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Fulltext Induction of apoptosis and role of paclitaxel-loaded hyaluronic acid-crosslinked nanoparticles in the regulation of AKT and RhoA

Chaudhry GE, Akim A, Zafar MN, Abdullah MA, Sung YY, Muhammad TST

J Adv Pharm Technol Res, 2020 07 14;11(3):101-106.
PMID: 33102192 DOI: 10.4103/japtr.JAPTR_26_20

Cancer is a complex multifactorial disease and leading causes of death worldwide. Despite the development of many anticancer drugs, there is a reduced survival rate due to severe side effects. The nontargeted approach of convention drugs is one of the leading players in context to toxicity. Hyaluronan is a versatile bio-polymer and ligand of the receptor (CD44) on cancer cells. The MCF-7 and HT-29 cancer cell lines treated with hyaluronic acid-paclitaxel (HA-PTX) showed the distinguishing morphological features of apoptosis. Flow cytometric analysis showed that HA-PTX induces apoptosis as a significant mode of cell death. The activation level of tumor suppressor protein (p53) increased after PTX treatment in MCF-7, but no changes observed in HT-29 might be due to hereditary mutations. The lack of suppression in AKT and Rho A protein suggest the use of possible inhibitors in future studies which might could play a role in increasing the sensitivity of drug towards mutated cells line and reducing the possibilities for cancer cell survival, migration, and metastasis.

Matched MeSH terms: Proto-Oncogene Proteins c-akt
Fulltext Expression of fibroblast growth factor receptor 4 (FGFR-4) in nasopharyngeal carcinoma (NPC) cell lines and its potential as therapeutic target

Hooi Yeen Yap, Jack Bee Chook, Sin Yeang Teow

Malaysian Journal of Medicine and Health Sciences, 2019;15(108):49-49.
MyJurnal

ntroduction: Nasopharyngeal carcinoma (NPC) is a prevalent cancer among human population in Southern China, Hong Kong and Southeast Asia. In Malaysia, NPC is the fourth most common cancer in both sexes, predominantly in the Chinese. Epstein-Barr virus (EBV) infection is known to be highly associated with NPC. Fibroblast growth factor receptor-4 (FGFR4) is part of the family of tyrosine kinase receptors that regulate cell survival, differentiation and pro-liferation. The binding of FGFR4 ligands such as fibroblasts growth factors (FGFs) has been shown to activate various oncogenic signalling pathway including MAPK, Ras and PI3K-Akt pathways. In the past, FGFR4 has been shown to promote tumorigenesis and tumour progression in various cancers such as liver, colon, breast and pancreatic and gastric cancers. However, its role in NPC establishment and pathogenesis is under-explored. This study aimed to evaluate the FGFR4 expression in NPC using various cell lines and its potential as a therapeutic target for NPC treat-ment by gene silencing. Methods: The basal FGFR4 level of NPC (EBV-positive: C666-1 and EBV-negative: HONE1 and HK1) and nasopharyngeal epithelial (NPE) normal (NP69 and NP460) cell lines was determined by western blot analysis and RT-qPCR. FGFR4 level at different time points (0, 24, 48, and 72 hours) in HONE1 and C666-1 cell lines were determined by western blot analysis. Luminescence-based assay was performed to determine the cell prolifer-ation of NPC cells in correlation with the FGFR4 expression. NPC cells were then treated with the optimised FGFR4 siRNA or FGFR inhibitor, BLU-9931 and the silencing/ inhibition of FGFR4 expression was confirmed by western blot analysis. The effect of FGFR4 inhibition on the cell proliferation and aggressiveness of NPC cells was then investigat-ed through wound healing assay and invasion marker analysis. Results: Out of the five tested cell lines, HONE1 and C666-1 highly expressed FGFR4, NP69 showed very low expression while HK1 and NP460 did not express FGFR4. In the time-point study, the FGFR4 level of HONE1 and C666-1 peaked at 24-48 hours which is the exponential phase of cells. Following that, the FGFR4 level decreased corresponding to the decreased cell growth rate due to the nutrient deprivation. siRNA experiments showed that 6.25nM of four siRNAs (5, 6, 9 and 10) could effectively target and silence the FGFR4 expression of HONE1, but not in C666-1 even up to 250nM was tested. When BLU-9931 was used, only modest inhibition was observed in both cells at 3uM. Compared to the untreated control, FGFR4-inhibited HONE1 exhibited decreased cell proliferation rate. Cell migration and invasion capabilities of HONE1 were also significantly reduced following the FGFR4 silencing, suggesting the potential of utilising FGFR4 as the therapeutic target. Conclusion: FGFR4 is highly expressed in C666-1 (EBV-positive) and HONE1 (initially EBV-positive, but lost EBV genome in subsequent in vitro passage) NPC cells, but not in EBV-negative HK1 NPC cell and normal NPE cells. FGFR4 gene silencing effectively inhibited the cell proliferation, migration and invasive potentials of NPC cell line. These findings highlight the therapeutic value of targeting FGFR4 for NPC treatment. Further investigations are war-ranted to reveal the molecular mechanism and the possible role of EBV in regulating FGFR4 pathway.

