Displaying publications 1 - 20 of 528 in total

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  1. Dahham SS, Tabana Y, Asif M, Ahmed M, Babu D, Hassan LE, et al.
    Int J Mol Sci, 2021 Sep 29;22(19).
    PMID: 34638895 DOI: 10.3390/ijms221910550
    Beta-Caryophyllene (BCP), a naturally occurring sesquiterpene abundantly found in cloves, hops, and cannabis, is the active candidate of a relatively new group of vascular-inhibiting compounds that aim to block existing tumor blood vessels. Previously, we have reported the anti-cancer properties of BCP by utilizing a series of in-vitro anti-tumor-related assays using human colorectal carcinoma cells. The present study aimed to investigate the effects of BCP on in-vitro, ex-vivo, and in-vivo models of anti-angiogenic assays and evaluate its anti-cancer activity in xenograft tumor (both ectopic and orthotopic) mice models of human colorectal cancer. Computational structural analysis and an apoptosis antibody array were also performed to understand the molecular players underlying this effect. BCP exhibited strong anti-angiogenic activity by blocking the migration of endothelial cells, tube-like network formation, suppression of vascular endothelial growth factor (VEGF) secretion from human umbilical vein endothelial cells and sprouting of rat aorta microvessels. BCP has a probable binding at Site#0 on the surface of VEGFR2. Moreover, BCP significantly deformed the vascularization architecture compared to the negative control in a chick embryo chorioallantoic membrane assay. BCP showed a remarkable reduction in tumor size and fluorescence molecular tomography signal intensity in all the mice treated with BCP, in a dose-dependent relationship, in ectopic and orthotopic tumor xenograft models, respectively. The histological analysis of the tumor from BCP-treated mice revealed a clear reduction of the density of vascularization. In addition, BCP induced apoptosis through downregulation of HSP60, HTRA, survivin, and XIAP, along with the upregulation of p21 expressions. These results suggest that BCP acts at multiple stages of angiogenesis and could be used as a promising therapeutic candidate to halt the growth of colorectal tumor cells.
  2. Yusof ENM, Latif MAM, Tahir MIM, Sakoff JA, Simone MI, Page AJ, et al.
    Int J Mol Sci, 2019 Feb 15;20(4).
    PMID: 30781445 DOI: 10.3390/ijms20040854
    Six new organotin(IV) compounds of Schiff bases derived from S-R-dithiocarbazate [R = benzyl (B), 2- or 4-methylbenzyl (2M and 4M, respectively)] condensed with 2-hydroxy-3-methoxybenzaldehyde (oVa) were synthesised and characterised by elemental analysis, various spectroscopic techniques including infrared, UV-vis, multinuclear (¹H, 13C, 119Sn) NMR and mass spectrometry, and single crystal X-ray diffraction. The organotin(IV) compounds were synthesised from the reaction of Ph₂SnCl₂ or Me₂SnCl₂ with the Schiff bases (S2MoVaH/S4MoVaH/SBoVaH) to form a total of six new organotin(IV) compounds that had a general formula of [R₂Sn(L)] (where L = Schiff base; R = Ph or Me). The molecular geometries of Me₂Sn(S2MoVa), Me₂Sn(S4MoVa) and Me₂Sn(SBoVa) were established by X-ray crystallography and verified using density functional theory calculations. Interestingly, each experimental structure contained two independent but chemically similar molecules in the crystallographic asymmetric unit. The coordination geometry for each molecule was defined by thiolate-sulphur, phenoxide-oxygen and imine-nitrogen atoms derived from a dinegative, tridentate dithiocarbazate ligand with the remaining positions occupied by the methyl-carbon atoms of the organo groups. In each case, the resulting five-coordinate C₂NOS geometry was almost exactly intermediate between ideal trigonal-bipyramidal and square-pyramidal geometries. The cytotoxic activities of the Schiff bases and organotin(IV) compounds were investigated against EJ-28 and RT-112 (bladder), HT29 (colon), U87 and SJ-G2 (glioblastoma), MCF-7 (breast) A2780 (ovarian), H460 (lung), A431 (skin), DU145 (prostate), BE2-C (neuroblastoma) and MIA (pancreatic) cancer cell lines and one normal breast cell line (MCF-10A). Diphenyltin(IV) compounds exhibited greater potency than either the Schiff bases or the respective dimethyltin(IV) compounds. Mechanistic studies on the action of these compounds against bladder cancer cells revealed that they induced the production of reactive oxygen species (ROS). The bladder cancer cells were apoptotic after 24 h post-treatment with the diphenyltin(IV) compounds. The interactions of the organotin(IV) compounds with calf thymus DNA (CT-DNA) were experimentally explored using UV-vis absorption spectroscopy. This study revealed that the organotin(IV) compounds have strong DNA binding affinity, verified via molecular docking simulations, which suggests that these organotin(IV) compounds interact with DNA via groove-binding interactions.
