-372-3p KD group (intramyocardial injection of miR-372-3p KD lentivirus at 109/mouse). Besides, the control group (injection of 0.9% normal saline) was also set up. LY294002, a PI3K inhibitor, was employed in the current study. Western blotting, immunofluorescence staining, quantitative ultrasound method, Masson's trichrome staining, and bioinformatics analysis were performed. Results It was found that miR-372-3p KD significantly improved left ventricular dysfunction and cardiac hypertrophy in DCM mice. Furthermore, it also improved myocardial interstitial fibrosis and remodeling in DCM mice. Immunofluorescence staining and RT-qPCR revealed that miR-372-3p KD might accelerate cardiac remodeling by increasing angiogenesis in DCM mice. Western blotting results revealed that miR-372-3p was an upstream target of the PI3K/AKT-mTOR and HIF-1α signals, as well as NOX2, NOX4, which were responsible for angiogenesis in DCM mice. Besides, the in vitro experiment showed that LY294002 markedly diminished the increased expression levels of p-PI3K, AKT, p-mTOR, p-P70S6K, HIF-1α, NOX2, and NOX4 in the model group and the miR-372-3p KD group, suggesting that PI3K signaling pathway and oxidative stress are involved in miR-372-3p KD-induced angiogenesis in HG-stimulated C166 cells. Conclusions MiR-372-3p KD inhibits the development of DCM via activating the PI3K/AKT/mTOR/HIF-1α signaling pathway or suppressing oxidative stress. This offers an applicable biomarker for DCM treatment.

Integrated multiple-omics reveals the regulatory mechanism underlying the effects of artificial feed and grass feeding on growth and muscle quality of grass carp (Ctenopharyngodon idellus)

The muscle quality of farmed fish has attracted widespread public attention. To understand a comprehensive molecular mechanism underlying the effects of artificial formula feed- (AF) and grass-feeding (GF) on muscle quality and growth of grass carp (Ctenopharyngodon idellus), muscular transcriptomics and proteomics of GF and AF C. idellus were characterized. A total of 834 DEGs (484 up-, 350 down-regulated genes) and 487 DEPs (271 up- and 216 down-regulations) were identified between groups. Then, the functional enrichment analysis of DEGs & DEPs (DEs) and the integration of multiple-Omics (SDFs), further reflected that the stronger myofiber differentiation and protein synthesis capacities are likely the main strategy of more muscle mass gain in AF C. idellus, while the muscle growth in GF C. idellus is consequent to the stronger muscle cell proliferation and hypertrophy. Secondly, there was a significant difference in muscle fiber types between GF and AF groups, this has a noticeable effect on muscle tenderness and quality. In combination with previously metabolic results, we established DEG-DEP-SDM interaction network, which validated that the slow-MyHC-I fiber, dense in AF C. idellus muscles, accumulated more glycogen and exhibited more powerful glycolytic activity. Meanwhile, the suppressed activity of eIF2α in AF C. idellus muscles promoted protein synthesis, the “Ubiquitin mediated proteolysis” was simultaneously restrained. However, the activities of TCA cycle and fatty acid oxidation were significantly enhanced in GF muscles (rich in fast-MyHC-IIb). Accordingly, the up-regulated ACSL1, ACADS, ppara, etc. were quantified in GF C. idellus samples with stronger fatty acids β-oxidation activity, then led to the reduction of cellular triglycerides and lipid droplet formation. Additionally, our results also provide key information for further understanding of the molecular mechanisms (e.g. MAPK and PI3K signaling pathways, Necroptosis and so on) of C. idellus under dietary treatments. In summary, the grass-feeding could effectively alleviate the negative effects of AF on fish, namely, reducing fat deposition, improving nutrients, flavor and texture of muscle, relieving insulin resistance and stress tolerance, finally lead to better nourishing and healthy C. idellus.

