Stochastic modelling of cancer cell proliferation and death in response to anticancer therapeutics of thymoquinone

Recent studies have revealed the role of Thymoquinone (TQ) as an active ingredient of black seed (Nigella Sativa) in apoptotic activities. TQ induced apoptotic (the program cell death) can modulate cell life and death, hence able to provide therapeutic potential in cancer disease. The biological mechanism of apoptotic induced by TQ is not yet fully understood. Mathematical model is useful in promoting effective knowledge about the effects of TQ in cancer proliferation and apoptotic activities. It provides an insightful way to explore and predict the growth of the cancer as well as the response to therapy. Furthermore, the cancer cell proliferation is subjected to uncontrolled factors, referred as white noise. Stochastic model provides a way to describe the process. Although potentially useful, no stochastic model has been formulated to represent the growth of cancer affected by anticancer therapeutic of TQ and apoptotic activities. This research is aimed to formulate a system of stochastic differential equations (SDEs) for the apoptosis process in signalling pathways of cancer cell proliferation and death in response to TQ. To achieve this objective, the logistic and Gompertz growth laws of population dynamics were included in the prey-predator model to form a deterministic model of ordinary differential equations (ODEs). Therefore, the deterministic form of logistic prey-predator and Gompertz prey-predator was developed to model the cancer cells proliferation (prey) in the presence of TQ. TQ was also recruited by the cancer cells through a Michaelis-Menten law which provided the saturation effect in the predator of the equation. The models were extended to their stochastic counterpart with the inclusion of the Wiener process to the kinetic growth rate parameters of cancer cells and TQ. The qualitative dynamic of the logistic and Gompertz prey-predator models had shown that the model possesses the properties of positive solution. Cancer cells would grow to the equilibrium point of the treatment failure, but under the success of treatment, the cancer cells would shrink to the equilibrium points of the treatment. Deterministic and stochastic models were simulated, and the results were compared with the experimental data of HSC-3 and HSC-4 lines. Laboratory experiment of TQ in response to cancer cell was carried out in International Islamic University Malaysia (IIUM) laboratory and the experimental data were used to validate the model. The simulated results of the deterministic and stochastic models were consistent with the experimental data and low values of root mean square error (RMSE) in SDEs model. This indicated good fit of the SDEs in modelling the proliferation of the cancer cells in the presence of TQ. Modelling of the system was extended to the mechanism of the apoptotic signalling pathway for cancer cells in the presence of TQ. Two pathways, which are the intrinsic mitochondrial pathway that promotes the activation of the Caspase 3 (pathway 1) and the intrinsic mitochondrial pathway that promotes the activation of the Caspase 10 (pathway 2) had been identified. The kinetic reaction of those pathways has been developed and mathematical model of a system of ODEs was constructed based on the biochemical kinetic reactions of the pathways 1 and 2. Then, the perturbation was performed through the kinetic rate parameters of external growth factor rate (EGFR) and apoptosis to form a system of SDEs. In this research, the kinetics parameter was estimated using Markov Chain Monte Carlo Method (MCMC). Numerical method of 4-stage stochastic Runge-Kutta (SRK4) was employed to simulate the solution of SDEs. The results showed that as the TQ reacted with EGFR, the activation of Caspase family for intrinsic pathways 1 and 2, led to the activation of the apoptosis mechanism. It was consistent with the results of the experimentation and modelling of the cancer size under treatment using two equations model, which was apoptosis mechanism (increasing trend in the amount of protein) that vi shrank the size of the cancer cells. The newly developed stochastic model can help oncologists to understand the physical and biological barriers in apoptotic activities of anticancer therapeutic. The model can be used to predict the growth of cancer affected by TQ accurately and subsequently help to plan better treatment strategies for cancer

Parameter estimation of the stochastic model for oral cancer in response to thymoquinone (TQ) as anticancer therapeutics