  3. Subach OM, Vlaskina AV, Agapova YK, Korzhenevskiy DA, Nikolaeva AY, Varizhuk AM, et al.
    Int J Mol Sci, 2022 Nov 23;23(23).
    PMID: 36498942 DOI: 10.3390/ijms232314614
    NTnC-like green fluorescent genetically encoded calcium indicators (GECIs) with two calcium ion binding sites were constructed using the insertion of truncated troponin C (TnC) from Opsanus tau into green fluorescent proteins (GFPs). These GECIs are small proteins containing the N- and C-termini of GFP; they exert a limited effect on the cellular free calcium ion concentration; and in contrast to calmodulin-based calcium indicators they lack undesired interactions with intracellular proteins in neurons. The available TnC-based NTnC or YTnC GECIs had either an inverted response and high brightness but a limited dynamic range or a positive response and fast kinetics in neurons but lower brightness and an enhanced but still limited dF/F dynamic range. Here, we solved the crystal structure of NTnC at 2.5 Å resolution. Based on this structure, we developed positive NTnC2 and inverted iNTnC2 GECIs with a large dF/F dynamic range in vitro but very slow rise and decay kinetics in neurons. To overcome their slow responsiveness, we swapped TnC from O. tau in NTnC2 with truncated troponin C proteins from the muscles of fast animals, namely, the falcon, hummingbird, cheetah, bat, rattlesnake, and ant, and then optimized the resulting constructs using directed molecular evolution. Characterization of the engineered variants using purified proteins, mammalian cells, and neuronal cultures revealed cNTnC GECI with truncated TnC from Calypte anna (hummingbird) to have the largest dF/F fluorescence response and fast dissociation kinetics in neuronal cultures. In addition, based on the insertion of truncated TnCs from fast animals into YTnC2, we developed fYTnC2 GECI with TnC from Falco peregrinus (falcon). The purified proteins cNTnC and fYTnC2 had 8- and 6-fold higher molecular brightness and 7- and 6-fold larger dF/F responses to the increase in Ca2+ ion concentration than YTnC, respectively. cNTnC GECI was also 4-fold more photostable than YTnC and fYTnC2 GECIs. Finally, we assessed the developed GECIs in primary mouse neuronal cultures stimulated with an external electric field; in these conditions, cNTnC had a 2.4-fold higher dF/F fluorescence response than YTnC and fYTnC2 and was the same or slightly slower (1.4-fold) than fYTnC2 and YTnC in the rise and decay half-times, respectively.
  4. Sasidharan S, Logeswaran S, Latha LY
    Int J Mol Sci, 2012;13(1):336-47.
    PMID: 22312255 DOI: 10.3390/ijms13010336
    Elaeis guineensis of the Arecaceae family is widely used in the traditional medicine of societies in West Africa for treating various ailments. To validate the ethnotherapeutic claims of the plant in skin diseases, wound healing activity was studied. The results showed that E. guineensis leaf extract had potent wound healing capacity as evident from the better wound closure (P < 0.05), improved tissue regeneration at the wound site, and supporting histopathological parameters pertaining to wound healing. Matrix metalloproteinases expression correlated well with the results thus confirming efficacy of E. guineensis in the treatment of the wound. E. guineensis accelerated wound healing in rats, thus supporting its traditional use. The result of this study suggested that, used efficiently, oil palm leaf extract is a renewable resource with wound healing properties.