Comprehensive analysis of the prognostic implications and functional exploration of PAK gene family in human cancer

BackgroundThe p21-activated kinase (PAK) family (PAKs) plays a key role in the formation and development of human tumors. However, a systematic analysis of PAKs in human cancers is lacking and the potential role of PAKs in cancer immunity has not been explored.MethodsWe used datasets from in The Cancer Genome Atlas (TCGA) database and Genotype-Tissue Expression database (GTEx).ResultsBased on TCGA datasets most PAKs show noteworthy differences in expression between tumors and corresponding normal tissues or across different tumor tissues. Patients with high expression of PAKs often show a worse prognosis. However, copy number variation, mutation, and DNA methylation of PAKs have limited impact on tumor development. Further analysis showed that the impact of PAKs on immunity varies with the type of tumor and the respective tumor microenvironment. PAK1 and PAK4 may be stronger predictors of immune characteristics, and are more suitable as drugs and molecular therapeutic targets. Furthermore, Cox regression analysis revealed that a PAK gene signature could be used as an independent prognostic factor for lower grade glioma (LGG) and glioblastoma (GBM). Gene set enrichment analysis (GSEA) analysis indicated that PAK genes may affect the occurrence and development of GBM through the PI3K signaling pathway. Further experiments verified that PAK1 and AKT1 have a significant interaction in GBM cells, and inhibiting the overactivation of PAK1 can significantly inhibit the proliferation of GBM cells.ConclusionsOur study provides a rationale for further research on the prognostic and therapeutic potential of PAKs in human tumors.

Gene Regulations upon Hydrogel-Mediated Drug Delivery Systems in Skin Cancers-An Overview.

The incidence of skin cancer has increased dramatically in recent years, particularly in Caucasian populations. Specifically, the metastatic melanoma is one of the most aggressive cancers and is responsible for more than 80% of skin cancer deaths around the globe. Though there are many treatment techniques, and drugs have been used to cure this belligerent skin cancer, the side effects and reduced bioavailability of drug in the targeted area makes it difficult to eradicate. In addition, cellular metabolic pathways are controlled by the skin cancer driver genes, and mutations in these genes promote tumor progression. Consequently, the MAPK (RAS–RAF–MEK–ERK pathway), WNT and PI3K signaling pathways are found to be important molecular regulators in melanoma development. Even though hydrogels have turned out to be a promising drug delivery system in skin cancer treatment, the regulations at the molecular level have not been reported. Thus, we aimed to decipher the molecular pathways of hydrogel drug delivery systems for skin cancer in this review. Special attention has been paid to the hydrogel systems that deliver drugs to regulate MAPK, PI3K–AKT–mTOR, JAK–STAT and cGAS-STING pathways. These signaling pathways can be molecular drivers of skin cancers and possible potential targets for the further research on treatment of skin cancers.

Oncogenetic landscape of T-cell lymphoblastic lymphomas compared to T-cell acute lymphoblastic leukemia

AbstractIn the latest 2016 World Health Organization classification of hematological malignancies, T-cell lymphoblastic lymphoma (T-LBL) and lymphoblastic leukemia (T-ALL) are grouped together into one entity called T-cell lymphoblastic leukemia/lymphoma (T-LBLL). However, the question of whether these entities represent one or two diseases remains. Multiple studies on driver alterations in T-ALL have led to a better understanding of the disease while, so far, little data on genetic profiles in T-LBL is available. We sought to define recurrent genetic alterations in T-LBL and provide a comprehensive comparison with T-ALL. Targeted whole-exome next-generation sequencing of 105 genes, multiplex ligation-dependent probe amplification, and quantitative PCR allowed comprehensive genotype assessment in 818, consecutive, unselected, newly diagnosed patients (342 T-LBL vs. 476 T-ALL). The median age at diagnosis was similar in T-LBL and T-ALL (17 vs. 15 years old, respectively; p = 0.2). Although we found commonly altered signaling pathways and co-occurring mutations, we identified recurrent dissimilarities in actionable gene alterations in T-LBL as compared to T-ALL. HOX abnormalities (TLX1 and TLX3 overexpression) were more frequent in T-ALL (5% of T-LBL vs 13% of T-ALL had TLX1 overexpression; p = 0.04 and 6% of T-LBL vs 17% of T-ALL had TLX3 overexpression; p = 0.006). The PI3K signaling pathway was significantly more frequently altered in T-LBL as compared to T-ALL (33% vs 19%; p < 0.001), especially through PIK3CA alterations (9% vs 2%; p < 0.001) with PIK3CAH1047 as the most common hotspot. Similarly, T-LBL genotypes were significantly enriched in alterations in genes coding for the EZH2 epigenetic regulator and in TP53 mutations (respectively, 13% vs 8%; p = 0.016 and 7% vs 2%; p < 0.001). This genetic landscape of T-LBLL identifies differential involvement of recurrent alterations in T-LBL as compared to T-ALL, thus contributing to better understanding and management of this rare disease.

