MyMedR

Displaying publications 241 - 260 of 386 in total

Abstract:

Sort:

Fulltext Gold-Hybridized Zinc Oxide Nanorods as Real-Time Low-Cost NanoBiosensors for Detection of virulent DNA signature of HPV-16 in Cervical Carcinoma

Ramesh T, Foo KL, R H, Sam AJ, Solayappan M

Sci Rep, 2019 Nov 19;9(1):17039.
PMID: 31745139 DOI: 10.1038/s41598-019-53476-9

Detection of host integrated viral oncogenes are critical for early and point-of-care molecular diagnostics of virus-induced carcinoma. However, available diagnostic approaches are incapable of combining both cost-efficient medical diagnosis and high analytical performances. To circumvent this, we have developed an improved IDE-based nanobiosensor for biorecognition of HPV-16 infected cervical cancer cells through electrochemical impedance spectroscopy. The system is fabricated by coating gold (Au) doped zinc oxide (ZnO) nanorods interfaced with HPV-16 viral DNA bioreceptors on top of the Interdigitated Electrode (IDE) chips surface. Due to the concurrently improved sensitivity and biocompatibility of the designed nanohybrid film, Au decorated ZnO-Nanorod biosensors demonstrate exceptional detection of HPV-16 E6 oncogene, the cancer biomarker for HPV infected cervical cancers. This sensor displayed high levels of sensitivity by detecting as low as 1fM of viral E6 gene target. The sensor also exhibited a stable functional life span of more than 5 weeks, good reproducibility and high discriminatory properties against HPV-16. Sensor current responses are obtained from cultured cervical cancer cells which are close to clinical cancer samples. Hence, the developed sensor is an adaptable tool with high potential for clinical diagnosis especially useful for economically challenged countries/regions.

Matched MeSH terms: Oncogene Proteins, Viral/genetics*
Fulltext Evaluation of phytoestrogens in inducing cell death mediated by decreasing Annexin A1 in Annexin A1-knockdown leukemia cells

Hasan M, Kumolosasi E, Jasamai M, Jamal JA, Azmi N, Rajab NF

Daru, 2020 Jun;28(1):97-108.
PMID: 31912375 DOI: 10.1007/s40199-019-00320-0

BACKGROUND: Phytoestrogens are plant compounds that are structurally similar to estrogen and that possess anti-cancer properties. Previous studies have reported that coumestrol, daidzein and genistein could induce cell death by reducing Annexin A1 protein in leukemic cell lines. Annexin A1 (ANXA1) is involved in cell progression, metastasis, and apoptosis in several types of cancer cells. The present study sought to investigate if the effects of phytoestrogens on apoptosis, cell cycle arrest and phagocytosis in ANXA1-knockdown leukemic cells are mediated through ANXA1 or occurred independently.
METHODS: Transfection of ANXA1 siRNA was conducted to downregulate ANXA1 expression in Jurkat, K562 and U937 cells. Apoptosis and cell cycle assays were conducted using flow cytometry. Western blot was performed to evaluate ANXA1, caspases and Bcl-2 proteins expression. Phagocytosis was determined using hematoxylin and eosin staining.
RESULTS: The expression of ANXA1 after the knockdown was significantly downregulated in all cell lines. Genistein significantly induced apoptosis associated with an upregulation of procaspase-3, -9, and - 1 in Jurkat cells. The Bcl-2 expression showed no significant difference in Jurkat, K562 and U937 cells. Treatment with phytoestrogens increased procaspase-1 expression in Jurkat and U937 cells while no changes were detected in K562 cells. Flow cytometry analysis demonstrated that after ANXA1 knockdown, coumestrol and genistein caused cell cycle arrest at G2/M phase in selected type of cells. The percentage of phagocytosis and phagocytosis index increased after the treatment with phytoestrogens in all cell lines.
CONCLUSION: Phytoestrogens induced cell death in ANXA1-knockdown leukemia cells, mediated by Annexin A1 proteins. Graphical abstract.

