Artemisia argyi extract ameliorates IL-17A-induced inflammatory response by regulation of NF-κB and Nrf2 expression in HIG-82 synoviocytes.

Rheumatoid arthritis (RA) is an autoimmune and chronic inflammatory disease that results in joint destruction and disability in the adult population. RA is characterized by the accumulation and proliferation of fibroblast-like synoviocytes. Many pro-inflammatory mediators are associated with RA, such as interleukin (IL)-1ß, IL-6, IL-17, cyclooxygenase-2 (COX-2), and nuclear factor kappa B (NF-κB). Furthermore, IL-17 upregulates the production of other pro-inflammatory mediators, including IL-1ß and IL-6, and promotes the recruitment of neutrophils in RA. Artemisia argyi, a traditional Chinese herbal medicine, is used for the treatment of diseases associated with inflammation and microbial infections. In this study, synoviocytes (HIG-82) were treated with varying doses of A. argyi extract (AAE) following IL-17A stimulation. Proliferation of the IL-17A-stimulated cells was increased compared to that of the non-stimulated control cells. However, cell proliferation decreased significantly in a dose-dependent manner following AAE treatment. Treatment of IL-17A-stimulated cells with AAE resulted in decreased levels of phosphorylated (p)-NF-κB, p-IκB-α, and COX-2. Enzyme-linked immunosorbent assay results showed that IL-1ß and IL-6 levels were increased in the IL-17A-stimulated group but decreased in the AAE treatment group. Additionally, we found that AAE facilitated nuclear factor erythroid 2-related factor 2 (Nrf2) expression and promoted its nuclear translocation, thereby inducing the expression of heme oxygenase-1. Moreover, AAE did not attenuate IL-17A-induced inflammatory mediator production in the presence of ML385, an Nrf2-specific inhibitor. These results suggest that the downregulation of expression of pro-inflammatory cytokines and the transcription factor NF-κB by AAE may be a potential therapeutic strategy for reducing inflammation associated with RA.

Daidzein Synergizes with Gefitinib to Induce ROS/JNK/c-Jun Activation and Inhibit EGFR-STAT/AKT/ERK Pathways to enhance Lung Adenocarcinoma cells chemosensitivity.

Lung cancer is the major cause of cancer associated mortality. Mutations in EGFR have been implicated in lung cancer pathogenesis. Gefitinib (GF) is a RTKI (receptor tyrosine kinase inhibitor) first-choice drug for EGFR mutated advanced lung cancer. However, drug toxicity and cancer cell resistance lead to treatment failure. Consequently, new therapeutic strategies are urgently required. Therefore, this study was aimed at identifying tumor suppressive compounds that can synergistically improve Gefitinib chemosensitivity in the lung cancer treatment. Medicinal plants offer a vast platform for the development of novel anticancer agents. Daidzein (DZ) is an isoflavone compound extracted from soy plants and has been shown to possess many medicinal benefits. The anticancer potential of GF and DZ combination treatment was investigated using MTT, western blot, fluorescent microscopy imaging, flow cytometry and nude mice tumor xenograft techniques. Our results demonstrate that DZ synergistically induces c-Jun nuclear translocation through ROS/ASK1/JNK and downregulates EGFR-STAT/AKT/ERK pathways to activate apoptosis and a G0/G1 phase cell cycle blockade. In in-vivo, the combination treatment significantly suppressed A549 lung cancer cells tumor xenograft growth without noticeable toxicity. Daidzein supplements with current chemotherapeutic agents may well be an alternative strategy to improve the treatment efficacy of lung adenocarcinoma.

Computational pharmaceutical analysis of anti-Alzheimer's Chinese medicine Coptidis Rhizoma alkaloids.

Alzheimer's disease (AD) is an age-related neurodegenerative disease, affecting over 20 million people worldwide. Until recently, two major hypotheses were proposed regarding the molecular mechanism of pathogenesis: the cholinergic hypothesis and the amyloid cascade hypothesis. At present, acetylcholinesterase inhibitors are the most effective therapy for AD. Most pharmacological research has focused on the ability of acetylcholinesterase to alleviate cholinergic deficit and improve neurotransmission. Coptidis rhizoma and its isolated alkaloids are reported to possess a variety of activities, including neuroprotective and antioxidant effects. However, as yet no theoretical analysis exists to support this hypothesis. To examine this theory, we applied a computational pharmaceutical analysis to reveal that Chinese medicine Coptidis rhizoma alkaloids have much higher activities than Donepezil (commercial name is Aricept) by docking and scoring.