  5. Soltani N, Saion E, Hussein MZ, Erfani M, Abedini A, Bahmanrokh G, et al.
    Int J Mol Sci, 2012;13(10):12242-58.
    PMID: 23202896 DOI: 10.3390/ijms131012242
    ZnS and CdS nanoparticles were prepared by a simple microwave irradiation method under mild conditions. The obtained nanoparticles were characterized by XRD, TEM and EDX. The results indicated that high purity of nanosized ZnS and CdS was successfully obtained with cubic and hexagonal crystalline structures, respectively. The band gap energies of ZnS and CdS nanoparticles were estimated using UV-visible absorption spectra to be about 4.22 and 2.64 eV, respectively. Photocatalytic degradation of methylene blue was carried out using physical mixtures of ZnS and CdS nanoparticles under a 500-W halogen lamp of visible light irradiation. The residual concentration of methylene blue solution was monitored using UV-visible absorption spectrometry. From the study of the variation in composition of ZnS:CdS, a composition of 1:4 (by weight) was found to be very efficient for degradation of methylene blue. In this case the degradation efficiency of the photocatalyst nanoparticles after 6 h irradiation time was about 73% with a reaction rate of 3.61 × 10-3 min-1. Higher degradation efficiency and reaction rate were achieved by increasing the amount of photocatalyst and initial pH of the solution.
  6. Ghanbari R, Anwar F, Alkharfy KM, Gilani AH, Saari N
    Int J Mol Sci, 2012;13(3):3291-3340.
    PMID: 22489153 DOI: 10.3390/ijms13033291
    The Olive tree (Olea europaea L.), a native of the Mediterranean basin and parts of Asia, is now widely cultivated in many other parts of the world for production of olive oil and table olives. Olive is a rich source of valuable nutrients and bioactives of medicinal and therapeutic interest. Olive fruit contains appreciable concentration, 1-3% of fresh pulp weight, of hydrophilic (phenolic acids, phenolic alchohols, flavonoids and secoiridoids) and lipophilic (cresols) phenolic compounds that are known to possess multiple biological activities such as antioxidant, anticarcinogenic, antiinflammatory, antimicrobial, antihypertensive, antidyslipidemic, cardiotonic, laxative, and antiplatelet. Other important compounds present in olive fruit are pectin, organic acids, and pigments. Virgin olive oil (VOO), extracted mechanically from the fruit, is also very popular for its nutritive and health-promoting potential, especially against cardiovascular disorders due to the presence of high levels of monounsaturates and other valuable minor components such as phenolics, phytosterols, tocopherols, carotenoids, chlorophyll and squalene. The cultivar, area of production, harvest time, and the processing techniques employed are some of the factors shown to influence the composition of olive fruit and olive oil. This review focuses comprehensively on the nutrients and high-value bioactives profile as well as medicinal and functional aspects of different parts of olives and its byproducts. Various factors affecting the composition of this food commodity of medicinal value are also discussed.
  7. Frimayanti N, Yam ML, Lee HB, Othman R, Zain SM, Rahman NA
    Int J Mol Sci, 2011;12(12):8626-44.
    PMID: 22272096 DOI: 10.3390/ijms12128626
    Photodynamic therapy is a relatively new treatment method for cancer which utilizes a combination of oxygen, a photosensitizer and light to generate reactive singlet oxygen that eradicates tumors via direct cell-killing, vasculature damage and engagement of the immune system. Most of photosensitizers that are in clinical and pre-clinical assessments, or those that are already approved for clinical use, are mainly based on cyclic tetrapyrroles. In an attempt to discover new effective photosensitizers, we report the use of the quantitative structure-activity relationship (QSAR) method to develop a model that could correlate the structural features of cyclic tetrapyrrole-based compounds with their photodynamic therapy (PDT) activity. In this study, a set of 36 porphyrin derivatives was used in the model development where 24 of these compounds were in the training set and the remaining 12 compounds were in the test set. The development of the QSAR model involved the use of the multiple linear regression analysis (MLRA) method. Based on the method, r(2) value, r(2) (CV) value and r(2) prediction value of 0.87, 0.71 and 0.70 were obtained. The QSAR model was also employed to predict the experimental compounds in an external test set. This external test set comprises 20 porphyrin-based compounds with experimental IC(50) values ranging from 0.39 μM to 7.04 μM. Thus the model showed good correlative and predictive ability, with a predictive correlation coefficient (r(2) prediction for external test set) of 0.52. The developed QSAR model was used to discover some compounds as new lead photosensitizers from this external test set.