Matched MeSH terms: Proto-Oncogene Proteins c-akt
Fulltext The Skeletal-Protecting Action and Mechanisms of Action for Mood-Stabilizing Drug Lithium Chloride: Current Evidence and Future Potential Research Areas

Wong SK, Chin KY, Ima-Nirwana S

Front Pharmacol, 2020;11:430.
PMID: 32317977 DOI: 10.3389/fphar.2020.00430

Lithium, the lightest natural-occurring alkali metal with an atomic number of three, stabilizes the mood to prevent episodes of acute manic and depression. Multiple lines of evidence point to lithium as an anti-suicidal, anti-viral, anti-cancer, immunomodulatory, neuroprotective and osteoprotective agent. This review article provides a comprehensive review of studies investigating the bone-enhancing effects of lithium and its possible underlying molecular mechanisms. Most of the animal experimental studies reported the beneficial effects of lithium in defective bones but not in healthy bones. In humans, the effects of lithium on bones remain heterogeneous. Mechanistically, lithium promotes osteoblastic activities by activating canonical Wingless (Wnt)/beta (β)-catenin, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) and bone morphogenetic protein-2 (BMP-2) transduction pathways but suppresses osteoclastic activities by inhibiting the receptor activator of nuclear factor-kappa B (RANK)/receptor activator of nuclear factor-kappa B ligand (RANKL)/osteoprotegerin (OPG) system, nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and calcium signaling cascades. In conclusion, lithium confers protection to the skeleton but its clinical utility awaits further validation from human clinical trials.

Matched MeSH terms: Proto-Oncogene Proteins c-akt
Diosgenin, a steroidal saponin, and its analogs: Effective therapies against different chronic diseases

Parama D, Boruah M, Yachna K, Rana V, Banik K, Harsha C, et al.

Life Sci, 2020 Nov 01;260:118182.
PMID: 32781063 DOI: 10.1016/j.lfs.2020.118182

BACKGROUND: Chronic diseases are a major cause of mortality worldwide, and despite the recent development in treatment modalities, synthetic drugs have continued to show toxic side effects and development of chemoresistance, thereby limiting their application. The use of phytochemicals has gained attention as they show minimal side effects. Diosgenin is one such phytochemical which has gained importance for its efficacy against the life-threatening diseases, such as cardiovascular diseases, cancer, nervous system disorders, asthma, arthritis, diabetes, and many more.
AIM: To evaluate the literature available on the potential of diosgenin and its analogs in modulating different molecular targets leading to the prevention and treatment of chronic diseases.
METHOD: A detailed literature search has been carried out on PubMed for gathering information related to the sources, biosynthesis, physicochemical properties, biological activities, pharmacokinetics, bioavailability and toxicity of diosgenin and its analogs.
KEY FINDINGS: The literature search resulted in many in vitro, in vivo and clinical trials that reported the efficacy of diosgenin and its analogs in modulating important molecular targets and signaling pathways such as PI3K/AKT/mTOR, JAK/STAT, NF-κB, MAPK, etc., which play a crucial role in the development of most of the diseases. Reports have also revealed the safety of the compound and the adaptation of nanotechnological approaches for enhancing its bioavailability and pharmacokinetic properties.
SIGNIFICANCE: Thus, the review summarizes the efficacy of diosgenin and its analogs for developing as a potent drug against several chronic diseases.

Matched MeSH terms: Proto-Oncogene Proteins c-akt
Fulltext Estrogen Receptors in Nonfunctioning Pituitary Neuroendocrine Tumors: Review on Expression and Gonadotroph Functions

Haydar Ali Tajuddin A, Kamaruddin N, Sukor N, Azizan EA, Omar AM

J Endocr Soc, 2020 Dec 01;4(12):bvaa157.
PMID: 33241169 DOI: 10.1210/jendso/bvaa157

Estrogen (17β-estradiol or E2) is a crucial regulator of the synthesis and secretion of pituitary reproductive hormones luteinizing hormone, follicle-stimulating hormone, and prolactin. In this review, we summarize the role of estrogen receptors in nonfunctioning pituitary neuroendocrine tumors (NF-Pitnets), focusing on immunoexpression and gonadotroph cell proliferation and apoptosis. Gonadotroph tumors are the most common subtype of NF-Pitnets. Two major estrogen receptor (ER) isoforms expressed in the pituitary are estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). Overall, estrogen actions are mostly exerted through the ERα isoform on the pituitary. The G protein-coupled estrogen receptor (GPER) located at the plasma membrane may contribute to nongenomic effects of estrogen. Nuclear immunoreactivity for ERα and ERβ was highest among gonadotroph and null cell tumors. Silent corticotroph tumors are the least immunoreactive for both receptors. A significantly elevated ERα expression was observed in macroadenomas compared with microadenomas. ERα and ERβ may act in opposite directions to regulate the Slug-E-cadherin pathway and to affect invasiveness of NF-Pitnets. In the cellular pathway, ERs regulate estrogen-induced proliferation and differentiation and impact several signaling pathways including the MAPK and PI3K/Akt pathway. Estrogen was the first-discovered inducer of pituitary tumor transforming gene 1 that was abundantly expressed in NF-Pitnets. ERα can be a potential biomarker for predicting tumor size and invasiveness as well as therapeutic target for NF-Pitnets. Selective estrogen receptor modulators or antiestrogen may represent as an alternative choice for the treatment of NF-Pitnets.