Predicting effects of blood flow rate and size of vessels in a vasculature on hyperthermia treatments using computer simulation.

BACKGROUND: Pennes Bio Heat Transfer Equation (PBHTE) has been widely used to approximate the overall temperature distribution in tissue using a perfusion parameter term in the equation during hyperthermia treatment. In the similar modeling, effective thermal conductivity (Keff) model uses thermal conductivity as a parameter to predict temperatures. However the equations do not describe the thermal contribution of blood vessels. A countercurrent vascular network model which represents a more fundamental approach to modeling temperatures in tissue than do the generally used approximate equations such as the Pennes BHTE or effective thermal conductivity equations was presented in 1996. This type of model is capable of calculating the blood temperature in vessels and describing a vasculature in the tissue regions. METHODS: In this paper, a countercurrent blood vessel network (CBVN) model for calculating tissue temperatures has been developed for studying hyperthermia cancer treatment. We use a systematic approach to reveal the impact of a vasculature of blood vessels against a single vessel which most studies have presented. A vasculature illustrates branching vessels at the periphery of the tumor volume. The general trends present in this vascular model are similar to those shown for physiological systems in Green and Whitmore. The 3-D temperature distributions are obtained by solving the conduction equation in the tissue and the convective energy equation with specified Nusselt number in the vessels. RESULTS: This paper investigates effects of size of blood vessels in the CBVN model on total absorbed power in the treated region and blood flow rates (or perfusion rate) in the CBVN on temperature distributions during hyperthermia cancer treatment. Also, the same optimized power distribution during hyperthermia treatment is used to illustrate the differences between PBHTE and CBVN models. Keff (effective thermal conductivity model) delivers the same difference as compared to the CBVN model. The optimization used here is adjusting power based on the local temperature in the treated region in an attempt to reach the ideal therapeutic temperature of 43 degrees C. The scheme can be used (or adapted) in a non-invasive power supply application such as high-intensity focused ultrasound (HIFU). Results show that, for low perfusion rates in CBVN model vessels, impacts on tissue temperature becomes insignificant. Uniform temperature in the treated region is obtained. CONCLUSION: Therefore, any method that could decrease or prevent blood flow rates into the tumorous region is recommended as a pre-process to hyperthermia cancer treatment. Second, the size of vessels in vasculatures does not significantly affect on total power consumption during hyperthermia therapy when the total blood flow rate is constant. It is about 0.8% decreasing in total optimized absorbed power in the heated region as gamma (the ratio of diameters of successive vessel generations) increases from 0.6 to 0.7, or from 0.7 to 0.8, or from 0.8 to 0.9. Last, in hyperthermia treatments, when the heated region consists of thermally significant vessels, much of absorbed power is required to heat the region and (provided that finer spatial power deposition exists) to heat vessels which could lead to higher blood temperatures than tissue temperatures when modeled them using PBHTE.

Feasibility of transrib focused ultrasound thermal ablation for liver tumors using a spherically curved 2D array: a numerical study.

The use of focused ultrasound thermal ablation to treat hepatocarcinoma and other liver tumors produces promising clinical results. However, one of the major drawbacks is the high absorption of ultrasonic energy by the rib, making partial rib removal necessary in many cases. This study numerically investigated the feasibility of using a spherical ultrasound phased array for transrib liver-tumor thermal ablation. An independently array-element activitation scheme, which switches off the transducer elements obstructed by the ribs based on feedback anatomical medical imaging, was proposed to reduce the rib-overheating problem. The numerical results showed that the proposed treatment planning strategy can effectively reduce the specific energy absorbed by the rib while maintaining the energy at the target position, which both reduces the rib-overheating problem and increases the possibility of treating a target lesion under an intact rib. The analysis also demonstrated that the target position and the ultrasound frequency play key roles in the treatment. Patients with diverse characteristics were also tested to show the generality of the proposed strategy. The proposed treatment planning strategy also provides useful information for evaluating the treatment effectiveness prior to clinically performing transrib ultrasound liver-tumor thermal ablation.