  8. Kovanich D, Low TY, Zaccolo M
    Int J Mol Sci, 2023 Feb 28;24(5).
    PMID: 36902098 DOI: 10.3390/ijms24054667
    cAMP is a second messenger that regulates a myriad of cellular functions in response to multiple extracellular stimuli. New developments in the field have provided exciting insights into how cAMP utilizes compartmentalization to ensure specificity when the message conveyed to the cell by an extracellular stimulus is translated into the appropriate functional outcome. cAMP compartmentalization relies on the formation of local signaling domains where the subset of cAMP signaling effectors, regulators and targets involved in a specific cellular response cluster together. These domains are dynamic in nature and underpin the exacting spatiotemporal regulation of cAMP signaling. In this review, we focus on how the proteomics toolbox can be utilized to identify the molecular components of these domains and to define the dynamic cellular cAMP signaling landscape. From a therapeutic perspective, compiling data on compartmentalized cAMP signaling in physiological and pathological conditions will help define the signaling events underlying disease and may reveal domain-specific targets for the development of precision medicine interventions.
  9. Ghazali MS, Zakaria A, Rizwan Z, Kamari HM, Hashim M, Zaid MH, et al.
    Int J Mol Sci, 2011;12(3):1496-504.
    PMID: 21673903 DOI: 10.3390/ijms12031496
    The optical band-gap energy (E(g)) is an important feature of semiconductors which determines their applications in optoelectronics. Therefore, it is necessary to investigate the electronic states of ceramic ZnO and the effect of doped impurities under different processing conditions. E(g) of the ceramic ZnO + xBi(2)O(3) + xTiO(2), where x = 0.5 mol%, was determined using a UV-Vis spectrophotometer attached to a Reflectance Spectroscopy Accessory for powdered samples. The samples was prepared using the solid-state route and sintered at temperatures from 1140 to 1260 °C for 45 and 90 minutes. E(g) was observed to decrease with an increase of sintering temperature. XRD analysis indicated hexagonal ZnO and few small peaks of intergranular layers of secondary phases. The relative density of the sintered ceramics decreased and the average grain size increased with the increase of sintering temperature.
  10. Wan-Mohtar WAAQI, Ilham Z, Jamaludin AA, Rowan N
    Int J Mol Sci, 2021 Feb 07;22(4).
    PMID: 33562361 DOI: 10.3390/ijms22041675
    Natural mycelial exopolysaccharide (EPS) and endopolysaccharide (ENS) extracted from bioreactor-cultivated European Ganoderma applanatum mushrooms are of potential high commercial value for both food and adjacent biopharmaceutical industries. In order to evaluate their potential toxicity for aquaculture application, both EPS (0.01-10 mg/mL) and ENS (0.01-10 mg/mL) extracts were tested for Zebrafish Embryo Toxicity (ZFET); early development effects on Zebrafish Embryos (ZE) were also analyzed between 24 and 120 h post-fertilization (HPF). Both EPS and ENS are considered non-toxic with LC50 of 1.41 mg/mL and 0.87 mg/mL respectively. Both EPS and ENS did not delay hatching and teratogenic defect towards ZE with <1.0 mg/mL, respectively. No significant changes in the ZE heart rate were detected following treatment with the two compounds tested (EPS: 0.01-10 mg/mL: 176.44 ± 0.77 beats/min and ENS: 0.01-10 mg/mL: 148.44 ± 17.75 beats/min) compared to normal ZE (120-180 beats/min). These initial findings support future pre-clinical trials in adult fish models with view to safely using EPS and ENS as potential feed supplements for supplements for development of the aquaculture industry.
