Enhancing anti-tumor potential: low-intensity vibration suppresses osteosarcoma progression and augments MSCs' tumor-suppressive abilities.

Rationale: Osteosarcoma (OS), a common malignant bone tumor, calls for the investigation of novel treatment strategies. Low-intensity vibration (LIV) presents itself as a promising option, given its potential to enhance bone health and decrease cancer susceptibility. This research delves into the effects of LIV on OS cells and mesenchymal stem cells (MSCs), with a primary focus on generating induced tumor-suppressing cells (iTSCs) and tumor-suppressive conditioned medium (CM). Methods: To ascertain the influence of vibration frequency, we employed numerical simulations and conducted experiments to determine the most effective LIV conditions. Subsequently, we generated iTSCs and CM through LIV exposure and assessed the impact of CM on OS cells. We also explored the underlying mechanisms of the tumor-suppressive effects of LIV-treated MSC CM, with a specific focus on vinculin (VCL). We employed cytokine array, RNA sequencing, and Western blot techniques to investigate alterations in cytokine profiles, transcriptomes, and tumor suppressor proteins. Results: Numerical simulations validated LIV frequencies within the 10-100 Hz range. LIV induced notable morphological changes in OS cells and MSCs, confirming its dual role in inhibiting OS cell progression and promoting MSC conversion into iTSCs. Upregulated VCL expression enhanced MSC responsiveness to LIV, significantly bolstering CM's efficacy. Notably, we identified tumor suppressor proteins in LIV-treated CM, including procollagen C endopeptidase enhancer (PCOLCE), histone H4 (H4), peptidylprolyl isomerase B (PPIB), and aldolase A (ALDOA). Consistently, cytokine levels decreased significantly in LIV-treated mouse femurs, and oncogenic transcript levels were downregulated in LIV-treated OS cells. Moreover, our study demonstrated that combining LIV-treated MSC CM with chemotherapy drugs yielded additive anti-tumor effects. Conclusions: LIV effectively impeded the progression of OS cells and facilitated the transformation of MSCs into iTSCs. Notably, iTSC-derived CM demonstrated robust anti-tumor properties and the augmentation of MSC responsiveness to LIV via VCL. Furthermore, the enrichment of tumor suppressor proteins within LIV-treated MSC CM and the reduction of cytokines within LIV-treated isolated bone underscore the pivotal tumor-suppressive role of LIV within the bone tumor microenvironment.

Enzymatic Glucose Fiber Sensor for Glucose Concentration Measurement with a Heterodyne Interferometry.

In this study, we developed a glucose fiber sensor incorporating heterodyne interferometry to measure the phase difference produced by the chemical reaction between glucose and glucose oxidase (GOx). Both theoretical and experimental results showed that the amount of phase variation is inversely proportional to glucose concentration. The proposed method provided a linear measurement range of the glucose concentration from 10 mg/dL to 550 mg/dL. The experimental results indicated that the sensitivity is proportional to the length of the enzymatic glucose sensor, and the optimum resolution can be obtained at a sensor length of 3 cm. The optimum resolution of the proposed method is better than 0.6 mg/dL. Moreover, the proposed sensor demonstrates good repeatability and reliability. The average relative standard deviation (RSD) is better than 10% and satisfied the minimum requirement for point-of-care devices.

Viscoelastic hydrogels for interrogating pancreatic cancer-stromal cell interactions.

The tumor microenvironment (TME) is known to direct cancer cell growth, migration, invasion into the matrix and distant tissues, and to confer drug resistance in cancer cells. While multiple aspects of TME have been studied using in vitro, ex vivo, and in vivo tumor models and engineering tools, the influence of matrix viscoelasticity on pancreatic cancer cells and its associated TME remained largely unexplored. In this contribution, we synthesized a new biomimetic hydrogel with tunable matrix stiffness and stress-relaxation for evaluating the effect of matrix viscoelasticity on pancreatic cancer cell (PCC) behaviors in vitro. Using three simple monomers and Reverse-Addition Fragmentation Chain-Transfer (RAFT) polymerization, we synthesized a new class of phenylboronic acid containing polymers (e.g., poly (OEGA-s-HEAA-s-APBA) or PEHA). Norbornene group was conjugated to HEAA on PEHA via carbic anhydride, affording a new NB and BA dually modified polymer - PEHNBA amenable for orthogonal thiol-norbornene photopolymerization and boronate ester diol complexation. The former provided tunable matrix elasticity, while the latter gave rise to matrix stress-relaxation (or viscoelasticity). The new PEHNBA polymers were shown to be highly cytocompatible for in situ encapsulation of PCCs and cancer-associated fibroblasts (CAFs). Furthermore, we demonstrated that hydrogels with high stress-relaxation promoted spreading of CAFs, which in turns promoted PCC proliferation and spreading in the viscoelastic matrix. Compared with elastic matrix, viscoelastic gels upregulated the secretion of soluble proteins known to promote epithelial-mesenchymal transition (EMT). This study demonstrated the crucial influence of matrix viscoelasticity on pancreatic cancer cell fate and provided an engineered viscoelastic matrix for future studies and applications related to TME.

Dissolvable microgel-templated macroporous hydrogels for controlled cell assembly.