Mechanism Study of Cinnamomi Ramulus and Paris polyphylla Sm. Drug Pair in the Treatment of Adenomyosis by Network Pharmacology and Experimental Validation.

Objective To explore the molecular mechanism of the Cinnamomi ramulus and Paris polyphylla Sm. (C-P) drug pair in the treatment of adenomyosis (AM) based on network pharmacology and animal experiments. Methods Via a network pharmacology strategy, a drug-component-target-disease network (D-C-T-D) and protein–protein interaction (PPI) network were constructed to explore the core components and key targets of C-P drug pair therapy for AM, and the core components and key targets were verified by molecular docking. Based on the results of network pharmacology, animal experiments were performed for further verification. The therapeutic effect of the C-P drug pair on uterine ectopic lesions was evaluated in a constructed AM rat model. Results A total of 30 components and 45 corresponding targets of C-P in the treatment of AM were obtained through network pharmacology. In the D-C-T-D network and PPI network, 5 core components and 10 key targets were identified. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed that the PI3K signaling pathway was the most significantly enriched nontumor pathway. Molecular docking showed that most of the core components and key targets docked completely. Animal experiments showed that the C-P drug pair significantly ameliorated the pathological changes of endometriotic lesions in AM model rats and inhibited PI3K and Akt gene expression, and PI3K and Akt protein phosphorylation. In addition, treatment with the C-P drug pair promoted AM cell apoptosis; upregulated the protein expression of Bax, Caspase-3, and cleaved Caspase-9; and restrained Bcl-2 expression. Conclusions We propose that the pharmacological mechanism of the C-P drug pair in the treatment of AM is related to inhibition of the PI3K/Akt pathway and promotion of apoptosis in AM ectopic lesions.

Investigation into the anti-airway inflammatory role of the PI3Kγ inhibitor JN-PK1: An in vitro and in vivo study

Phosphatidylinositol 3-kinase gamma (PI3Kγ) has been proven to be a potential target for the treatment of inflammatory diseases of the airway; however, there are few reports of selective PI3Kγ inhibitors being used in the field of airway inflammation thus far. Herein, a study employing in vitro and in vivo methodologies was carried out to assess the anti-airway inflammatory effects of JN-PK1, a selective PI3Kγ inhibitor. In RAW264.7 macrophages, JN-PK1 inhibited PI3Kγ-dependent, cellular C5a-induced AKT Ser473 phosphorylation in a concentration- and time-dependent manner and had no significant effect on cell viability.Furthermore, JN-PK1 significantly suppressed LPS-induced, proinflammatory cytokine expression and nitric oxide production through inhibition of the PI3K signaling pathway in RAW264.7 cells. Then, a murine asthma model was established to evaluate the anti-airway inflammation effect of JN-PK1. BALB/c mice were sensitized and challenged with ovalbumin (OVA) to develop an inflammatory response, fibrosis formation, and other airway changes similar to the symptomatology of asthma in humans. Oral administration of JN-PK1 remarkably attenuated OVA-induced asthma in association with the inhibition of the PI3K signaling pathway. That is to say, the oral administration significantly inhibited increases in inflammatory cell counts and reduced T-helper type 2 cytokine production in bronchoalveolar lavage fluid. Pulmonary histological studies showed that oral administration of JN-PK1 not only reduced the infiltration of inflammatory cells but also retarded airway inflammation and fibration. Taken together, JN-PK1 could be developed as a promising candidate for inflammation therapy, and our findings support some potential for therapeutic inhibition of PI3Kγ to treat inflammatory airway diseases.