  11. Dek MSP, Padmanabhan P, Sherif S, Subramanian J, Paliyath AG
    Int J Mol Sci, 2017 Jul 15;18(7).
    PMID: 28714880 DOI: 10.3390/ijms18071533
    Phosphatidylinositol 3-kinase (PI3K) is a key enzyme that phosphorylates phosphatidylinositol at 3'-hydroxyl position of the inositol head group initiating the generation of several phosphorylated phosphatidylinositols, collectively referred to as phosphoinositides. The function of PI3K in plant senescence and ethylene signal transduction process was studied by expression ofSolanum lycopersicumPI3K in transgenicNicotiana tabacum, and delineating its effect on flower senescence. Detached flowers of transgenic tobacco plants with overexpressedSl-PI3K(OX) displayed accelerated senescence and reduced longevity, when compared to the flowers of wild type plants. Flowers from PI3K-overexpressing plants showed enhanced ethylene production and upregulated expression of 1-aminocyclopropane-1-carboxylic acid oxidase 1 (ACO1). Real time polymerase chain reaction (PCR) analysis showed thatPI3Kwas expressed at a higher level in OX flowers than in the control. Seedlings of OX-lines also demonstrated a triple response phenotype with characteristic exaggerated apical hook, shorter hypocotyls and increased sensitivity to 1-aminocyclopropane-1-carboxylate than the control wild type seedlings. In floral tissue from OX-lines,Solanum lycopersicumphosphatidylinositol 3-kinase green fluorescent protein (PI3K-GFP) chimera protein was localized primarily in stomata, potentially in cytoplasm and membrane adjacent to stomatal pores in the guard cells. Immunoblot analysis of PI3K expression in OX lines demonstrated increased protein level compared to the control. Results of the present study suggest that PI3K plays a crucial role in senescence by enhancing ethylene biosynthesis and signaling.
  12. Barathan M, Ng SL, Lokanathan Y, Ng MH, Law JX
    Int J Mol Sci, 2024 Mar 07;25(6).
    PMID: 38542054 DOI: 10.3390/ijms25063080
    This paper sheds light on the alarming issue of antibiotic resistance (ABR) in aquatic environments, exploring its detrimental effects on ecosystems and public health. It examines the multifaceted role of antibiotic use in aquaculture, agricultural runoff, and industrial waste in fostering the development and dissemination of resistant bacteria. The intricate interplay between various environmental factors, horizontal gene transfer, and bacterial extracellular vesicles (BEVs) in accelerating the spread of ABR is comprehensively discussed. Various BEVs carrying resistance genes like blaCTX-M, tetA, floR, and sul/I, as well as their contribution to the dominance of multidrug-resistant bacteria, are highlighted. The potential of BEVs as both a threat and a tool in combating ABR is explored, with promising strategies like targeted antimicrobial delivery systems and probiotic-derived EVs holding significant promise. This paper underscores the urgency of understanding the intricate interplay between BEVs and ABR in aquatic environments. By unraveling these unseen weapons, we pave the way for developing effective strategies to mitigate the spread of ABR, advocating for a multidisciplinary approach that includes stringent regulations, enhanced wastewater treatment, and the adoption of sustainable practices in aquaculture.
  13. Lim HX, Kim TS, Poh CL
    Int J Mol Sci, 2020 May 20;21(10).
    PMID: 32443699 DOI: 10.3390/ijms21103599
    There has been a great interest in myeloid-derived suppressor cells (MDSCs) due to their biological functions in tumor-mediated immune escape by suppressing antitumor immune responses. These cells arise from altered myelopoiesis in response to the tumor-derived factors. The most recognized function of MDSCs is suppressing anti-tumor immune responses by impairing T cell functions, and these cells are the most important players in cancer dissemination and metastasis. Therefore, understanding the factors and the mechanism of MDSC differentiation, expansion, and recruitment into the tumor microenvironment can lead to its control. However, most of the studies only defined MDSCs with no further characterization of granulocytic and monocytic subsets. In this review, we discuss the mechanisms by which specific MDSC subsets contribute to cancers. A better understanding of MDSC subset development and the specific molecular mechanism is needed to identify treatment targets. The understanding of the specific molecular mechanisms responsible for MDSC accumulation would enable more precise therapeutic targeting of these cells.