Matched MeSH terms: Proto-Oncogene Proteins c-akt
Fulltext Antioxidant and Anti-Inflammatory Effects of Genus Gynura: A Systematic Review

Tan JN, Mohd Saffian S, Buang F, Jubri Z, Jantan I, Husain K, et al.

Front Pharmacol, 2020;11:504624.
PMID: 33328981 DOI: 10.3389/fphar.2020.504624

Background:Gynura species have been used traditionally to treat various ailments, such as fever, pain, and to control blood glucose level. This systematic review critically discusses studies regarding Gynura species that exhibited antioxidant and anti-inflammatory effects, thus providing perspectives and instructions for future research of the plants as a potential source of new dietary supplements or medicinal agents. Methods: A literature search from internet databases of PubMed, Scopus, Science Direct, e-theses Online Service, and ProQuest was carried out using a combination of keywords such as "Gynura," "antioxidant," "anti-inflammatory," or other related words. Research articles were included in this study if they were experimental (in vitro and in vivo) or clinical studies on the antioxidant or anti-inflammatory effects of Gynura species and if they were articles published in English. Results: Altogether, 27 studies on antioxidant and anti-inflammatory effects of Gynura species were selected. The antioxidant effects of Gynura species were manifested by inhibition of reactive oxygen species production and lipid peroxidation, modulation of glutathione-related parameters, and enzymatic antioxidant production or activities. The anti-inflammatory effects of Gynura species were through the modulation of inflammatory cytokine production, inhibition of prostaglandin E2 and nitric oxide production, cellular inflammatory-related parameters, and inflammation in animal models. The potential anti-inflammatory signaling pathways modulated by Gynura species are glycogen synthase kinase-3, nuclear factor erythroid 2-related factor 2, PPARγ, MAPK, NF-κB, and PI3K/Akt. However, most reports on antioxidant and anti-inflammatory effects of the plants were on crude extracts, and the chemical constituents contributing to bioactivities were not clearly understood. There is a variation in quality of studies in terms of design, conduct, and interpretation, and in-depth studies on the underlying mechanisms involved in antioxidant and anti-inflammatory effects of the plants are in demand. Moreover, there is limited clinical study on antioxidant and anti-inflammatory effects of Gynura species. Conclusion: This review highlighted antioxidant and anti-inflammatory effects of genus Gynura and supported their traditional uses to treat oxidative stress and inflammatory-related diseases. This review is expected to catalyze further studies on genus Gynura. However, extensive preclinical data need to be generated from toxicity and pharmacokinetic studies before clinical studies can be pursued for their development into clinical medicines to treat oxidative stress and inflammatory conditions.

Matched MeSH terms: Proto-Oncogene Proteins c-akt
The crosstalk of hedgehog, PI3K and Wnt pathways in diabetes

Benchoula K, Parhar IS, Wong EH

Arch Biochem Biophys, 2021 Feb 15;698:108743.
PMID: 33382998 DOI: 10.1016/j.abb.2020.108743

Hyperglycaemia causes pancreatic β-cells to release insulin that then attaches to a specific expression of receptor isoform and reverses high glucose concentrations. It is well known that insulin is capable of initiating insulin-receptor substrate (IRS)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) signaling pathways in target cells; such as liver, adipose tissues, and muscles. However, recent discoveries indicate that many other pathways, such as the Hedgehog (Hh) and growth factor-stimulating Wingless-related integration (Wnt) signaling pathways; are activated in hyperglycaemia as well. Although these two pathways are traditionally thought to have a decisive role in cellular growth and differentiation only, recent reports show that they are involved in regulating cellular homeostasis and energy balance. While insulin-activated IRS/PI3K/PKB pathway cascades are primarily known to reduce glucose production, it was recently discovered to increase the Hh signaling pathway's stability, thereby activating the PI3K/PKB/mammalian target of rapamycin complex 2 (mTORC2) signaling pathway. The Hh signaling pathway not only plays a role in lipid metabolism, insulin sensitivity, inflammatory response, diabetes-related complications, but crosstalks with the Wnt signaling pathway resulting in improved insulin sensitivity and decrease inflammatory response in diabetes.

Matched MeSH terms: Proto-Oncogene Proteins c-akt
Fulltext Safrana l Prevents Prostate Cancer Recurrence by Blocking the Re-activation of Quiescent Cancer Cells via Downregulation of S-Phase Kinase-Associated Protein 2

Jiang X, Li Y, Feng JL, Nik Nabil WN, Wu R, Lu Y, et al.

