Mechanistic insight into toxicity of phthalates, the involved receptors, and the role of Nrf2, NF-κB, and PI3K/AKT signaling pathways

Background: AKT/PKB is an important enzyme with numerous biological functions, and its overexpression is related to the carcinogenesis. AKT stimulates different signaling pathways that are downstream of activated tyrosine kinases and phosphatidylinositol 3-kinase, hence functions as an important target for anti-cancer drugs. Objective: In this review article, we have interpreted the role of AKT signaling pathways in cancer and natural inhibitory effect of Thymoquinone (TQ) in AKT and its possible mechanism. Method: We have collected the updated information and data on AKT, their role in cancer and inhibitory effect of TQ in AKT signaling pathway from google scholar, PubMed, Web of Science, Elsevier, Scopus and many more. Results: There are many drugs already developed, which can target AKT, but very few among them have passed clinical trials. TQ is a natural compound, mainly found in black cumin, which has been found to have potential anti-cancer activities. TQ targets numerous signaling pathways, including AKT, in different cancers. In fact, many studies revealed that AKT is one of the major targets of TQ. The preclinical success of TQ suggests its clinical studies on cancer. Conclusion: This review article summarizes the role of AKT in carcinogenesis, its potent inhibitors in clinical trials, and how TQ acts as an inhibitor of AKT and TQ’s future as a cancer therapeutic drug.

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Akt signaling is activated by TGFβ2 and impacts tenogenic induction of mesenchymal stem cells

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02167-2 ◽

2021 ◽

Vol 12 (1) ◽

Cited By ~ 1

Author(s):

Sophia K. Theodossiou ◽

Jett B. Murray ◽

LeeAnn A. Hold ◽

Jeff M. Courtright ◽

Anne M. Carper ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Signaling Pathways ◽

Transforming Growth Factor ◽

Akt Signaling ◽

Cell Alignment ◽

Limited Information ◽

Akt Inhibitor ◽

Tenogenic Differentiation

Abstract Background Tissue engineered and regenerative approaches for treating tendon injuries are challenged by the limited information on the cellular signaling pathways driving tenogenic differentiation of stem cells. Members of the transforming growth factor (TGF) β family, particularly TGFβ2, play a role in tenogenesis, which may proceed via Smad-mediated signaling. However, recent evidence suggests some aspects of tenogenesis may be independent of Smad signaling, and other pathways potentially involved in tenogenesis are understudied. Here, we examined the role of Akt/mTORC1/P70S6K signaling in early TGFβ2-induced tenogenesis of mesenchymal stem cells (MSCs) and evaluated TGFβ2-induced tenogenic differentiation when Smad3 is inhibited. Methods Mouse MSCs were treated with TGFβ2 to induce tenogenesis, and Akt or Smad3 signaling was chemically inhibited using the Akt inhibitor, MK-2206, or the Smad3 inhibitor, SIS3. Effects of TGFβ2 alone and in combination with these inhibitors on the activation of Akt signaling and its downstream targets mTOR and P70S6K were quantified using western blot analysis, and cell morphology was assessed using confocal microscopy. Levels of the tendon marker protein, tenomodulin, were also assessed. Results TGFβ2 alone activated Akt signaling during early tenogenic induction. Chemically inhibiting Akt prevented increases in tenomodulin and attenuated tenogenic morphology of the MSCs in response to TGFβ2. Chemically inhibiting Smad3 did not prevent tenogenesis, but appeared to accelerate it. MSCs treated with both TGFβ2 and SIS3 produced significantly higher levels of tenomodulin at 7 days and morphology appeared tenogenic, with localized cell alignment and elongation. Finally, inhibiting Smad3 did not appear to impact Akt signaling, suggesting that Akt may allow TGFβ2-induced tenogenesis to proceed during disruption of Smad3 signaling. Conclusions These findings show that Akt signaling plays a role in TGFβ2-induced tenogenesis and that tenogenesis of MSCs can be initiated by TGFβ2 during disruption of Smad3 signaling. These findings provide new insights into the signaling pathways that regulate tenogenic induction in stem cells.