  14. Heng WS, Kruyt FAE, Cheah SC
    Int J Mol Sci, 2021 May 27;22(11).
    PMID: 34071790 DOI: 10.3390/ijms22115697
    Lung cancer is still one of the deadliest cancers, with over two million incidences annually. Prevention is regarded as the most efficient way to reduce both the incidence and death figures. Nevertheless, treatment should still be improved, particularly in addressing therapeutic resistance due to cancer stem cells-the assumed drivers of tumor initiation and progression. Phytochemicals in plant-based diets are thought to contribute substantially to lung cancer prevention and may be efficacious for targeting lung cancer stem cells. In this review, we collect recent literature on lung homeostasis, carcinogenesis, and phytochemicals studied in lung cancers. We provide a comprehensive overview of how normal lung tissue operates and relate it with lung carcinogenesis to redefine better targets for lung cancer stem cells. Nine well-studied phytochemical compounds, namely curcumin, resveratrol, quercetin, epigallocatechin-3-gallate, luteolin, sulforaphane, berberine, genistein, and capsaicin, are discussed in terms of their chemopreventive and anticancer mechanisms in lung cancer and potential use in the clinic. How the use of phytochemicals can be improved by structural manipulations, targeted delivery, concentration adjustments, and combinatorial treatments is also highlighted. We propose that lung carcinomas should be treated differently based on their respective cellular origins. Targeting quiescence-inducing, inflammation-dampening, or reactive oxygen species-balancing pathways appears particularly interesting.
  15. Lee CY, Huang CH, Rastegari E, Rengganaten V, Liu PC, Tsai PH, et al.
    Int J Mol Sci, 2021 Sep 13;22(18).
    PMID: 34576032 DOI: 10.3390/ijms22189869
    The coronavirus disease 2019 (COVID-19) pandemic with high infectivity and mortality has caused severe social and economic impacts worldwide. Growing reports of COVID-19 patients with multi-organ damage indicated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) may also disturb the cardiovascular system. Herein, we used human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iCMs) as the in vitro platform to examine the consequence of SARS-CoV2 infection on iCMs. Differentiated iCMs expressed the primary SARS-CoV2 receptor angiotensin-converting enzyme-II (ACE2) and the transmembrane protease serine type 2 (TMPRSS2) receptor suggesting the susceptibility of iCMs to SARS-CoV2. Following the infection of iCMs with SARS-CoV2, the viral nucleocapsid (N) protein was detected in the host cells, demonstrating the successful infection. Bioinformatics analysis revealed that the SARS-CoV2 infection upregulates several inflammation-related genes, including the proinflammatory cytokine tumor necrosis factor-α (TNF-α). The pretreatment of iCMs with TNF-α for 24 h, significantly increased the expression of ACE2 and TMPRSS2, SASR-CoV2 entry receptors. The TNF-α pretreatment enhanced the entry of GFP-expressing SARS-CoV2 pseudovirus into iCMs, and the neutralization of TNF-α ameliorated the TNF-α-enhanced viral entry. Collectively, SARS-CoV2 elevated TNF-α expression, which in turn enhanced the SARS-CoV2 viral entry. Our findings suggest that, TNF-α may participate in the cytokine storm and aggravate the myocardial damage in COVID-19 patients.
  16. Lin Lin Lee V, Kar Meng Choo B, Chung YS, P Kundap U, Kumari Y, Shaikh MF
    Int J Mol Sci, 2018 Mar 15;19(3).