Matched MeSH terms: Proto-Oncogene Proteins c-bcl-2/metabolism
Alpha-tomatine synergises with paclitaxel to enhance apoptosis of androgen-independent human prostate cancer PC-3 cells in vitro and in vivo

Lee ST, Wong PF, Hooper JD, Mustafa MR

Phytomedicine, 2013 Nov 15;20(14):1297-305.
PMID: 23920276 DOI: 10.1016/j.phymed.2013.07.002

Alpha (α)-tomatine, a major saponin found in tomato has been shown to inhibit the growth of androgen-independent prostate cancer PC-3 cells. The effects of α-tomatine in combination with the chemotherapeutic agent paclitaxel against PC-3 cells were investigated in the present study. Combined treatment with a sub-toxic dose of α-tomatine and paclitaxel significantly decreased cell viability with concomitant increase in the percentage of apoptotic PC-3 cells. The combined treatment, however, had no cytotoxic effect on the non-neoplastic prostate RWPE-1 cells. Apoptosis of PC-3 cells was accompanied by the inhibition of PI3K/Akt pro-survival signaling, an increase in the expression of the pro-apoptotic protein BAD but a decrease in the expressions of anti-apoptotic proteins, Bcl-2 and Bcl-xL. Results from a mouse xenograft model showed the combined treatment completely suppressed subcutaneous tumor growth without significant side effects. Consistent with its in vitro anti-cancer effects, tumor materials from mice showed increased apoptosis of tumor cells with reduced protein expression of activated PI3K/Akt. These results suggest that the synergistic anti-cancer effects of paclitaxel and α-tomatine may be beneficial for refractory prostate cancer treatment.

Matched MeSH terms: Proto-Oncogene Proteins c-bcl-2/metabolism; Proto-Oncogene Proteins c-akt/metabolism
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 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 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
An oncological curiosity of a male patient with a huge leiomyoma of the terminal ileum

Zainudin S, Rajanthran SK, Azizan N, Hayati F, Ginawoi J, Suhaimi KA, et al.

Oxf Med Case Reports, 2020 Oct;2020(10):omaa086.
PMID: 33133619 DOI: 10.1093/omcr/omaa086

Leiomyoma is a smooth muscle tumour that can arise in any part of the body especially the uterus. Even though it is traditionally linked with hormonal influence, it can also develop in extrauterine organs with a slight female predominance. It is indistinguishable with gastrointestinal stromal tumour (GIST) histologically. We report a case of a 30-year-old gentleman who presented with a huge painful mass in the right iliac fossa. Computed tomography revealed a 10 × 10 cm homogeneous mass arising from the terminal ileum; he subsequently underwent an open right hemicolectomy. Histology showed a well-circumscribed lesion composed of interlacing bundles of smooth muscle fibres of the submucosa with positive smooth muscle actin and H-Caldesmon stains but negative for DOG-1 and CD117 (c-kit) stains which were consistent with leiomyoma. Despite its rarity, this hormone-related tumour needs to be considered regardless of gender. Immunohistochemistry is paramount as it is histologically identical to GIST.

Matched MeSH terms: Proto-Oncogene Proteins c-kit
Effects of palbociclib on oral squamous cell carcinoma and the role of PIK3CA in conferring resistance

Zainal NS, Lee BKB, Wong ZW, Chin IS, Yee PS, Gan CP, et al.