A novel strategy to increase heating efficiency in a split-focus ultrasound phased array.

Focus splitting using sector-based phased arrays increases the necrosed volume in a single sonication and reduces the total treatment time in the treatment of large tumors. However, split-focus sonication results in a lower energy density and worse focal-beam distortion, which limits its usefulness in practical treatments. Here, we propose a new heating strategy involving consecutive strongly focused and split-focus sonications to improve the heating efficiency. Theoretical predictions including linear and thermal-dose-dependent attenuation change were employed to investigate potential factors of this strategy, and ex vivo tissue experiments were conducted to confirm its effectiveness. Results showed that the thermal lesions produced by the proposed strategy could be increased when comparing with the previous reported strategies. The proposed heating strategy also induces a thermal lesion more rapidly, and exhibits higher robustness to various blood perfusion conditions, higher robustness to various power/heating time combinations, and superiority to generate deep-seated lesions through tissues with complex interfaces. Possible mechanisms include the optimization of the thermal conduction created by the strongly focused sonication and the temperature buildup gained from thermally induced tissue attenuation change based on the theoretical analysis. This may represent a useful technique for increasing the applicability of split-focus and multiple-focus sonication techniques, and solve the obstacles encountered when attempting to use these methods to shorten the total clinical treatment time.

Effects of pulsatile blood flow in large vessels on thermal dose distribution during thermal therapy.

The aim of this study is to evaluate the effect of pulsatile blood flow in thermally significant blood vessels on the thermal lesion region during thermal therapy of tumor. A sinusoidally pulsatile velocity profile for blood flow was employed to simulate the cyclic effect of the heart beat on the blood flow. The evolution of temperature field was governed by the energy transport equation for blood flow together with Pennes' bioheat equation for perfused tissue encircling the blood vessel. The governing equations were numerically solved by a novel multi-block Chebyshev pseudospectral method and the accumulated thermal dose in tissue was computed. Numerical results show that pulsatile velocity profile, with various combinations of pulsatile amplitude and frequency, has little difference in effect on the thermal lesion region of tissue compared with uniform or parabolic velocity profile. However, some minor differences on the thermal lesion region of blood vessel is observed for middle-sized blood vessel. This consequence suggests that, in this kind of problem, we may as well do the simulation simply by a steady uniform velocity profile for blood flow.

Interactions between consecutive sonications for characterizing the thermal mechanism in focused ultrasound therapy.

The use of focused ultrasound for thermal ablation or therapy has become a promising modality due to its high selectivity and noninvasiveness. The temperature increase that induces thermal necrosis in the focal beam area has been reported to be attributed to the absorption of ultrasound energy and heating enhancement by acoustic cavitation. The purpose of this study is to propose a novel experimental arrangement to observe the thermal lesion formation and to demonstrate that the presence of the ultrasound-induced, macroscopically-visible bubbles may exert a key effect in thermal lesion formation. In our experiments, consecutive sonications with orthogonal intersections were applied to observe the thermal lesion interaction induced by 577- or 1155-kHz ultrasound. Results showed that the 1155-kHz heating was dominated by ultrasound energy absorption, with blocking of consecutive sonications being evident only rarely. However, in 577-kHz sonications, the thermal process was dominated by inertial cavitation and the corresponding ultrasound-induced, macroscopically-visible bubbles, which was verified from the later lesion being blocked by the former one and direct observation from light microscopy. This study demonstrates that the operating frequency for ultrasound thermal ablation should be selected based on the intended specific thermal mechanisms to be induced.

Cavitation-enhanced ultrasound thermal therapy by combined low- and high-frequency ultrasound exposure.