    PMID: 29543761 DOI: 10.3390/ijms19030871
    Metabolic epilepsy is a metabolic abnormality which is associated with an increased risk of epilepsy development in affected individuals. Commonly used antiepileptic drugs are typically ineffective against metabolic epilepsy as they do not address its root cause. Presently, there is no review available which summarizes all the treatment options for metabolic epilepsy. Thus, we systematically reviewed literature which reported on the treatment, therapy and management of metabolic epilepsy from four databases, namely PubMed, Springer, Scopus and ScienceDirect. After applying our inclusion and exclusion criteria as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we reviewed a total of 43 articles. Based on the reviewed articles, we summarized the methods used for the treatment, therapy and management of metabolic epilepsy. These methods were tailored to address the root causes of the metabolic disturbances rather than targeting the epilepsy phenotype alone. Diet modification and dietary supplementation, alone or in combination with antiepileptic drugs, are used in tackling the different types of metabolic epilepsy. Identification, treatment, therapy and management of the underlying metabolic derangements can improve behavior, cognitive function and reduce seizure frequency and/or severity in patients.
  17. Farhana A, Koh AE, Kothandan S, Alsrhani A, Mok PL, Subbiah SK
    Int J Mol Sci, 2021 Nov 13;22(22).
    PMID: 34830168 DOI: 10.3390/ijms222212286
    Cancer cells are able to proliferate in an unregulated manner. There are several mechanisms involved that propel such neoplastic transformations. One of these processes involves bypassing cell death through changes in gene expression and, consequently, cell growth. This involves a complex epigenetic interaction within the cell, which drives it towards oncogenic transformations. These epigenetic events augment cellular growth by potentially altering chromatin structures and influencing key gene expressions. Therapeutic mechanisms have been developed to combat this by taking advantage of the underlying oncogenic mechanisms through chemical modulation. Camptothecin (CPT) is an example of this type of drug. It is a selective topoisomerase I inhibitor that is effective against many cancers, such as colorectal cancer. Previously, we successfully formulated a magnetic nanocarrier-conjugated CPT with β-cyclodextrin and iron NPs (Fe3O4) cross-linked using EDTA (CPT-CEF). Compared to CPT alone, it boasts higher efficacy due to its selective targeting and increased solubility. In this study, we treated HT29 colon cancer cells with CPT-CEF and attempted to investigate the cytotoxic effects of the formulation through an epigenetic perspective. By using RNA-Seq, several differentially expressed genes were obtained (p < 0.05). Enrichr was then used for the over-representation analysis, and the genes were compared to the epigenetic roadmap and histone modification database. The results showed that the DEGs had a high correlation with epigenetic modifications involving histone H3 acetylation. Furthermore, a subset of these genes was shown to be associated with the Wnt/β-catenin signaling pathway, which is highly upregulated in a large number of cancer cells. These genes could be investigated as downstream therapeutic targets against the uncontrolled proliferation of cancer cells. Further interaction analysis of the identified genes with the key genes of the Wnt/β-catenin signaling pathway in colorectal cancer identified the direct interactors and a few transcription regulators. Further analysis in cBioPortal confirmed their genetic alterations and their distribution across patient samples. Thus, the findings of this study reveal that colorectal cancer could be reversed by treatment with the CPT-CEF nanoparticle-conjugated nanocarrier through an epigenetic mechanism.
  18. Mat Razali N, Cheah BH, Nadarajah K
    Int J Mol Sci, 2019 Jul 23;20(14).
    PMID: 31340492 DOI: 10.3390/ijms20143597
    Transposable elements (TEs) are agents of genetic variability in phytopathogens as they are a source of adaptive evolution through genome diversification. Although many studies have uncovered information on TEs, the exact mechanism behind TE-induced changes within the genome remains poorly understood. Furthermore, convergent trends towards bigger genomes, emergence of novel genes and gain or loss of genes implicate a TE-regulated genome plasticity of fungal phytopathogens. TEs are able to alter gene expression by revamping the cis-regulatory elements or recruiting epigenetic control. Recent findings show that TEs recruit epigenetic control on the expression of effector genes as part of the coordinated infection strategy. In addition to genome plasticity and diversity, fungal pathogenicity is an area of economic concern. A survey of TE distribution suggests that their proximity to pathogenicity genes TEs may act as sites for emergence of novel pathogenicity factors via nucleotide changes and expansion or reduction of the gene family. Through a systematic survey of literature, we were able to conclude that the role of TEs in fungi is wide: ranging from genome plasticity, pathogenicity to adaptive behavior in evolution. This review also identifies the gaps in knowledge that requires further elucidation for a better understanding of TEs' contribution to genome architecture and versatility.