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KH-type splicing regulatory protein is a new component of chromatoid body

Reproduction ◽

10.1530/rep-17-0169 ◽

2017 ◽

Vol 154 (6) ◽

pp. 723-733 ◽

Cited By ~ 1

Author(s):

Huijuan Zhang ◽

Guishuan Wang ◽

Lin Liu ◽

Xiaolin Liang ◽

Yu Lin ◽

...

Keyword(s):

Gene Expression ◽

Germ Cell ◽

Knockout Mice ◽

Binding Protein ◽

Regulatory Protein ◽

Somatic Cells ◽

Chromatoid Body ◽

Mechanistic Insight ◽

Insight Into

The chromatoid body (CB) is a specific cloud-like structure in the cytoplasm of haploid spermatids. Recent findings indicate that CB is identified as a male germ cell-specific RNA storage and processing center, but its function has remained elusive for decades. In somatic cells, KH-type splicing regulatory protein (KSRP) is involved in regulating gene expression and maturation of select microRNAs (miRNAs). However, the function of KSRP in spermatogenesis remains unclear. In this study, we showed that KSRP partly localizes in CB, as a component of CB. KSRP interacts with proteins (mouse VASA homolog (MVH), polyadenylate-binding protein 1 (PABP1) and polyadenylate-binding protein 2 (PABP2)), mRNAs (Tnp2 and Odf1) and microRNAs (microRNA-182) in mouse CB. Moreover, KSRP may regulate the integrity of CB via DDX5-miRNA-182 pathway. In addition, we found abnormal expressions of CB component in testes of Ksrp-knockout mice and of patients with hypospermatogenesis. Thus, our results provide mechanistic insight into the role of KSRP in spermatogenesis.

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Abstract T P87: Hydrogen Sulfide Enhances Neurogenesis through the IRAK-1/GSK3β/AKT Signaling Pathways after Ischemic Stroke

Stroke ◽

10.1161/str.46.suppl_1.tp87 ◽

2015 ◽

Vol 46 (suppl_1) ◽

Author(s):

Pradip K Kamat ◽

Anuradha Kalani ◽

Neetu Tyagi

Keyword(s):

Hydrogen Sulfide ◽

Signaling Pathways ◽

Ventricular Zone ◽

Ischemia Reperfusion ◽

Analysis Data ◽

Akt Signaling ◽

Artery Occlusion ◽

Cortical Region ◽

Neuronal Function

Background and purpose: Increasing evidence signifying that inflammation has an ample role in the ischemia and; neurogenesis is somehow affected by inflammation. Current approved therapy for stroke is limited and new strategies need to be investigated. Hydrogen sulfide (H2S) showed neuro-protective however, role of H2S in stroke-induced neurogenesis is not known. Therefore, the present study was to determine the role of H2S in ischemia induced neurogenesis. Methods: To perform this study; we employed 8-10 weak old C57BL/6 mice with following groups: WT-Sham; WT+ ischemia reperfusion (IR) for 7 days; IR+GYY4137 (H2S donor, 30μM for 7 days; Intra peritoneal injection); and Sham+ GYY4137 (30μM for 7 day). Ischemia was created by the middle cerebral artery occlusion, (MCAO) for 50 min followed by reperfusion for 7 days. The brain tissue from different groups was used for biochemical, infarct area molecular and immunohistochemistry analysis. Data were analyzed by one way ANOVA followed by Tukey test. Results: We found increased protein expression of IRAK-1 (F=3, 27.01; P<.005), GSK3β 9 (F=3, 89.47; P<.005), p-AKT (F=3, 89.47; P<.005) and reduced expression of AKT p-AKT(F=3, 112.2; P<.005) in I/R group as compared to sham that indicates alteration of inflammatory signaling pathways. Further, we also found decreased level of Nestin (F=3, 35.32; P<.005), GFAP (F=3, 95.14; P<.001), NeuN (F=3, 123.4; P<.001), TUJ-1 (F=3, 112; P<.005), MAP-2 (F=3, 31.54; P<.0001), IL-6 (F=3, 55.7; p<.05) and BDNF (F=3, 166.5; P<.005) in cortical region of I/R group which indicates loss of neuronal function. Additionally, immunohistochemistry assay also revealed the loss of Nestin (P<.05), BDNF (P<.05), MAP-2 (P<.05) along with increased GSK-3β (P<.005) expression in sub ventricular zone (SVZ) and hippocampal region. Further, GYY4137 treatment for 7 days in ischemic group significantly restored the Nestin, GFAP, IL-6, NeuN, TUJ-1, MAP-2 and BDNF levels via regulating IRAK-1/GSK3β/AKT signaling pathways. Conclusion: Present study clearly demonstrate that H2S plays an important role in ischemia induced neurogenesis as well as protecting neuronal function through inhibition of IRAK1/GSK3β/AKT signaling pathways. Acknowledgement: This work was supported by NTHL107640-NT.