Dopamine receptor D2 regulates GLUA1-containing AMPA receptor trafficking and central sensitization through the PI3K signaling pathway in a male rat model of chronic migraine

BackgroundThe pathogenesis of chronic migraine remains unresolved. Recent studies have affirmed the contribution of GLUA1-containing AMPA receptors to chronic migraine. The dopamine D2 receptor, a member of G protein-coupled receptor superfamily, has been proven to have an analgesic effect on pathological headaches. The present work investigated the exact role of the dopamine D2 receptor in chronic migraine and its effect on GLUA1-containing AMPA receptor trafficking.MethodsA chronic migraine model was established by repeated inflammatory soup stimulation. Mechanical, periorbital, and thermal pain thresholds were assessed by the application of von Frey filaments and radiant heat. The mRNA and protein expression levels of the dopamine D2 receptor were analyzed by qRT‒PCR and western blotting. Colocalization of the dopamine D2 receptor and the GLUA1-containing AMPAR was observed by immunofluorescence. A dopamine D2 receptor agonist (quinpirole) and antagonist (sulpiride), a PI3K inhibitor (LY294002), a PI3K pathway agonist (740YP), and a GLUA1-containing AMPAR antagonist (NASPM) were administered to confirm the effects of the dopamine D2 receptor, the PI3K pathway and GULA1 on central sensitization and the GLUA1-containing AMPAR trafficking. Transmission electron microscopy and Golgi-Cox staining were applied to assess the impact of the dopamine D2 receptor and PI3K pathway on synaptic morphology. Fluo-4-AM was used to clarify the role of the dopamine D2 receptor and PI3K signaling on neuronal calcium influx. The Src family kinase (SFK) inhibitor PP2 was used to explore the effect of Src kinase on GLUA1-containing AMPAR trafficking and the PI3K signaling pathway.ResultsInflammatory soup stimulation significantly reduced pain thresholds in rats, accompanied by an increase in PI3K-P110β subunit expression, loss of dopamine receptor D2 expression, and enhanced GLUA1-containing AMPA receptor trafficking in the trigeminal nucleus caudalis (TNC). The dopamine D2 receptor colocalized with the GLUA1-containing AMPA receptor in the TNC; quinpirole, LY294002, and NASPM alleviated pain hypersensitivity and reduced GLUA1-containing AMPA receptor trafficking in chronic migraine rats. Sulpiride aggravated pain hypersensitivity and enhanced GLUA1 trafficking in CM rats. Importantly, the anti-injury and central sensitization-mitigating effects of quinpirole were reversed by 740YP. Both quinpirole and LY294002 inhibited calcium influx to neurons and modulated the synaptic morphology in the TNC. Additional results suggested that DRD2 may regulate PI3K signaling through Src family kinases.ConclusionModulation of GLUA1-containing AMPA receptor trafficking and central sensitization by the dopamine D2 receptor via the PI3K signaling pathway may contribute to the pathogenesis of chronic migraine in rats, and the dopamine D2 receptor could be a valuable candidate for chronic migraine treatment.