Cancer Biol Med, 2019 May;16(2):264-275.
PMID: 31516747 DOI: 10.20892/j.issn.2095-3941.2018.0257

Objective: Lack of effective therapies remains a problem in the treatment of oral squamous cell carcinoma (OSCC), especially in patients with advanced tumors. OSCC development is driven by multiple aberrancies within the cell cycle pathway, including amplification of cyclin D1 and loss of p16. Hence, cell cycle inhibitors of the CDK4/6-cyclin D axis are appealing targets for OSCC treatment. Here, we determined the potency of palbociclib and identified genetic features that are associated with the response of palbociclib in OSCC.
Methods: The effect of palbociclib was evaluated in a panel of well-characterized OSCC cell lines by cell proliferation assays and further confirmed by in vivo evaluation in xenograft models. PIK3CA-mutant isogenic cell lines were used to investigate the effect of PIK3CA mutation towards palbociclib response.
Results: We demonstrated that 80% of OSCC cell lines are sensitive to palbociclib at sub-micromolar concentrations. Consistently, palbociclib was effective in controlling tumor growth in mice. We identified that palbociclib-resistant cells harbored mutations in PIK3CA. Using isogenic cell lines, we showed that PIK3CA mutant cells are less responsive to palbociclib as compared to wild-type cells with concurrent upregulation of CDK2 and cyclin E1 protein levels. We further demonstrated that the combination of a PI3K/mTOR inhibitor (PF-04691502) and palbociclib completely controlled tumor growth in mice.
Conclusions: This study demonstrated the potency of palbociclib in OSCC models and provides a rationale for the inclusion of PIK3CA testing in the clinical evaluation of CDK4/6 inhibitors and suggests combination approaches for further clinical studies.

Matched MeSH terms: Oncogene Proteins
Fulltext Intracellular Delivery of siRNAs Targeting AKT and ERBB2 Genes Enhances Chemosensitization of Breast Cancer Cells in a Culture and Animal Model

Fatemian T, Moghimi HR, Chowdhury EH

Pharmaceutics, 2019 Sep 03;11(9).
PMID: 31484456 DOI: 10.3390/pharmaceutics11090458

: Pharmacotherapy as the mainstay in the management of breast cancer suffers from various drawbacks, including non-targeted biodistribution, narrow therapeutic and safety windows, and also resistance to treatment. Thus, alleviation of the constraints from the pharmacodynamic and pharmacokinetic profile of classical anti-cancer drugs could lead to improvements in efficacy and patient survival in malignancies. Moreover, modifications in the genetic pathophysiology of cancer via administration of small nucleic acids might pave the way towards higher response rates to chemotherapeutics. Inorganic pH-dependent carbonate apatite (CA) nanoparticles were utilized in this study to efficiently deliver various classes of therapeutics into cancer cells. Co-delivery of drugs and genetic materials was successfully attained through a carbonate apatite delivery device. On 4T1 cells, siRNAs against AKT and ERBB2 plus paclitaxel or docetaxel resulted in the largest increase in anti-cancer effects compared to CA/paclitaxel or CA/docetaxel. Therefore, these ingredients were selected for further in vivo investigations. Animals receiving injections of CA/paclitaxel or CA/docetaxel loaded with siRNAs against AKT and ERBB2 possessed significantly smaller tumors compared to CA/drug-treated mice. Interestingly, synergistic interactions in target protein knock down with combinations of CA/AKT/paclitaxel, CA/ERBB2/docetaxel were documented via western blotting.

Matched MeSH terms: Proto-Oncogene Proteins c-akt
Fulltext Maternal Cognitive Impairment Associated with Gestational Diabetes Mellitus-A Review of Potential Contributing Mechanisms