Front Cell Dev Biol, 2020;8:598620.
PMID: 33392189 DOI: 10.3389/fcell.2020.598620

The re-proliferation of quiescent cancer cells is considered to be the primary contributor to prostate cancer (Pca) recurrence and progression. In this study, we investigated the inhibitory effect of safranal, a monoterpene aldehyde isolated from Crocus sativus (saffron), on the re-proliferation of quiescent Pca cells in vitro and in vivo. The results showed that safranal efficiently blocked the re-activation of quiescent Pca cells by downregulating the G0/G1 cell cycle regulatory proteins CDK2, CDK4, CDK6, and phospho-Rb at Ser807/811 and elevating the levels of cyclin-dependent kinase inhibitors, p21 and p27. Further investigation on the underlying mechanisms revealed that safranal suppressed the mRNA and protein expression levels of Skp2, possibly through the deregulation of the transcriptional activity of two major transcriptional factors, E2F1 and NF-κB subunits. Moreover, safranal inhibited AKT phosphorylation at Ser473 and deregulated both canonical and non-canonical NF-κB signaling pathways. Safranal suppressed the tumor growth of quiescent Pca cell xenografts in vivo. Furthermore, safranal-treated tumor tissues exhibited a reduction in Skp2, E2F1, NF-κB p65, p-IκBα (Ser32), c-MYC, p-Rb (Ser807), CDK4, CDK6, and CDK2 and an elevation of p27 and p21 protein levels. Therefore, our findings demonstrate that safranal suppresses cell cycle re-entry of quiescent Pca cells in vitro and in vivo plausibly by repressing the transcriptional activity of two major transcriptional activators of Skp2, namely, E2F1 and NF-κB, through the downregulation of AKT phosphorylation and NF-κB signaling pathways, respectively.

Matched MeSH terms: Proto-Oncogene Proteins c-akt
Fulltext Identification of Predictive DNA Methylation Biomarkers for Chemotherapy Response in Colorectal Cancer

Baharudin R, Ab Mutalib NS, Othman SN, Sagap I, Rose IM, Mohd Mokhtar N, et al.

Front Pharmacol, 2017;8:47.
PMID: 28243201 DOI: 10.3389/fphar.2017.00047

Resistance to 5-Fluorouracil (5-FU) is a major obstacle to the successful treatment of colorectal cancer (CRC) and posed an increased risk of recurrence. DNA methylation has been suggested as one of the underlying mechanisms for recurrent disease and its contribution to the development of drug resistance remains to be clarified. This study aimed to determine the methylation phenotype in CRC for identification of predictive markers for chemotherapy response. We performed DNA methylation profiling on 43 non-recurrent and five recurrent CRC patients using the Illumina Infinium HumanMethylation450 Beadchip assay. In addition, CRC cells with different genetic backgrounds, response to 5-FU and global methylation levels (HT29 and SW48) were treated with 5-FU and DNA methylation inhibitor 5-aza-2'-deoxycytidine (5-azadC). The singular and combined effects of these two drug classes on cell viability and global methylation profiles were investigated. Our genome-wide methylation study on the clinical specimens showed that recurrent CRCs exhibited higher methylation levels compared to non-recurrent CRCs. We identified 4787 significantly differentially methylated genes (P < 0.05); 3112 genes were hyper- while 1675 genes were hypomethylated in the recurrent group compared to the non-recurrent. Fifty eight and 47 of the significantly hypermethylated and hypomethylated genes have an absolute recurrent/non-recurrent methylation difference of ≥20%. Most of the hypermethylated genes were involved in the MAPK signaling pathway which is a key regulator for apoptosis while the hypomethylated genes were involved in the PI3K-AKT signaling pathway and proliferation process. We also demonstrate that 5-azadC treatment enhanced response to 5-FU which resulted in significant growth inhibition compared to 5-FU alone in hypermethylated cell lines SW48. In conclusion, we found the evidence of five potentially biologically important genes in recurrent CRCs that could possibly serve as a new potential therapeutic targets for patients with chemoresistance. We postulate that aberrant methylation of CCNEI, CCNDBP1, PON3, DDX43, and CHL1 in CRC might be associated with the recurrence of CRC and 5-azadC-mediated restoration of 5-FU sensitivity is mediated at least in part by MAPK signaling pathway.

Matched MeSH terms: Proto-Oncogene Proteins c-akt
Fulltext PH-responsive strontium nanoparticles for targeted gene therapy against mammary carcinoma cells

Bakhtiar A, Chowdhury EH

Asian J Pharm Sci, 2021 Mar;16(2):236-252.
PMID: 33995617 DOI: 10.1016/j.ajps.2020.11.002

Genetic intervention via the delivery of functional genes such as plasmid DNA (pDNA) and short-interfering RNA (siRNA) offers a great way to treat many single or multiple genetic defects effectively, including mammary carcinoma. Delivery of naked therapeutic genes or siRNAs is, however, short-lived due to biological clearance by scavenging nucleases and circulating monocytes. Low cellular internalization of negatively-charged nucleic acids further causes low transfection or silencing activity. Development of safe and effectual gene vectors is therefore undeniably crucial to the success of nucleic acid delivery. Inorganic nanoparticles have attracted considerable attention in the recent years due to their high loading capacity and encapsulation activity. Here we introduce strontium salt-based nanoparticles, namely, strontium sulfate, strontium sulfite and strontium fluoride as new inorganic nanocarriers. Generated strontium salt particles were found to be nanosized with high affinity towards negatively-charged pDNA and siRNA. Degradation of the particles was seen with a drop in pH, suggesting their capacity to respond to pH change and undergo dissolution at endosomal pH to release the genetic materials. While the particles are relatively nontoxic towards the cells, siRNA-loaded SrF2 and SrSO3 particles exerted superior transgene expression and knockdown activity of MAPK and AKT, leading to inhibition of their phosphorylation to a distinctive extent in both MCF-7 and 4T1 cells. Strontium salt nanoparticles have thus emerged as a promising tool for applications in cancer gene therapy.