  19. Pinheiro TDM, Rego ECS, Alves GSC, Fonseca FCA, Cotta MG, Antonino JD, et al.
    Int J Mol Sci, 2022 Nov 05;23(21).
    PMID: 36362377 DOI: 10.3390/ijms232113589
    Banana (Musa spp.), which is one of the world's most popular and most traded fruits, is highly susceptible to pests and diseases. Pseudocercospora musae, responsible for Sigatoka leaf spot disease, is a principal fungal pathogen of Musa spp., resulting in serious economic damage to cultivars in the Cavendish subgroup. The aim of this study was to characterize genetic components of the early immune response to P. musae in Musa acuminata subsp. burmannicoides, var. Calcutta 4, a resistant wild diploid. Leaf RNA samples were extracted from Calcutta 4 three days after inoculation with fungal conidiospores, with paired-end sequencing conducted in inoculated and non-inoculated controls using lllumina HiSeq 4000 technology. Following mapping to the reference M. acuminata ssp. malaccensis var. Pahang genome, differentially expressed genes (DEGs) were identified and expression representation analyzed on the basis of gene ontology enrichment, Kyoto Encyclopedia of Genes and Genomes orthology and MapMan pathway analysis. Sequence data mapped to 29,757 gene transcript models in the reference Musa genome. A total of 1073 DEGs were identified in pathogen-inoculated cDNA libraries, in comparison to non-inoculated controls, with 32% overexpressed. GO enrichment analysis revealed common assignment to terms that included chitin binding, chitinase activity, pattern binding, oxidoreductase activity and transcription factor (TF) activity. Allocation to KEGG pathways revealed DEGs associated with environmental information processing, signaling, biosynthesis of secondary metabolites, and metabolism of terpenoids and polyketides. With 144 up-regulated DEGs potentially involved in biotic stress response pathways, including genes involved in cell wall reinforcement, PTI responses, TF regulation, phytohormone signaling and secondary metabolism, data demonstrated diverse early-stage defense responses to P. musae. With increased understanding of the defense responses occurring during the incompatible interaction in resistant Calcutta 4, these data are appropriate for the development of effective disease management approaches based on genetic improvement through introgression of candidate genes in superior cultivars.
  20. Qu D, Show PL, Miao X
    Int J Mol Sci, 2021 Feb 27;22(5).
    PMID: 33673599 DOI: 10.3390/ijms22052387
    Saline-alkali soil has become an important environmental problem for crop productivity. One of the most effective approaches is to cultivate new stress-tolerant plants through genetic engineering. Through RNA-seq analysis and RT-PCR validation, a novel bZIP transcription factor ChbZIP1, which is significantly upregulated at alkali conditions, was obtained from alkaliphilic microalgae Chlorella sp. BLD. Overexpression of ChbZIP1 in Saccharomyces cerevisiae and Arabidopsis increased their alkali resistance, indicating ChbZIP1 may play important roles in alkali stress response. Through subcellular localization and transcriptional activation activity analyses, we found that ChbZIP1 is a nuclear-localized bZIP TF with transactivation activity to bind with the motif of G-box 2 (TGACGT). Functional analysis found that genes such as GPX1, DOX1, CAT2, and EMB, which contained G-box 2 and were associated with oxidative stress, were significantly upregulated in Arabidopsis with ChbZIP1 overexpression. The antioxidant ability was also enhanced in transgenic Arabidopsis. These results indicate that ChbZIP1 might mediate plant adaptation to alkali stress through the active oxygen detoxification pathway. Thus, ChbZIP1 may contribute to genetically improving plants' tolerance to alkali stress.
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