Ubiquitous toxicity of Mercuric Chloride in target tissues and organs: Impact of Ubidecarenone and liposomal-Ubidecarenone STAT 5A/ PTEN /PI3K/AKT signaling pathways

BackgroundMercuric chloride (HgCl3) is categorized as class II B hazardous metal that is present in many occupational and environmental conditions. In the meantime, Hg exists in the environment in such an abundant manner, it is virtually impossible for humans to avoid exposure to different forms of Hg. In addition to environmental exposure, individuals may be exposed to Hg from dental amalgams, medicinal treatments and dietary sources. Nevertheless, Liposomal drug delivery system is a promising era in the field of Nano-medicine and have the advantageous of increasing drug bioavailability and retention phenomena in addition to targeting organ for all mentioned the present study was designed to investigate the hypothesis that messenger RNA gene expression of Signal transducer and activator of transcription- 5 A (STAT-5A), Phosphatase and tensin homolog (PTEN), phosphoinositol kinase (PI3K) and alpha serine/threonine-protein kinase (AKT) can trigger HgCl3 induced nephrotoxicity post Ubidecarenone and liposomal Ubidecarenone therapy. MethodsHgCl3 toxicity was induced in rats via a dose of 5 mg/kg BW for one week followed by Ubidecarenone and liposomal Ubidecarenone therapy in a dose of 10 & 3 mg/kg BW for one month, respectively. Then kidney function tests, Glutathione and gene expression for PI3K, AKT, PTEN and STAT-5A was investigated. ResultsHgCl3 intoxication significantly up regulated PI3K, AKT, PTEN and STAT-5A signaling pathways meanwhile, Ubidecarenone and liposomal- Ubidecarenone treatment significantly reduced PI3K, AKT, PTEN and STAT-5A gene expression post HgCl3 intoxication with the liposomal regimen revealing the most significant impact. Furthermore, renal toxicity was confirmed via monitoring urea and creatinine which were modulated post Ubidecarenone and liposomal-Ubidecarenone treatment. Wide evidence declared that mercuric S-conjugates of small endogenous thiols (such as Hcy, NAC and Cys) are probably the main transportable forms of Hg2+ to the kidneys thus reduced glutathione was investigated which reflected a significant down regulation post Hgcl3 toxicity. Conclusionliposomal drug delivery system including liposomal-Ubidecarenone can be considered as a prospective candidate for treating HgCl3 renal toxicity via modulating STAT-5A, PTEN, PI3K and AKT signaling pathways and via increasing retention time, bioavailability, shielding from macrophage recognition and targeting organs.

PI3K and Notch signaling pathway play a synergistic regulatory role in the proliferation and activation of CD4+T cells in peripheral blood of patients with psoriasis vulgaris

PI3K and Notch signaling pathway play a synergistic regulatory role in the proliferation and activation of CD4+T cells in peripheral blood of patients with psoriasis vulgaris

Mechanisms and pathogenicity of the PI3K pathway: from basic research to clinical application

PI3K signaling pathway is one of the most important signaling pathways in tumorigenesis. Dysfunction of PI3K signalling pathway has been widely found in lymphatic hematologic tumors and solid tumors. Different PI3K inhibitors have shown anti-tumor activity against a variety of tumors. Furthermore, the FDA has approved various PI3K inhibitors for marketing or clinical studies, and have achieved considerable efficacy, especially in lymphoma and breast cancer. However, drug resistance and treatment-related adverse reactions remain unsolved. The PI3K signaling pathway also involves several other physiological functions related signaling pathway networks, and the combination therapy of selective inhibition of these signaling pathways needs to be further explored. New strategies include the combination of allosteric inhibitors and orthosteric inhibitors of PI3Kα and the development of inhibitors of salvage mutation sites. This review summarizes the clinical research progress and common drug resistance mechanisms of various common malignancies involved in PI3K inhibitors. In addition to targeting cancer cells, PI3K inhibitors also have great potential in cancer immunotherapy in the future.