Matched MeSH terms: Proto-Oncogene Proteins c-akt
Fulltext Gene regulation in β-sitosterol-mediated stimulation of adipogenesis, glucose uptake, and lipid mobilization in rat primary adipocytes

Chai JW, Lim SL, Kanthimathi MS, Kuppusamy UR

Genes Nutr, 2011 May;6(2):181-8.
PMID: 21484150 DOI: 10.1007/s12263-010-0196-4

The nutraceutical benefits of β-sitosterol (SIT) are well documented. The present study investigated the in vitro effects of SIT on adipogenesis, glucose transport, and lipid mobilization in rat adipocytes. Primary cultures of rat preadipocytes and differentiated adipocytes were used in this study. Glucose uptake was measured by the uptake of radio-labeled glucose. Adipogenesis and lipolysis were measured by oil-red-O and glycerol quantification methods, respectively. The expression of protein kinase B (Akt), glucose transporter 4 (GLUT4), hormone sensitive lipase (HSL), and phosphatidylinositol-3-kinase (PI3 K) genes in SIT-treated adipocytes were assessed by real-time reverse transcription polymerase chain reaction (RT-PCR). The data showed that SIT induced glucose uptake in adipocytes. It also stimulated adipogenesis in differentiating preadipocytes. Interestingly, although SIT displayed general insulin-mimetic activity by stimulating glucose uptake and adipogenesis, it also induced lipolysis in adipocytes. Furthermore, the SIT-induced lipolysis was not attenuated by insulin and co-incubation of SIT with epinephrine improved epinephrine-induced lipolysis. GLUT4 gene expression was highly down-regulated in SIT-treated adipocytes, compared to insulin-treated adipocytes, which was up-regulated. Insulin- and SIT-treated adipocytes showed similar levels of Akt, HSL, and PI3 K gene down-regulation. These observations suggest that the elevation of glucose uptake in SIT-treated adipocytes was unrelated to de novo synthesis of GLUT4 and the SIT-induced lipolysis is associated with the down-regulation of Akt and PI3K genes. The unique effects of SIT on the regulation of glucose uptake, adipogenesis, and lipolysis in adipocytes show that it has potential to be utilized in diabetes and weight management.

Matched MeSH terms: Proto-Oncogene Proteins c-akt
Fulltext Antioxidative Effects of Germinated Brown Rice-Derived Extracts on H2O2-Induced Oxidative Stress in HepG2 Cells

Md Zamri ND, Imam MU, Abd Ghafar SA, Ismail M

Evid Based Complement Alternat Med, 2014;2014:371907.
PMID: 25431609 DOI: 10.1155/2014/371907

The antioxidant properties of germinated brown rice (GBR) are likely mediated by multiple bioactives. To test this hypothesis, HepG2 cells pretreated with GBR extracts, rich in acylated steryl glycoside (ASG), gamma amino butyric acid GABA), phenolics or oryzanol, were incubated with hydrogen peroxide (H2O2) and their hydroxyl radical (OH(•)) scavenging capacities and thiobarbituric acid-reactive substances (TBARS) generation were evaluated. Results showed that GBR-extracts increased OH(•) scavenging activities in both cell-free medium and posttreatment culture media, suggesting that the extracts were both direct- and indirect-acting against OH(•). The levels of TBARS in the culture medium after treatment were also reduced by all the extracts. In addition, H2O2 produced transcriptional changes in p53, JNK, p38 MAPK, AKT, BAX, and CDK4 that were inclined towards apoptosis, while GBR-extracts showed some transcriptional changes (upregulation of BAX and p53) that suggested an inclination for apoptosis although other changes (upregulation of antioxidant genes, AKT, JNK, and p38 MAPK) suggested that GBR-extracts favored survival of the HepG2 cells. Our findings show that GBR bioactive-rich extracts reduce oxidative stress through improvement in antioxidant capacity, partly mediated through transcriptional regulation of antioxidant and prosurvival genes.

Matched MeSH terms: Proto-Oncogene Proteins c-akt
Fulltext Phyllanthus Suppresses Prostate Cancer Cell, PC-3, Proliferation and Induces Apoptosis through Multiple Signalling Pathways (MAPKs, PI3K/Akt, NFκB, and Hypoxia)

Tang YQ, Jaganath I, Manikam R, Sekaran SD

Evid Based Complement Alternat Med, 2013;2013:609581.
PMID: 23690850 DOI: 10.1155/2013/609581

Phyllanthus is a traditional medicinal plant that has been found to have antihepatitis, antibacterial, and anticancer properties. The present studies were to investigate the in vitro molecular mechanisms of anticancer effects of Phyllanthus (P. amarus, P. niruri, P. urinaria, and P. watsonii) plant extracts in human prostate adenocarcinoma. The cancer ten-pathway reporter array was performed and revealed that the expression of six pathway reporters were significantly decreased (Wnt, NFκB, Myc/Max, hypoxia, MAPK/ERK, and MAPK/JNK) in PC-3 cells after treatment with Phyllanthus extracts. Western blot was conducted and identified several signalling molecules that were affected in the signalling pathways including pan-Ras, c-Raf, RSK, Elk1, c-Jun, JNK1/2, p38 MAPK, c-myc, DSH, β-catenin, Akt, HIF-1α, GSK3β, NFκB p50 and p52, Bcl-2, Bax, and VEGF, in treated PC-3 cells. A proteomics-based approach, 2D gel electrophoresis, was performed, and mass spectrometry (MS/MS) results revealed that there were 72 differentially expressed proteins identified in treated PC-3 cells and were involved in tumour cell adhesion, apoptosis, glycogenesis and glycolysis, metastasis, angiogenesis, and protein synthesis and energy metabolism. Overall, these findings suggest that Phyllanthus can interfere with multiple signalling cascades involved in tumorigenesis and be used as a potential therapeutic candidate for treatment of cancer.

