A cable model that includes polarization-induced capacitive current is derived for modeling the solitonic conduction of electrotonic potentials in neuronal branchlets with microstructure containing endoplasmic membranes. A solution of the nonlinear cable equation modified for fissured intracellular medium with a source term representing charge 'soakage' is used to show how intracellular capacitive effects of bound electrical charges within mitochondrial membranes can influence electrotonic signals expressed as solitary waves. The elastic collision resulting from a head-on collision of two solitary waves results in localized and non-dispersing electrical solitons created by the nonlinearity of the source term. It has been shown that solitons in neurons with mitochondrial membrane and quasi-electrostatic interactions of charges held by the microstructure (i.e., charge 'soakage') have a slower velocity of propagation compared with solitons in neurons with microstructure, but without endoplasmic membranes. When the equilibrium potential is a small deviation from rest, the nonohmic conductance acts as a leaky channel and the solitons are small compared when the equilibrium potential is large and the outer mitochondrial membrane acts as an amplifier, boosting the amplitude of the endogenously generated solitons. These findings demonstrate a functional role of quasi-electrostatic interactions of bound electrical charges held by microstructure for sustaining solitons with robust self-regulation in their amplitude through changes in the mitochondrial membrane equilibrium potential. The implication of our results indicate that a phenomenological description of ionic current can be successfully modeled with displacement current in Maxwell's equations as a conduction process involving quasi-electrostatic interactions without the inclusion of diffusive current. This is the first study in which solitonic conduction of electrotonic potentials are generated by polarization-induced capacitive current in microstructure and nonohmic mitochondrial membrane current.
Photobiomodulation (PBM) is a non-plant-cell manipulation through a transfer of energy by means of light sources at the non-ablative or thermal intensity. Authors showed that cytochrome-c-oxidase (complex IV) is the specific chromophore's target of PBM at the red (600-700 nm) and NIR (760-900 nm) wavelength regions. Recently, it was suggested that the infrared region of the spectrum could influence other chromospheres, despite the interaction by wavelengths higher than 900 nm with mitochondrial chromophores was not clearly demonstrated. We characterized the interaction between mitochondria respiratory chain, malate dehydrogenase, a key enzyme of Krebs cycle, and 3-hydroxyacyl-CoA dehydrogenase, an enzyme involved in the β-oxidation (two mitochondrial matrix enzymes) with the 1064 nm Nd:YAG (100mps and 10 Hz frequency mode) irradiated at the average power density of 0.50, 0.75, 1.00, 1.25 and 1.50 W/cm2 to generate the respective fluences of 30, 45, 60, 75 and 90 J/cm2 . Our results show the effect of laser light on the transmembrane mitochondrial complexes I, III, IV and V (adenosine triphosphate synthase) (window effects), but not on the extrinsic mitochondrial membrane complex II and mitochondria matrix enzymes. The effect is not due to macroscopical thermal change. An interaction of this wavelength with the Fe-S proteins and Cu-centers of respiratory complexes and with the water molecules could be supposed.
The tumour suppressor gene p53 and the proto-oncogene Bcl-2 encode respectively, for a nuclear phosphoprotein and for a mitochondrial membrane protein involved in multiple cellular functions. Both proteins are linked to programmed cell death pathways and provide prognostic information on breast carcinoma. Our aim is to study the expression of p53 and Bcl-2 oncoproteins in breast carcinoma and correlate with patients’ age, tumour size, disease stage and histological grade. Fifty nine cases of breast carcinomas from Universiti Kebangsaan Malaysia Medical Centre (UKMMC) were studied with the immunohistochemical method. Our results showed 45.8% (27 of 59) and 40.7% (24 of 59) of the breast carcinomas were immunopositive for p53 and Bcl-2 respectively. There was significant correlation between Bcl-2 expression with early tumour stage (p=0.01). No significant relationship was seen with other variables. Results also showed an inverse relationship between p53 and Bcl-2 expression (p=0.001). These findings indicate a down regulation of Bcl-2 by p53 in breast carcinogenesis.
Tualang honey (TH) is rich in flavonoids and phenolic acids and has significant anticancer activity against breast cancer cells comparable to the effect of tamoxifen (TAM), in vitro. The current study evaluated the effects of TH when used in combination with TAM on MCF-7 and MDA-MB-231 cells. We observed that TH promoted the anticancer activity of TAM in both the estrogen receptor-(ER-)responsive and ER-nonresponsive human breast cancer cell lines. Flow cytometric analyses indicated accelerated apoptosis especially in MDA-MB-231 cells and with the involvement of caspase-3/7, -8 and -9 activation as shown by fluorescence microscopy. Depolarization of the mitochondrial membrane was also increased in both cell lines when TH was used in combination with TAM compared to TAM treatment alone. TH may therefore be a potential adjuvant to be used with TAM for reducing the dose of TAM, hence, reducing TAM-induced adverse effects.
OBJECTIVES: To investigate the cytotoxic effect of anastrozole on breast (MCF7), liver hepatocellular (HepG2), and prostate (PC3) cancer cells. Methods: This is a prospective study. Anastrozole's mechanism of apoptosis in living cells was also determined by high content screening (HCS) assay. Methylthiazol tetrazolium (MTT) assay was carried out at the Centre of Biotechnology Research's, Al-Nahrain University, Baghdad, Iraq between July 2015 and October 2015. The HCS assay was performed at the Centre for Natural Product Research and Drug Discovery, Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia between November 2015 and February 2016. Results: The most significant cytotoxic effect of anastrozole towards 3 cancer cell lines was obtained when its concentration was 400 µg/mL. The MCF7 cells were more sensitive to anastrozole compared with the HepG2 and PC-3 cells. There was a significant increase in membrane permeability, cytochrome c and nuclear intensity when anastrozole (200 µg/mL) was used compared with doxorubicin (20 µg/mL) as a standard. Also, there was a significant decrease in cell viability and mitochondrial membrane permeability when anastrozole (200 µg/mL) was used compared with positive control. Conclusion: Anastrozole showed cytotoxic effects against the MCF7, HepG2, and PC3 cell lines as determined in-vitro by the MTT assay. The HCS technique also showed toxic effect towards MCF7. It is evident that anastrozole inhibits the aromatase enzyme preventing the aromatization mechanism; however, it has a toxic effect.