John CM, Mohamed Yusof NIS, Abdul Aziz SH, Mohd Fauzi F

Int J Mol Sci, 2018 Dec 05;19(12).
PMID: 30563117 DOI: 10.3390/ijms19123894

Gestational diabetes mellitus (GDM) carries many risks, where high blood pressure, preeclampsia and future type II diabetes are widely acknowledged, but less focus has been placed on its effect on cognitive function. Although the multifactorial pathogenesis of maternal cognitive impairment is not completely understood, it shares several features with type 2 diabetes mellitus (T2DM). In this review, we discuss some key pathophysiologies of GDM that may lead to cognitive impairment, specifically hyperglycemia, insulin resistance, oxidative stress, and neuroinflammation. We explain how these incidents: (i) impair the insulin-signaling pathway and/or (ii) lead to cognitive impairment through hyperphosphorylation of τ protein, overexpression of amyloid-β and/or activation of microglia. The aforementioned pathologies impair the insulin-signaling pathway primarily through serine phosphorylation of insulin receptor substances (IRS). This then leads to the inactivation of the phosphatidylinositol 3-kinase/Protein kinase B (PI3K/AKT) signaling cascade, which is responsible for maintaining brain homeostasis and normal cognitive functioning. PI3K/AKT is crucial in maintaining normal cognitive function through the inactivation of glycogen synthase kinase 3β (GSκ3β), which hyperphosphorylates τ protein and releases pro-inflammatory cytokines that are neurotoxic. Several biomarkers were also highlighted as potential biomarkers of GDM-related cognitive impairment such as AGEs, serine-phosphorylated IRS-1 and inflammatory markers such as tumor necrosis factor α (TNF-α), high-sensitivity C-reactive protein (hs-CRP), leptin, interleukin 1β (IL-1β), and IL-6. Although GDM is a transient disease, its complications may be long-term, and hence increased mechanistic knowledge of the molecular changes contributing to cognitive impairment may provide important clues for interventional strategies.

Matched MeSH terms: Proto-Oncogene Proteins c-akt
Fulltext Paediatric Gliomas: BRAF and Histone H3 as Biomarkers, Therapy and Perspective of Liquid Biopsies

Tan JY, Wijesinghe IVS, Alfarizal Kamarudin MN, Parhar I

Cancers (Basel), 2021 Feb 04;13(4).
PMID: 33557011 DOI: 10.3390/cancers13040607

Paediatric gliomas categorised as low- or high-grade vary markedly from their adult counterparts, and denoted as the second most prevalent childhood cancers after leukaemia. As compared to adult gliomas, the studies of diagnostic and prognostic biomarkers, as well as the development of therapy in paediatric gliomas, are still in their infancy. A body of evidence demonstrates that B-Raf Proto-Oncogene or V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF) and histone H3 mutations are valuable biomarkers for paediatric low-grade gliomas (pLGGs) and high-grade gliomas (pHGGs). Various diagnostic methods involving fluorescence in situ hybridisation, whole-genomic sequencing, PCR, next-generation sequencing and NanoString are currently used for detecting BRAF and histone H3 mutations. Additionally, liquid biopsies are gaining popularity as an alternative to tumour materials in detecting these biomarkers, but still, they cannot fully replace solid biopsies due to several limitations. Although histone H3 mutations are reliable prognosis biomarkers in pHGGs, children with these mutations have a dismal prognosis. Conversely, the role of BRAF alterations as prognostic biomarkers in pLGGs is still in doubt due to contradictory findings. The BRAF V600E mutation is seen in the majority of pLGGs (as seen in pleomorphic xanthoastrocytoma and gangliomas). By contrast, the H3K27M mutation is found in the majority of paediatric diffuse intrinsic pontine glioma and other midline gliomas in pHGGs. pLGG patients with a BRAF V600E mutation often have a lower progression-free survival rate in comparison to wild-type pLGGs when treated with conventional therapies. BRAF inhibitors (Dabrafenib and Vemurafenib), however, show higher overall survival and tumour response in BRAF V600E mutated pLGGs than conventional therapies in some studies. To date, targeted therapy and precision medicine are promising avenues for paediatric gliomas with BRAF V600E and diffuse intrinsic pontine glioma with the H3K27M mutations. Given these shortcomings in the current treatments of paediatric gliomas, there is a dire need for novel therapies that yield a better therapeutic response. The present review discusses the diagnostic tools and the perspective of liquid biopsies in the detection of BRAF V600E and H3K27M mutations. An in-depth understanding of these biomarkers and the therapeutics associated with the respective challenges will bridge the gap between paediatric glioma patients and the development of effective therapies.