Matched MeSH terms: Proto-Oncogene Proteins c-akt
Fulltext Gelam Honey Attenuates the Oxidative Stress-Induced Inflammatory Pathways in Pancreatic Hamster Cells

Safi SZ, Batumalaie K, Qvist R, Mohd Yusof K, Ismail IS

Evid Based Complement Alternat Med, 2016;2016:5843615.
PMID: 27034691 DOI: 10.1155/2016/5843615

Purpose. Type 2 diabetes consists of progressive hyperglycemia and insulin resistance, which could result from glucose toxicity, inflammatory cytokines, and oxidative stress. In the present study we investigated the effect of Gelam honey and quercetin on the oxidative stress-induced inflammatory pathways and the proinflammatory cytokines. Methods. HIT-T15 cells were cultured and preincubated with the extract of Gelam honey (20, 40, 60, and 80 μg/mL), as well as quercetin (20, 40, 60, and 80 μM), prior to stimulation by 20 and 50 mM glucose. Results. HIT-T15 cells cultured under hyperglycemic condition showed a significant increase in the inflammatory pathways by phosphorylating JNK, IKK-β, and IRS-1 at Ser307 (p < 0.05). There was a significant decrease in the phosphorylation of Akt at Ser473 (p < 0.05). Pretreatment with Gelam honey and quercetin reduced the expression of phosphorylated JNK, IKK-β, and IRS-1, thereby significantly reducing the expression of proinflammatory cytokines like TNF-α, IL-6, and IL-1β (p < 0.05). At the same time there was a significant increase in the phosphorylated Akt showing the protective effects against inflammation and insulin resistance (p < 0.05). In conclusion, our data suggest the potential use of the extract from Gelam honey and quercetin in modulating the inflammation induced insulin signaling pathways.

Matched MeSH terms: Proto-Oncogene Proteins c-akt
Hypoxia-regulated microRNAs: the molecular drivers of tumor progression

Sawai S, Wong PF, Ramasamy TS

Crit Rev Biochem Mol Biol, 2022 Aug;57(4):351-376.
PMID: 35900938 DOI: 10.1080/10409238.2022.2088684

Hypoxia is a common feature of the tumor microenvironment (TME) of nearly all solid tumors, leading to therapeutic failure. The changes in stiffness of the extracellular matrix (ECM), pH gradients, and chemical balance that contribute to multiple cancer hallmarks are closely regulated by intratumoral oxygen tension via its primary mediators, hypoxia-inducible factors (HIFs). HIFs, especially HIF-1α, influence these changes in the TME by regulating vital cancer-associated signaling pathways and cellular processes including MAPK/ERK, NF-κB, STAT3, PI3K/Akt, Wnt, p53, and glycolysis. Interestingly, research has revealed the involvement of epigenetic regulation by hypoxia-regulated microRNAs (HRMs) of downstream target genes involved in these signaling. Through literature search and analysis, we identified 48 HRMs that have a functional role in the regulation of 5 key cellular processes: proliferation, metabolism, survival, invasion and migration, and immunoregulation in various cancers in hypoxic condition. Among these HRMs, 17 were identified to be directly associated with HIFs which include miR-135b, miR-145, miR-155, miR-181a, miR-182, miR-210, miR-224, miR-301a, and miR-675-5p as oncomiRNAs, and miR-100-5p, miR-138, miR-138-5p, miR-153, miR-22, miR-338-3p, miR-519d-3p, and miR-548an as tumor suppressor miRNAs. These HRMs serve as a potential lead in the development of miRNA-based targeted therapy for advanced solid tumors. Future development of combined HIF-targeted and miRNA-targeted therapy is possible, which requires comprehensive profiling of HIFs-HRMs regulatory network, and improved formula of the delivery vehicles to enhance the therapeutic kinetics of the targeted cancer therapy (TCT) moving forward.