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Mechanistic insight into the role of metformin in Alzheimer's disease

Life Sciences ◽

10.1016/j.lfs.2021.120299 ◽

2022 ◽

pp. 120299

Author(s):

Mehdi Sanati ◽

Samaneh Aminyavari ◽

Amir R. Afshari ◽

Amirhossein Sahebkar

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mechanistic Insight ◽

Insight Into

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Histone H3K23-specific acetylation by MORF is coupled to H3K14 acylation

Nature Communications ◽

10.1038/s41467-019-12551-5 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 4

Author(s):

Brianna J. Klein ◽

Suk Min Jang ◽

Catherine Lachance ◽

Wenyi Mi ◽

Jie Lyu ◽

...

Keyword(s):

Posttranslational Modification ◽

Memory Impairment ◽

Target Genes ◽

Epigenetic Mark ◽

Mechanistic Insight ◽

Genomic Analyses ◽

Insight Into

Abstract Acetylation of histone H3K23 has emerged as an essential posttranslational modification associated with cancer and learning and memory impairment, yet our understanding of this epigenetic mark remains insufficient. Here, we identify the native MORF complex as a histone H3K23-specific acetyltransferase and elucidate its mechanism of action. The acetyltransferase function of the catalytic MORF subunit is positively regulated by the DPF domain of MORF (MORFDPF). The crystal structure of MORFDPF in complex with crotonylated H3K14 peptide provides mechanistic insight into selectivity of this epigenetic reader and its ability to recognize both histone and DNA. ChIP data reveal the role of MORFDPF in MORF-dependent H3K23 acetylation of target genes. Mass spectrometry, biochemical and genomic analyses show co-existence of the H3K23ac and H3K14ac modifications in vitro and co-occupancy of the MORF complex, H3K23ac, and H3K14ac at specific loci in vivo. Our findings suggest a model in which interaction of MORFDPF with acylated H3K14 promotes acetylation of H3K23 by the native MORF complex to activate transcription.

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Role of non-electrostatic forces in antimicrobial potency of a dengue-virus derived fusion peptide VG16KRKP: Mechanistic insight into the interfacial peptide-lipid interactions

Biochimica et Biophysica Acta (BBA) - Biomembranes ◽

10.1016/j.bbamem.2019.01.011 ◽

2019 ◽

Vol 1861 (4) ◽

pp. 798-809 ◽

Cited By ~ 7

Author(s):

Dipita Bhattacharyya ◽

Minsoo Kim ◽

Kamal H. Mroue ◽

MinSeok Park ◽

Anuj Tiwari ◽

...