This paper demonstrates a novel approach for enhancing ultrasound-induced heating by the introduction of acoustic cavitation using simultaneous sonication with low- and high-frequency ultrasound. A spherical focused transducer (566 or 1155 kHz) was used to generate the thermal lesions, and a low-frequency planar transducer (40 or 28 kHz) was used to enhance the bubble activity. Ex vivo fresh porcine muscles were used as the target of ultrasound ablation. The emitted signals and the signals backscattered from the bubble activity were also recorded during the heating process by a PVDF-type needle hydrophone, and thermocouples were inserted to measure temperatures. Compared with the lesions formed by a single focused transducer, the size of the lesions generated by this approach were as much as 140% larger along the axial direction and 200% larger along the radial direction for combined 566- and 40-kHz sonication. They were 47% and 66% larger along the axial and radial directions, respectively, for combined 1155- and 28-kHz sonication. Cavitation activities enhanced by low-frequency ultrasound were confirmed by the presence of subharmonics in the spectrum and temperature increase as a result of increased tissue absorption. These observations imply that cavitation-enhanced lesions can be generated without reducing the penetration ability; they also show the advantage of producing larger and more uniform thermal lesions by multiple sonications. This technique provides an easy and effective way to achieve cavitation-enhanced heating, and may be useful for generating large and deep-seated thermal lesions.

The impact of thermal wave characteristics on thermal dose distribution during thermal therapy: a numerical study.

The aim of this study was to investigate the effects of the propagation speed of a thermal wave in terms of the thermal relaxation time on the temperature/thermal dose distributions in living tissue during thermal therapies. The temperature field in tissue was solved by the finite difference method, and the thermal dose was calculated from the formulation proposed by Sapareto and Dewey [Int. J. Radiat. Oncol. Biol. Phys. 10, 787-800 (1984)]. Under the same total deposited energy, for a rapid heating process the time lagging behavior of the peak temperature became pronounced and the level of the peak temperature was decreased with increasing the thermal relaxation time. When the heating duration was longer than the thermal relaxation time of tissues, there was no significant difference between the thermal dose distributions with/without considering the effect of the thermal relaxation time. In other words, when the heating duration is comparable to or shorter than the thermal relaxation time of tissue, the results of the wave bioheat transfer equation (WBHTE) are fully different from that of the Pennes' bioheat transfer equation (PBHTE). Besides, for a rapid heating process the dimension of thermal lesion was still significantly affected by perfusion, because this is what is predicted by the WBHTE but not by the PBHTE, i.e., the wave feature of the temperature field cannot fully be predicted by the PBHTE.

Reconstruction of the temperature field for inverse ultrasound hyperthermia calculations at a muscle/bone interface.

An inverse algorithm with Tikhonov regularization of order zero has been used to estimate the intensity ratios of the reflected longitudinal wave to the incident longitudinal wave and that of the refracted shear wave to the total transmitted wave into bone in calculating the absorbed power field and then to reconstruct the temperature distribution in muscle and bone regions based on a limited number of temperature measurements during simulated ultrasound hyperthermia. The effects of the number of temperature sensors are investigated, as is the amount of noise superimposed on the temperature measurements, and the effects of the optimal sensor location on the performance of the inverse algorithm. Results show that noisy input data degrades the performance of this inverse algorithm, especially when the number of temperature sensors is small. Results are also presented demonstrating an improvement in the accuracy of the temperature estimates by employing an optimal value of the regularization parameter. Based on the analysis of singular-value decomposition, the optimal sensor position in a case utilizing only one temperature sensor can be determined to make the inverse algorithm converge to the true solution.

Effect of the directional blood flow on thermal dose distribution during thermal therapy: an application of a Green's function based on the porous model.

This study presents the effects of directional blood flow and heating schemes on the distributions of temperature and thermal dose during thermal therapy. In this study, a transient bioheat transfer equation based on the porous medium property is proposed to encompass the directional effect of blood flow. A Green's function is used to obtain the temperature distribution for this modified bioheat transfer equation, and the thermal dose equivalence is used to evaluate the heating results for a set of given parameters. A 10 x 10 x 10 mm3 tumour tissue is heated by different heating schemes to investigate the thermal dose variation with the clinical therapeutic arrangement. For a rapid heating scheme, the domain of thermal lesion can effectively cover the desired therapeutic region. However, this domain of thermal lesion may extend to the downstream normal tissue if the porosity is high and the averaged blood velocity has a larger value.