Matched MeSH terms: Proto-Oncogene Proteins c-akt
Fulltext Highlighting the effects of high-intensity interval training on the changes associated with hypertrophy, apoptosis, and histological proteins of the heart of old rats with type 2 diabetes

Rami M, Ahmadi Hekmatikar A, Rahdar S, Marashi SS, Daud DMA

Sci Rep, 2024 Mar 26;14(1):7133.
PMID: 38531890 DOI: 10.1038/s41598-024-57119-6

T2DM is known to cause disturbances in glucose homeostasis and negative changes in the heart muscle, while aging and diabetes are recognized risk factors for CVD. Given this, our study aims to investigate a method for controlling and managing CVDs induced by T2DM in elderly populations. To achieve this, we categorized 40 rats into 5 groups, including HAD (n = 8), HA (n = 8), AD (n = 8), AHT (n = 8), and ADT (n = 8). The exercise protocol consisted of eight weeks of HIIT (three sessions per week) performed at 90-95% of maximal speed. Following cardiac tissue extraction, we assessed the levels of IGF-1, PI3K, and AKT proteins using Western blot technique, and analyzed the histopathological variations of the heart tissue using H&E, Sudan Black, and Masson's trichrome tissue staining. The histological findings from our study demonstrated that T2DM had a significant impact on the development of pathological hypertrophy and fibrosis in the heart tissue of elderly individuals. However, HIIT not only effectively controlled pathological hypertrophy and fibrosis, but also induced physiological hypertrophy in the AHT and ADT groups compared to the HA and AD groups. Results from Sudan Black staining indicated that there was an increase in lipid droplet accumulation in the cytoplasm of cardiomyocytes and their nuclei in the HA and AD groups, while the accumulation of lipid droplets decreased significantly in the AHT and ADT groups. In both the AHT group and the ADT group, a single HIIT session led to a reduction in collagen fiber accumulation and fibrotic frameworks. Our research also revealed that diabetes caused a significant elevation in the levels of IGF-1, PI3K, and AKT proteins, but after eight weeks of HIIT, the levels of these proteins decreased significantly in the training groups. Overall, our findings suggest that HIIT may be a suitable non-pharmacological approach for improving histological and physiological changes in elderly individuals with T2DM. However, we recommend further research to examine the impact of HIIT training on both healthy and diseased elderly populations.

Matched MeSH terms: Proto-Oncogene Proteins c-akt
p38 inhibitor inhibits the apoptosis of cowanin-treated human colorectal adenocarcinoma cells

Chowchaikong N, Nilwarangkoon S, Laphookhieo S, Tanunyutthawongse C, Watanapokasin R

Int J Oncol, 2018 Jun;52(6):2031-2040.
PMID: 29620273 DOI: 10.3892/ijo.2018.4353

Colorectal cancer, which is the third most common type of cancer diagnosed in both men and women, is the leading cause of cancer-related deaths worldwide. Cowanin is a pure compound extracted from Garcinia cowa Roxb., a tree species present in Thailand, Malaysia and Myanmar. The crude extract has been demonstrated to have antitumor activity, inflammation induction, antibacterial activity, anti-inflammatory activity and antimalarial activity. In the present study, the effects of cowanin on apoptosis induction and on the apoptosis-related and mitogen-activated protein kinase (MAPK) pathways were investigated in the LoVo human colorectal cancer cell line. The cytotoxicity of cowanin in LoVo cells was determined by MTT assay. Hoechst 33342 and JC‑1 staining were used to determine nuclear morphological changes and mitochondrial membrane potential, respectively. The expression levels of BCL2 apoptosis regulator (Bcl‑2) family, MAPK and AKT serine/threonine kinase 1 (Akt) pathway proteins following cowanin treatment were determined by western blot analysis. The results demonstrated that cowanin inhibited cell proliferation and induced cell death via the apoptosis pathway. Cowanin treatment increased BCL2 associated X (Bax) and decreased Bcl‑2 expression. In addition, cowanin activated caspase‑9, -7 and poly-ADP-ribose-polymerase expression. Furthermore, cowanin decreased the levels of phosphorylated extracellular signal-regulated kinase (p‑ERK), p‑Akt, p‑3‑phosphoinositide‑dependent protein kinase‑1, while it increased p‑p38 expression, thus resulting in the induction of apoptosis. In conclusion, cowanin inhibited cell proliferation and induced apoptosis of LoVo cells via the MAPK and Akt signaling pathways. Notably, inhibition of p38 by using a p38 inhibitor (SB203580) prevented the cowanin-induced apoptosis in LoVo cells. These results suggested that cowanin may be a potential candidate for the treatment of colorectal cancer and provided important information on the molecular mechanisms underlying its antitumor activity.

Matched MeSH terms: Proto-Oncogene Proteins c-akt/metabolism
Fulltext Polyphenol-rich ethyl acetate fraction isolated from Molineria latifolia ameliorates insulin resistance in experimental diabetic rats via IRS1/AKT activation

Ooi J, Adamu HA, Imam MU, Ithnin H, Ismail M

Biomed Pharmacother, 2018 Feb;98:125-133.
PMID: 29248832 DOI: 10.1016/j.biopha.2017.12.002

This study aimed to evaluate the effect of ethyl acetate fraction (EAF) isolated from Molineria latifolia rhizome as dietary interventions for type 2 diabetes mellitus (T2DM) and its underlying molecular mechanisms in vivo. Experimental rats were induced by high fat diet feeding coupled with combined exposure to streptozotocin and nicotinamide. Treatment with EAF improved glucose tolerance and lipid profiles, but the insulin secretion was unaltered. Gene expression analyses on insulin/adipocytokine signalling-related genes demonstrated tissue-specific transcriptional responses. In skeletal muscle and liver tissues, Socs1, Tnf and Mapk8 showed consistent transcript regulation. Furthermore, hepatic translational analyses revealed sensitization on proximal insulin signalling, with reduced expression of IRS1 serine phosphorylation, increased IRS1 tyrosine phosphorylation and increased phospho-AKT (Ser473). The present findings suggested that EAF exerted its effect by modulating insulin signalling, potentially via IRS1/AKT activation. The pharmacological attributes of EAF may implicate its potential therapeutic applications for diabetes management.