Matched MeSH terms: Proto-Oncogene Proteins B-raf
Fulltext Increased fucoxanthin in Chaetoceros calcitrans extract exacerbates apoptosis in liver cancer cells via multiple targeted cellular pathways

Foo SC, Yusoff FM, Imam MU, Foo JB, Ismail N, Azmi NH, et al.

Biotechnol Rep (Amst), 2019 Mar;21:e00296.
PMID: 30581767 DOI: 10.1016/j.btre.2018.e00296

In this study, anti-proliferative effects of C. calcitrans extract and its fucoxanthin rich fraction (FxRF) were assessed on human liver HepG2 cancer cell line. Efficacy from each extract was determined by cytotoxicity assay, morphological observation, and cell cycle analysis. Mechanisms of action observed were evaluated using multiplex gene expression analysis. Results showed that CME and FxRF induced cytotoxicity to HepG2 cells in a dose and time-dependent manner. FxRF (IC50: 18.89 μg.mL-1) was found to be significantly more potent than CME (IC50: 87.5 μg.mL-1) (p

Matched MeSH terms: Proto-Oncogene Proteins c-bcl-2
Fulltext K-Ras Peptide Mimotope Induces Antigen Specific Th1 and B-Cell Immune Responses against G12A-Mutated K-Ras Antigen in Balb/c Mice

Siak PY, Wong KY, Song AA, Rahim RA, In LLA

Vaccines (Basel), 2021 Feb 26;9(3).
PMID: 33652552 DOI: 10.3390/vaccines9030195

KRAS G12A somatic point mutation in adenocarcinomas is categorized clinically as ineligibility criteria for anti-epidermal growth factor receptor (EGFR) monoclonal antibody therapies. In this study, a modified G12A-K-ras epitope (139A) with sequence-specific modifications to improve immunogenicity was developed as a potential vaccine against G12A-mutant KRAS cancers. Additionally, coupling of the 139A epitope with a tetanus toxoid (TTD) universal T-cell epitope to improve antigenicity was also reported. To facilitate convenient oral administration, Lactococcus lactis, which possesses innate immunomodulatory properties, was chosen as a live gastrointestinal delivery vehicle. Recombinant L. lactis strains secreting a G12A mutated K-ras control and 139A with and without TTD fusion were generated for comparative immunogenicity assessment. BALB/c mice were immunized orally, and high survivability of L. lactis passage through the gastrointestinal tract was observed. Elevations in B-cell count with a concomitant titre of antigen-specific IgG and interferon-γ secreting T-cells were observed in the 139A treated mice group. Interestingly, an even higher antigen-specific IgA response and interferon-γ secreting T-cell counts were observed in 139A-TTD mice group upon re-stimulation with the G12A mutated K-ras antigen. Collectively, these results indicated that an antigen-specific immune response was successfully stimulated by 139A-TTD vaccine, and a TTD fusion was successful in further enhancing the immune responses.
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 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
Fulltext Tocotrienols and oxidative stress in ocytes and developing embryos

Yuhaniza Shafinie Kamsani, Mohd Hamim Rajikin

Journal of Clinical and Health Sciences, 2017;2:8-18.

This review summarizes the impact of tocotrienols (TCTs) as antioxidants in minimizing
oxidative stress (OS), particularly in embryos exposed to OS causing agents. OS level is
increased, for example, by nicotine, a major alkaloid content in cigarette, which is also a source
of exogenous reactive oxygen species (ROS). Increased nicotine-induced OS increases cell
stress response, which is a common trigger leading to embryonic cell death. Having more
profound anti-oxidative stress effects than its counterpart tocopherol, TCTs improve blastocyst
implantation, foetal growth, pregnancy outcome and survival of the neonates affected by
nicotine. In reversing cell developmental arrest caused by nicotine-induced OS, TCTs enhances
PDK-1 expression in the P13K/Akt pathway and permit embryonic development beyond the 4-
cell stage with the production of more morulae. At the cytoskeletal level, TCTs increase the
number of nicotine-induced apoptotic cells, through caspase 8 activation in the mitochondria.
TCTs facilitate rough endoplasmic reticulum (rER) stress-mediated apoptosis and autophagy,
resulting from nicotine-induced OS. Reduced vesicular population in TCT supplemented
oocytes on the other hand may suggest reduced secretion of apoptotic cell bodies thus probably
minimizing vesicular apoptosis during oocyte maturation. Further extensive research is
required to develop TCTs as a tool in specific therapeutic approaches to overcome the
detrimental effects of OS.

