Mechanobiology of cancer cell responsiveness to chemotherapy and immunotherapy: Mechanistic insights and biomaterial platforms.

Mechanical forces are central to how cancer treatments such as chemotherapeutics and immunotherapies interact with cells and tissues. At the simplest level, electrostatic forces underlie the binding events that are critical to therapeutic function. However, a growing body of literature points to mechanical factors that also affect whether a drug or an immune cell can reach a target, and to interactions between a cell and its environment affecting therapeutic efficacy. These factors affect cell processes ranging from cytoskeletal and extracellular matrix remodeling to transduction of signals by the nucleus to metastasis of cells. This review presents and critiques the state of the art of our understanding of how mechanobiology impacts drug and immunotherapy resistance and responsiveness, and of the in vitro systems that have been of value in the discovery of these effects.

Preconditioning and anti-apoptotic effects of Metformin and Cyclosporine-A in an isolated bile duct-ligated rat heart.

Despite all previous studies relating to the mechanism of cirrhotic cardiomyopathy (CCM), the role of cirrhosis on Ischemic Preconditioning (IPC) has not yet been explored. The present study strives to assess the cardioprotective role of IPC in bile duct ligated (BDL) rats as well as the cardioprotective role of Cyclosporin-A (CsA) and Metformin (Met) in CCM. Cirrhosis was induced by bile duct ligation (BDL). Rats' hearts were isolated and attached to a Langendorff Apparatus. The pharmacological preconditioning with Met and CsA was done before the main ischemia. Myocardial infarct size, hemodynamic and electrophysiological parameters, biochemical markers, and apoptotic indices were determined at the end of the experiment. Infarct size, apoptotic indices, arrhythmia score, and incidence of VF decreased significantly in the IPC group in comparison with the I/R group. These significant decreases were abolished in the IPC (BDL) group. Met significantly decreased the infarct size and apoptotic indices compared with I/R (BDL) and normal groups, while CsA led to similar decreases except in the level of caspase-3 and -8. Met and CsA decreased and increased the arrhythmia score and incidence of VF in the BDL groups, respectively. Functional recovery indices decreased in the I/R (BDL) and IPC (BDL) groups. Met improved these parameters. Therefore, the current study depicted that the cardioprotective effect of Met and CsA on BDL rats is mediated through the balance between pAMPK and apoptosis in the mitochondria.

The Balance between Actomyosin Contractility and Microtubule Polymerization Regulates Hierarchical Protrusions That Govern Efficient Fibroblast-Collagen Interactions.

Fibroblasts undergo a critical transformation from an initially inactive state to a morphologically different and contractile state after several hours of being embedded within a physiologically relevant three-dimensional (3D) fibrous collagen-based extracellular matrix (ECM). However, little is known about the critical mechanisms by which fibroblasts adapt themselves and their microenvironment in the earliest stage of cell-matrix interaction. Here, we identified the mechanisms by which fibroblasts interact with their 3D collagen fibrous matrices in the early stages of cell-matrix interaction and showed that fibroblasts use energetically efficient hierarchical micro/nano-scaled protrusions in these stages as the primary means for the transformation and adaptation. We found that actomyosin contractility in these protrusions in the early stages of cell-matrix interaction restricts the growth of microtubules by applying compressive forces on them. Our results show that actomyosin contractility and microtubules work in concert in the early stages of cell-matrix interaction to adapt fibroblasts and their microenvironment to one another. These early stage interactions result in responses to disruption of the microtubule network and/or actomyosin contractility that are opposite to well-known responses to late-stage disruption and reveal insight into the ways that cells adapt themselves and their ECM recursively.

Acute effects of simvastatin to terminate fast reentrant tachycardia through increasing wavelength of atrioventricular nodal reentrant tachycardia circuit.

Simvastatin (SV) leads to reduction of ventricular rhythm during atrial fibrillation on rabbit atrioventricular (AV) nodes. The aim of our study was (i) to determine the frequency-dependent effects of SV in a functional model, and (ii) to assess the effects of SV to suppress experimental AV nodal reentrant tachycardia (AVNRT). Selective stimulation protocols were used with two different pacing protocols, His to atrial, and atrial to atrial (AA). An experimental AVNRT model with various cycle lengths was created in three groups of perfused rabbit AV nodal preparations (n = 24) including: SV 3 µm, SV 7 µm, and verapamil 0.1 µm. SV increased nodal conduction time and refractoriness by AA pacing. Different simulated models of slow/fast and fast/slow reentry were induced. SV caused inhibitory effects on the slow anterograde conduction (origin of refractoriness) more than on the fast anterograde conduction time, leading to an increase of tachycardia cycle length, tachycardia wavelength and termination of slow/fast reentrant tachyarrhythmia. Verapamil significantly suppressed the basic and frequency-dependent intrinsic nodal properties. In addition, SV decreased the incidence of gap and echo beats. The present study showed that SV in a concentration and rate-dependent manner increased the AV effective refractory period and reentrant tachycardia wavelength that lead to slowing or termination of experimental fast AVNRT. The direction-dependent inhibitory effect of SV on the anterograde and retrograde dual pathways explains its specific antireentrant actions.

Protective role of simvastatin on isolated rabbit atrioventricular node during experimental atrial fibrillation model: role in rate control of ventricular beats.

The purpose of the present study was to determine (1) whether simvastatin (SV) modifies the rate-dependent conduction time and refractoriness of the atrioventricular (AV) node and (2) how it can change the protective mechanism of the AV node during atrial fibrillation (AF). Predefined stimulation protocols were applied to detect the electrophysiological parameters of the AV node, including atrial-His conduction time, effective refractory period (ERP), functional refractory period (FRP), concealed conduction, excitable index, and fatigue in two groups of isolated, perfused rabbit AV nodal preparations (N=16). The stimulation protocols (fatigue, recovery) were carried out during control and in the presence of SV (0.5, 0.8, 3, and 10 µM). Simulated AF was executed in a separate group (N=8), and specific indexes, including H-H mean, zone of concealment (ZOC), and concealed beats were recorded. SV, in a concentration-dependent manner, prolonged ERP, FRP, and Wenckebach cycle lengths. It (10 µM) significantly increased fatigue and the excitable index. In addition, SV elicited prolongation of ZOC and H-H mean at 3 and 10 µM. SV-evoked prolongation of nodal refractoriness and concealed conduction caused rate-dependent ventricular slowing effects during AF. The ability of simvastatin to decrease the excitable gap by its heterogeneous effects on nodal dual pathways proposes its protective role in AF.