Matched MeSH terms: Proto-Oncogene Proteins c-akt/metabolism*
Phyllanthin from Phyllanthus amarus inhibits LPS-induced proinflammatory responses in U937 macrophages via downregulation of NF-κB/MAPK/PI3K-Akt signaling pathways

Harikrishnan H, Jantan I, Haque MA, Kumolosasi E

Phytother Res, 2018 Dec;32(12):2510-2519.
PMID: 30238535 DOI: 10.1002/ptr.6190

Phyllanthin, a lignan from Phyllanthus species, has been reported to possess potent immunosuppressive properties on immune cells and on adaptive and innate immune responses in animal models. Herein, we investigated the inhibitory effects of phyllanthin isolated from Phyllanthus amarus on nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and PI3K-Akt signal transducing pathways in LPS-activated U937 cells. The lipopolysaccharide-stimulated excess production of prostaglandin was significantly suppressed by phyllanthin via the mechanisms linked to the modulatory effects of cyclooxygenase 2 protein and gene expression. Phyllanthin also significantly inhibited the release and mRNA expression of proinflammatory cytokines (interleukin-1 beta and tumor necrosis factor-alpha). Phyllanthin also significantly downregulated the phosphorylation of IκBα, NF-κB (p65), and IKKα/β and suppressed the activation of JNK, ERK, p38MAPK, and Akt in a concentration-dependent manner. Additionally, phyllanthin downregulated the expression of upstream signaling molecules including MyD88 and toll-like receptor 4 that are essential for the activation of NF-κB, MAPKs, and PI3K-Akt signal transducing pathways. Based on these observations, phyllanthin may exert their suppressive effects on inflammatory process by mediating the release of inflammatory signaling molecules via the NF-κB, MAPKs, and PI3K-Akt signal transducing pathways. Thus, phyllanthin holds a great promise as a potential anti-inflammatory agent to treat various inflammatory diseases.

Matched MeSH terms: Proto-Oncogene Proteins c-akt/metabolism
Standardized extract of Zingiber zerumbet suppresses LPS-induced pro-inflammatory responses through NF-κB, MAPK and PI3K-Akt signaling pathways in U937 macrophages

Haque MA, Jantan I, Harikrishnan H, Ghazalee S

Phytomedicine, 2019 Feb 15;54:195-205.
PMID: 30668369 DOI: 10.1016/j.phymed.2018.09.183

BACKGROUND: Zingiber zerumbet rhizome has been used as spices and in traditional medicine to heal various immune-inflammatory related ailments. Although the plant was reported to have potent anti-inflammatory and immunosuppressive properties by several studies, the molecular mechanisms underlying the effects have not been well justified.
PURPOSE: The study was carried out to investigate the molecular mechanisms underlying the anti-inflammatory properties of the standardized 80% ethanol extract of Z. zerumbet through its effect on mitogen-activated protein kinase (MyD88)-dependent nuclear factor-kappa B (NF-кB), mitogen activated protein kinase (MAPK) and phosphatidylinositol 3-kinase/Akt (PI3K-Akt) signaling pathways in lipopolysaccharide (LPS)-induced U937 human macrophages.
METHODS: Standardization of the 80% ethanol extract of Z. zerumbet was performed by using a validated reversed-phase HPLC method, while LC-MS/MS was used to profile the secondary metabolites. The release of pro-inflammatory markers, tumor necrosis factor (TNF)-α, interleukin (IL)-1β and prostaglandin E2 (PGE2) was evaluated by enzyme-linked immunosorbent assay (ELISA), while the Western blot technique was executed to elucidate the expression of mediators linked to MyD88-dependent respective signaling pathways. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay was carried out to quantify the relative gene expression of cyclooxygenase (COX)-2 and pro-inflammatory mediators at the transcriptional level.
RESULTS: The quantitative and qualitative analyses of Z. zerumbet extract showed the presence of several compounds including the major chemical marker zerumbone. Z. zerumbet extract suppressed the release of pro-inflammatory mediators, COX-2 protein expression and downregulated the mRNA expression of pro-inflammatory markers. Z. zerumbet-treatment also blocked NF-κB activation by preventing the phosphorylation of IKKα/β and NF-κB (p65) as well as the phosphorylation and degradation of IκBα. Z. zerumbet extract concentration-dependently inhibited the phosphorylation of respective MAPKs (JNK, ERK, and p38) as well as Akt. Correspondingly, Z. zerumbet extract suppressed the upstream signaling adaptor molecules, TLR4 and MyD88 prerequisite for the NF-κB, MAPKs, and PI3K-Akt activation.
CONCLUSION: The findings suggest that Z. zerumbet has impressive role in suppressing inflammation and related immune disorders by inhibition of various pro-inflammatory markers through the imperative MyD88-dependent NF-κB, MAPKs, and PI3K-Akt activation.

Matched MeSH terms: Proto-Oncogene Proteins c-akt/metabolism

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