Oral Cancer is considered as one of the common problems of global public health and despite the progress in advanced research, the mortality rate has not been improved significantly in the last few decades. A natural product such as Thymoquinone, black seeds (TQ), is an active component of Nigella sativa or black cumin elicits cytotoxic effects on various oral cancer cell lines. A wide range of studies have been concluded that the TQ has two different anti-neoplastic actions that might trigger apoptosis, have the capacity to induce cell death in oral cancer cells. In the presence of TQ, oral cancer has been proved experimentally shows the decelerating trend of the growth. This article models the decelerating of the oral cancer growth by using a linear stochastic differential equation (SDEs). The Markov Chain Monte Carlo (MCMC) method used to estimate model parameters for 100, 500,1000 and 2000 simulations. The best set of kinetic parameters are identified. It can be seen that for 1000 simulations of the sample paths, the model fitted well the data, hence indicating a good fit. However, if the number of simulation is increasing up to 2000, the parameter obtained shows instability of the solution. This is due to the high numbers of noise generated, may influenced the stability of the solution

High methoxyl pectin extracts from hylocereus polyrhizus's peels: Extraction kinetics and thermodynamic studies

The effect of physicochemical treatment on pectin yield, degree of esterification, along with the kinetics and thermodynamics characteristics was investigated in the present study. Several extraction parameters were observed to have impacted the yield and degree of esterification significantly, and the best extraction condition was as follows: agitation rate of 250 rpm, temperature of 70 °C, extraction time of 120 min, pH 2, and liquid to solid ratio of 10 v/w which has resulted in 28.20% of pectin yield, with DE (degree of esterification) of 57.00%. A theoretical model which describes the extractability, dissolution and degradation rate of pectin to predict the maximal yield at the maximal time was established to study the extraction kinetics of pectin from HPP. The kinetic analysis from Panchev's model shows the extraction rate was found highest at LSR 10 with ymax 30.85%. The calculated activation energy for pectin dissolution and degradation was found to be 4.532 kJ/mol and 28.054 kJ/mol, respectively. The thermodynamic study has suggested that the process was endothermic, spontaneous and reversible. These results suggest that the physical and chemical treatment applied could be an efficient technique for the extraction of pectin from Hylocereus polyrhizus peels

Thymoquinone and its pharmacological perspective: A review

Thymoquinone (TQ) a plant-derived dietary of Nigella sativa, is a well-known traditionally and clinically used natural medicine. The diverse pharmacological properties of TQ have been identified including antimicrobial, antihistamine, antioxidant effects, immunomodulator, and anticancer activities. In this review, investigations regarding the effects of TQ in oxidative stress, immunomodulation, and various type of cancer have been reviewed based on the available relevant literature. TQ-based induction of the immune system by modulating different inflammatory mediators i.e., cytokines, leukins, interleukins, interferons, and other immune cells have been reviewed here. Several studies signified remarkable anticancer potentials of TQ depending upon its concentration and type of cancer cell. Conclusively, understanding pharmacological activities of TQ its molecular mechanism could help researchers to develop a potent analog of well-established chemotherapeutic drugs in clinical trials

Stochastic modelling of the oral cancer proliferation and death in the presence of Thymoquinone as anticancer therapeutics

Oral cancer is one of the most commonly known cancer worldwide. Thymoquinone (TQ) an extract from Nigella sativa, has clinically been proven as an anticancer therapeutic agent for oral cancer due to its intrinsic pharmacological characteristics. Understanding the mechanisms of oral cancer proliferation and death in the presence of TQ is crucial so that the insight of the interaction of cancer cells and TQ can be discovered. Cancer cells in the presence of TQ is subjected to the uncontrolled factors of the environmental noise. Deterministic model is inadequate to explain this behaviour. Herein, a stochastic model is proposed to illustrate the dynamics of HSC-3 oral cancer cell lines in the presence of TQ. The deterministic model is perturbed with the noisy behaviour which then leads to the stochastic model. The model is simulated by using a four-stage stochastic Runge-Kutta (SRK4) method and the kinetic parameters are estimated by using the maximum likelihood estimation (MLE) method. The prediction quality of the model is measured by using root mean square error (RMSE). The low values of RMSE show the best-fit of the stochastic model