Cruciferous vegetable consumption correlates with reduced risk of cancer. This chemopreventative activity may involve glucosinolates and their hydrolysis products. Glucosinolate-derived isothiocyanates have been studied for their toxicity and chemopreventative properties, but other hydrolysis products (epithionitriles and nitriles) have not been thoroughly examined. We report that these hydrolysis products differ in their cytotoxicity to human cells, with toxicity most strongly associated with isothiocyanates rather than epithionitriles and nitriles. We explored mechanisms of this differential cytotoxicity by examining the role of oxidative metabolism, oxidative stress, mitochondrial permeability, reduced glutathione levels, cell cycle arrest and apoptosis. 2-Propenylisothiocyanate and 3-butenylisothiocyanate both inhibited cytochome P450 1A (CYP1A) enzyme activity in CYP expressing MCL-5 cells at high cytotoxic doses. Incubation of MCL-5 cells with non-cytotoxic doses of 2-propenylisothiocyanate for 24h resulted in a dose-dependent inhibition of ethoxyresorufin O-deethylase, yet failed to affect CYP1A1 mRNA expression indicating interference with enzyme activity rather than inhibition of transcription. Increased reactive oxygen species (ROS) production was observed only for 2-propenylisothiocyanate treatment. 2-Propenylisothiocyanate treatment lowered reduced glutathione levels whereas no changes were noted with 3,4-epithiobutylnitrile. Cell cycle analysis showed that 2-propenylisothiocyanate induced a G2/M block whereas other hydrolysis products showed only marginal effects. We found that 2-propenylisothiocyanate and 3-butenylisothiocyanate induced cell death predominantly via necrosis whereas, 3,4-epithiobutylnitrile promoted both necrosis and apoptosis. Thus the activity of glucosinolate hydrolysis products includes cytotoxicity that is compound-class specific and may contribute to their putative chemoprotection properties.
14-Deoxy-11,12-didehydroandrographolide (14-DDA), a major diterpenoid isolated from Andrographis paniculata (Burm.f.) Nees, is known to be cytotoxic and elicits a non-apoptotic cell death in T-47D breast carcinoma cells. In this study, the mechanistic toxicology properties of 14-DDA in T-47D cells were further investigated. 14-DDA is found to induce the formation of endoplasmic reticulum (ER) vacuoles and autophagosomes, with concurrent upregulation of LC3-II in the breast carcinoma cells. It stimulated an increase in cytosolic calcium concentration and caused a collapse in mitochondrial membrane potential in these cells. In addition, both DDIT3 and GADD45A, molecules implicated in ER stress pathway, were significantly upregulated. DDIT3 knockdown suppressed the formation of both ER vacuoles and autophagosomes, indicating that 14-DDA-induced ER stress and autophagy is dependent on this transcription factor. Collectively, it is possible that GADD45A/p38 MAPK/DDIT3 pathway is involved in the 14-DDA-induced ER-stress-mediated autophagy in T-47D cells.
The use of honey as a therapeutic agent dates back at 8000 years and has markedly increased interest into its potential
health benefits. The by-products of the flower nectar have a complex chemical composition which promotes benefits in
underlying mechanism of human diseases. Malaysian Tualang Honey (MTH) is a multifloral jungle honey produced by
the rock bee (Apis dorsata). This review consolidates the results of carious studies involving biochemical assays of tissue
culture and animal trials of anti-cancer properties of MTH. Often studied in the context of breast cancer cell lines, MTH
has promising data for possible mechanisms in anti-cancer activity. These include apoptosis via depolarization of the
mitochondrial membrane, caspase-dependent apoptosis, reduction of angiogenesis and the promotion of cell cycle arrest
without posing cytotoxic effect on normal cell lines. Despite positive outcomes in tissue cultures, the oral administration
of MTH in breast cancer animal models showed slower tumour progression, reduction in tumour size and better grading
of histological features. The alleviation of breast carcinogenesis via modulation of hematologic, estrogenic and apoptotic
activities promotes MTH as a promising anticancer agent. With confidence in a conclusion that MTH is a useful treatment
for cancer, further experimental and clinical studies should be conducted.
Medicinal plants become very important in our days for their therapeutic benefits to humankind. It sustains human health, and it is commonly known as herbal medicines since ancient times. Annona muricata is a heart-shaped fruit that is consumed raw or as the fruit juice in the tropical area. A. muricata is used in traditional and alternative medicine to treat different ailments such as diabetes, hypertension, respiratory and skin illness, inflammation and cancer. A. muricata contains essential anticancer agents named acetogenins that play the significant role in various cancer types. Acetogenins are strong nicotinamide adenine dinucleotide oxidase inhibitors of the cancer cell's mitochondrial membrane but showed neurotoxic effects in rats. Therefore, acetogenins need to be further investigated to determine the exact mechanisms of action, long-term safety, optimal dosage, and potential side effects. Given the extensive studies on A. muricata, this review focuses on the phytochemistry, medicinal uses, biological activities and the mechanisms of action for the fruit extracts and acetogenins, to stimulate further studies on the fruit pulp used for human consumption.