Keyword(s):

Dengue Virus ◽

Fusion Peptide ◽

Electrostatic Forces ◽

Lipid Interactions ◽

Mechanistic Insight ◽

Insight Into ◽

Antimicrobial Potency

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NUMB regulates the endocytosis and activity of the anaplastic lymphoma kinase in an isoform-specific manner

Journal of Molecular Cell Biology ◽

10.1093/jmcb/mjz003 ◽

2019 ◽

Vol 11 (11) ◽

pp. 994-1005 ◽

Cited By ~ 2

Author(s):

Ran Wei ◽

Xuguang Liu ◽

Courtney Voss ◽

Wentao Qin ◽

Lina Dagnino ◽

...

Keyword(s):

Cell Fate ◽

Receptor Tyrosine Kinase ◽

Anaplastic Lymphoma Kinase ◽

Degradation Pathway ◽

Anaplastic Lymphoma ◽

Mechanistic Insight ◽

Evolutionarily Conserved ◽

Specific Manner ◽

Insight Into

Abstract NUMB is an evolutionarily conserved protein that plays an important role in cell adhesion, migration, polarity, and cell fate determination. It has also been shown to play a role in the pathogenesis of certain cancers, although it remains controversial whether NUMB functions as an oncoprotein or tumor suppressor. Here, we show that NUMB binds to anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase aberrantly activated in several forms of cancer, and this interaction regulates the endocytosis and activity of ALK. Intriguingly, the function of the NUMB–ALK interaction is isoform-dependent. While both p66-NUMB and p72-NUMB isoforms are capable of mediating the endocytosis of ALK, the former directs ALK to the lysosomal degradation pathway, thus decreasing the overall ALK level and the downstream MAP kinase signal. In contrast, the p72-NUMB isoform promotes ALK recycling back to the plasma membrane, thereby maintaining the kinase in its active state. Our work sheds light on the controversial role of different isoforms of NUMB in tumorigenesis and provides mechanistic insight into ALK regulation.

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Thrombin Preconditioning Boosts Biogenesis of Extracellular Vesicles from Mesenchymal Stem Cells and Enriches Their Cargo Contents via Protease-Activated Receptor-Mediated Signaling Pathways

International Journal of Molecular Sciences ◽

10.3390/ijms20122899 ◽

2019 ◽

Vol 20 (12) ◽

pp. 2899 ◽

Cited By ~ 5

Author(s):

Dong Kyung Sung ◽

Se In Sung ◽

So Yoon Ahn ◽

Yun Sil Chang ◽

Won Soon Park

Keyword(s):

Stem Cells ◽

Signaling Pathways ◽

Extracellular Vesicles ◽

Akt Signaling ◽

Human Umbilical Cord Blood ◽

Human Umbilical Cord ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal ◽

Specific Antagonist

We investigated the role of protease-activated receptor (PAR)-mediated signaling pathways in the biogenesis of human umbilical cord blood-derived mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) and the enrichment of their cargo content after thrombin preconditioning. Immunoblot analyses showed that MSCs expressed two PAR subtypes: PAR-1 and PAR-3. Thrombin preconditioning significantly accelerated MSC-derived EV biogenesis more than five-fold and enriched their cargo contents by more than two-fold via activation of Rab5, early endosomal antigen (EEA)-1, and the extracellular signal regulated kinase (ERK)1/2 and AKT signaling pathways. Blockage of PAR-1 with the PAR-1-specific antagonist, SCH79797, significantly suppressed the activation of Rab5, EEA-1, and the ERK1/2 and AKT pathways and subsequently increased EV production and enriched EV cargo contents. Combined blockage of PAR-1 and PAR-3 further and significantly inhibited the activation of Rab5, EEA-1, and the ERK1/2 and AKT pathways, accelerated EV production, and enriched EV cargo contents. In summary, thrombin preconditioning boosted the biogenesis of MSC-derived EVs and enriched their cargo contents largely via PAR-1-mediated pathways and partly via PAR-1-independent, PAR-3-mediated activation of Rab5, EEA-1, and the ERK1/2 and AKT signaling pathways.

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