Role of the NRG1/ErbB4 and PI3K/AKT/mTOR signaling pathways in the anti-psychotic effects of aripiprazole and sertindole in ketamine-induced schizophrenia-like behaviors in rats

Schizophrenia is a common mental disorder affecting patients’ thoughts, behavior, and cognition. Recently, the NRG1/ErbB4 signaling pathway emerged as a candidate therapeutic target for schizophrenia. This study investigates the effects of aripiprazole and sertindole on the NRG1/ErbB4 and PI3K/AKT/mTOR signaling pathways in ketamine-induced schizophrenia in rats. Young male Wistar rats received ketamine (30 mg/kg, intraperitoneally) for 5 consecutive days and aripiprazole (3 mg/kg, orally) or sertindole (2.5 mg/kg, orally) for 14 days. The proposed pathway was investigated by injecting LY294002 (a selective PI3K inhibitor) (25 μg/kg, intrahippocampal injection) 30 min before the drugs. Twenty-four hours after the last injection, animals were subjected to behavioral tests: the open field test, sucrose preference test, novel object recognition task, and social interaction test. Both aripiprazole and sertindole significantly ameliorated ketamine-induced schizophrenic-like behavior, as expected, because of their previously demonstrated antipsychotic activity. Besides, both drugs alleviated ketamine-induced oxidative stress and neurotransmitter level changes in the hippocampus. They also increased the gamma-aminobutyric acid and glutamate levels and glutamate decarboxylase 67 and parvalbumin mRNA expression in the hippocampus. Moreover, aripiprazole and sertindole increased the NRG1 and ErbB4 mRNA expression levels and PI3K, p-Akt, and mTOR protein expression levels. Interestingly, pre-injecting LY294002 abolished all the effects of the drugs. This study reveals that the antipsychotic effects of aripiprazole and sertindole are partly due to oxidative stress reduction as well as NRG1/ErbB4 and PI3K/AKT/mTOR signaling pathways activation. The NRG1/ErbB4 and PI3K signaling pathways may offer a new therapeutic approach for treating schizophrenia in humans.

EPDR1 is a noncanonical effector of insulin-mediated angiogenesis regulated by an endothelial-specific TGF-β receptor complex

Insulin signaling in blood vessels primarily functions to stimulate angiogenesis and maintain vascular homeostasis through the canonical PI3K and MAPK signaling pathways. However, angiogenesis is a complex process coordinated by multiple other signaling events. Here, we report a distinct crosstalk between the insulin receptor and endoglin/activin receptor-like kinase 1 (ALK1), an endothelial cell–specific TGF-β receptor complex essential for angiogenesis. While the endoglin–ALK1 complex normally binds to TGF-β or bone morphogenetic protein 9 (BMP9) to promote gene regulation via transcription factors Smad1/5, we show that insulin drives insulin receptor oligomerization with endoglin–ALK1 at the cell surface to trigger rapid Smad1/5 activation. Through quantitative proteomic analysis, we identify ependymin-related protein 1 (EPDR1) as a major Smad1/5 gene target induced by insulin but not by TGF-β or BMP9. We found endothelial EPDR1 expression is minimal at the basal state but is markedly enhanced upon prolonged insulin treatment to promote cell migration and formation of capillary tubules. Conversely, we demonstrate EPDR1 depletion strongly abrogates these angiogenic effects, indicating that EPDR1 is a crucial mediator of insulin-induced angiogenesis. Taken together, these results suggest important therapeutic implications for EPDR1 and the TGF-β pathways in pathologic angiogenesis during hyperinsulinemia and insulin resistance.

080 Current treatment options for patients with unresectable cutaneous melanoma

Cutaneous Melanoma (CM) remains the leading cause of skin-related mortality in the U.S. The U.S. Surveillance, Epidemiology and End Results database reports 5.6% of all new cancer cases in 2021 attributed to CM, with incidences rising annually since 2009. Several subtypes of CM are thought to arise from early driver mutations in BRAF, RAS, and NF1 genes resulting in unopposed activation of MAPK and PI3K signaling pathways, unregulated growth and malignant transformation of melanocytes. Due to the metastatic potential of CM, emphasis on systemic treatment has been an area of interest when surgical resection is insufficient for curative prognosis.