Green biosynthesis of silver nanoparticles (AgNPs) FROM Vitex negundo plant extract and its phytochemical screening and antimicrobial assessment next to pathogenic microbes

In the present study, green synthesis of silver-nanoparticle (AgNPs) is demonstrated using plant extract of Vitex negundo. Plant extract through six different solvents, including petroleum ether, benzene, chloroform, acetone, methanol, and water, was prepared and further investigated for its antimicrobial and antifungal activities using different bacterial and fungal strains. The phytochemical analysis was performed, where saponins, tannins, steroids, flavonoids and glycosides were detected in acetone, chloroform and methanolic extract. Subsequent analysis of synthesized AgNPs through dynamic light scattering suggested that particle sizes were 10-300 nm in size. The study indicated that the chloroform, acetone, and methanol extracts of Vitex negundo showed good inhibitory activity against Staphylococcus aureus, Pseudomonas aeruginosa, Bacillus subtilis based on the zone of inhibition. The antimicrobial activity of the synthesized AgNPs suggested that it can inhibit the growth of both gram +ve and gram -ve microorganisms. The MIC value of AgNPs of methanolic extract of V. negundo detected was 0.078 mg/mL, which was relatively lower than that of the MIC value of its crude extract (1.25mg/mL). The observed MIC values concluded that the synthesized AgNPs had better antimicrobial activity and could be necessary for various applications, including medicine, biology, and industr

Therapeutic implications of thymoquinone and its molecular and functional mechanisms against oral and lung cancer

Thymoquinone, a bioactive component of the black seed of Nigella sativa, has received great attention from researchers due to its wide spectrum of pharmacological potentials. The present review highlights the molecular and functional mechanisms of thymoquinone serving as a therapeutic molecule combating oral and lung cancer by following the most recent literature. This summarized the latest nanotechnological interventions enhancing the efficacy and availability of thymoquinone in the in-vitro and in-vivo cancer models. Thymoquinone exhibits a significantly promising anticancer effect against oral and lung cancer by prompting intrinsic and extrinsic pathways of apoptosis through the activation of different caspases cascades, up and downregulation of apoptotic genes, antitumor cell proliferation, ROS regulation, etc. The accomplished insight into molecular and functional mechanisms of thymoquinone particularly combating oral and lung cancer will provide a better understanding and exploration of thymoquinone in an ethnopharmacological context

Production and Partial Characterization of Protease from Aspergillus Flavus using Rice Mill Waste as a Substrate and its Comparision with Aspergillus Niger Protease

Abstract Proteases are one of the most important groups of industrial enzymes and occur widely in plants an

Proximate characteristics and statistical optimization of ultrasound-assisted extraction of high-methoxyl-pectin from Hylocereus polyrhizus peels

Ultrasound-assisted-extraction (UAE) and statistical optimization of significant process parameters for high methoxy pectin (HMP) from Hylocereus polyrhizus peels (HPP) were examined and functional properties and proximate chemical characteristics were evaluated in the present study. Statistically, the maximum yield of HMP of 31.4% with a 56.10% degree of esterification (DE) was achieved by a quadratic polynomial equation and regression analysis of 88% and 86%, respectively. The optimal observed conditions for UAE of HMP were; agitation 250 rpm, extraction temperature 65ᵒC, extraction time at 70 min, extraction solvent with pH value of 2 and LSR of 12:1 (v/w). The proximate characteristics showed 17.93% of mannose, 7.65% of rhamnose, 44.34% of galacturonic acid, 2.8% of glucose, 27.32% of galactose with 79.8% purity of the total sugar extracted from HPP. Conclusively, that the extracted HMP from HPP using UAE possesses a high yield of pectin with a significant lower extraction temperature