Matched MeSH terms: Proto-Oncogene Proteins c-akt
Fulltext Dietary Crocin is Protective in Pancreatic Cancer while Reducing Radiation-Induced Hepatic Oxidative Damage

Bakshi HA, Zoubi MSA, Hakkim FL, Aljabali AAA, Rabi FA, Hafiz AA, et al.

Nutrients, 2020 06 26;12(6).
PMID: 32604971 DOI: 10.3390/nu12061901

Pancreatic cancer is one of the fatal causes of global cancer-related deaths. Although surgery and chemotherapy are standard treatment options, post-treatment outcomes often end in a poor prognosis. In the present study, we investigated anti-pancreatic cancer and amelioration of radiation-induced oxidative damage by crocin. Crocin is a carotenoid isolated from the dietary herb saffron, a prospect for novel leads as an anti-cancer agent. Crocin significantly reduced cell viability of BXPC3 and Capan-2 by triggering caspase signaling via the downregulation of Bcl-2. It modulated the expression of cell cycle signaling proteins P53, P21, P27, CDK2, c-MYC, Cyt-c and P38. Concomitantly, crocin treatment-induced apoptosis by inducing the release of cytochrome c from mitochondria to cytosol. Microarray analysis of the expression signature of genes induced by crocin showed a substantial number of genes involved in cell signaling pathways and checkpoints (723) are significantly affected by crocin. In mice bearing pancreatic tumors, crocin significantly reduced tumor burden without a change in body weight. Additionally, it showed significant protection against radiation-induced hepatic oxidative damage, reduced the levels of hepatic toxicity and preserved liver morphology. These findings indicate that crocin has a potential role in the treatment, prevention and management of pancreatic cancer.

Matched MeSH terms: Proto-Oncogene Proteins c-bcl-2
Fulltext A Clinicopathologic Study of Seven Cases of Orbital Solitary Fibrous Tumours

Ting XW, Sothiraghagan S, W Md Kasim WM, Muhammed J

Cureus, 2020 May 24;12(5):e8259.
PMID: 32596077 DOI: 10.7759/cureus.8259

Objective To describe the patient demographics, clinical findings, investigations, surgical outcomes, and histopathological findings of seven cases of orbital solitary fibrous tumours. Method This was a retrospective review of seven cases of orbital solitary fibrous tumour, which were followed up in Hospital Serdang, a national oculoplastic centre, from years 2008-2017. Results This study included seven patients with ages between 21 and 35 years old; two were males and five were females. All seven patients presented with painless chronic unilateral proptosis. Radiological imaging of the orbit showed a localized contrast enhancing intraorbital mass. All patients underwent orbitotomy and excisional biopsy. Intraoperative findings showed a well-encapsulated and vascularized mass. Histological findings of spindle-shaped cells were noted. All cases had positive staining for cluster of differentiation (CD) 34, five were positive for CD 99, four were positive for B-cell lymphoma (BCL-2), and five patients had positive staining for S-100. Three of the patients did not have clear margins during the primary operation and subsequently had a recurrence within two years. Conclusion A solitary fibrous tumour is a rare mesenchymal tumour with a pleural origin. The orbit is the most common extrapleural site of the tumour and they are usually benign. Immunohistochemistry is important to differentiate it from other, more aggressive forms of orbital tumours. Regular follow-up is important to monitor for recurrence.

Matched MeSH terms: Proto-Oncogene Proteins c-bcl-2
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
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

Filters

Please provide feedback to Administrator (afdal@afpm.org.my)

External Links