Mesenchymal stem cells (MSCs)-based therapies have been widely used to promote tissue regeneration and to modulate immune/inflammatory response. The therapeutic potential of MSCs can be further improved by forming multi-cellular spheroids. Meanwhile, hydrogels with macroporous structures are advantageous for improving mass transport properties for the cell-laden matrices. Herein, we report the fabrication of MSC-laden macroporous hydrogel scaffolds through incorporating rapidly dissolvable spherical cell-laden microgels. Dissolvable microgels were fabricated by tandem droplet-microfluidics and thiol-norbornene photopolymerization using a novel fast-degrading macromer poly(ethylene glycol)-norbornene-dopamine (PEGNB-Dopa). The cell-laden PEGNB-Dopa microgels were subsequently encapsulated within another bulk hydrogel matrix, whose porous structure was generated efficiently by the rapid degradation of the PEGNB-Dopa microgels. The cytocompatibility of this in situ pore-forming approach was demonstrated with multiple cell types. Furthermore, adjusting the stiffness and cell adhesiveness of the bulk hydrogels afforded the formation of solid cell spheroids or hollow spheres. The assembly of solid or hollow MSC spheroids led to differential activation of AKT pathway. Finally, MSCs solid spheroids formed in situ within the macroporous hydrogels exhibited robust secretion of HGF, VEGF-A, IL-6, IL-8, and TIMP-2. In summary, this platform provides an innovative method for forming cell-laden macroporous hydrogels for a variety of future biomedical applications.

Dual Functionalization of Gelatin for Orthogonal and Dynamic Hydrogel Cross-Linking.

Gelatin-based hydrogels are widely used in biomedical fields because of their abundance of bioactive motifs that support cell adhesion and matrix remodeling. Although inherently bioactive, unmodified gelatin exhibits temperature-dependent rheology and solubilizes at body temperature, making it unstable for three-dimensional (3D) cell culture. Therefore, the addition of chemically reactive motifs is required to render gelatin-based hydrogels with highly controllable cross-linking kinetics and tunable mechanical properties that are critical for 3D cell culture. This article provides a series of methods toward establishing orthogonally cross-linked gelatin-based hydrogels for dynamic 3D cell culture. In particular, we prepared dually functionalized gelatin macromers amenable for sequential, orthogonal covalent cross-linking. Central to this material platform is the synthesis of norbornene-functionalized gelatin (GelNB), which forms covalently cross-linked hydrogels via orthogonal thiol-norbornene click cross-linking. Using GelNB as the starting material, we further detail the methods for synthesizing gelatin macromers susceptible to hydroxyphenylacetic acid (HPA) dimerization (i.e., GelNB-HPA) and hydrazone bonding (i.e., GelNB-CH) for on-demand matrix stiffening. Finally, we outline the protocol for synthesizing a gelatin macromer capable of adjusting hydrogel stress relaxation via boronate ester bonding (i.e., GelNB-BA). The combination of these orthogonal chemistries affords a wide range of gelatin-based hydrogels as biomimetic matrices in tissue engineering and regenerative medicine applications.

Biomimetic stiffening of cell-laden hydrogels via sequential thiol-ene and hydrazone click reactions.

Hydrogels with dynamically tunable crosslinking are invaluable for directing stem cell fate and mimicking a stiffening matrix during fibrosis or tumor development. The increases in matrix stiffness during tissue development are often accompanied by the accumulation of extracellular matrices (e.g., collagen, hyaluronic acid (HA)), a phenomenon that has received little attention in the development of dynamic hydrogels. In this contribution, we present a gelatin-based cell-laden hydrogel system capable of being dynamically stiffened while accumulating HA, a key glycosaminoglycans (GAG) increasingly deposited by stromal cells during tumor progression. Central to this strategy is the synthesis of a dually-modified gelatin macromer - gelatin-norbornene-carbohydrazide (GelNB-CH), which is susceptible to both thiol-norbornene photopolymerization and hydrazone click chemistry. We demonstrate that the crosslinking density of cell-laden thiol-norbornene hydrogels can be dynamically tuned via simple incubation with aldehyde-bearing macromers (e.g., oxidized dextran (oDex) or oHA). The GelNB-CH hydrogel system is highly cytocompatible, as demonstrated by in situ encapsulation of pancreatic cancer cells (PCC) and cancer-associated fibroblasts (CAF). This unique dynamic stiffening scheme provides a platform to study tandem accumulation of HA and elevation in matrix stiffness in the pancreatic tumor microenvironment. STATEMENT OF SIGNIFICANCE: Hydrogels permitting on-demand and secondary crosslinking are ideal for mimicking a stiffening tumor microenvironment (TME). However, none of the current dynamic hydrogels account for both stiffening and accumulation of hyaluronic acid (HA), a major extracellular matrix component increasingly deposited in tumor stromal tissues, including pancreatic ductal adenocarcinoma (PDAC). The current work addresses this gap by developing a dynamic hydrogel system capable of simultaneously increasing stiffness and HA accumulation. This is achieved by a new gelatin macromer permitting sequential thiol-norbornene (for primary network crosslinking) and hydrazone click chemistry (for bioinert or biomimetic stiffening with oxidized dextran (oDex) or oHA, respectively). The results of this study provide new insights into how dynamically changing physicochemical matrix properties guide cancer cell fate processes.

Hydrogel Models with Stiffness Gradients for Interrogating Pancreatic Cancer Cell Fate.

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and has seen only modest improvements in patient survival rate over the past few decades. PDAC is highly aggressive and resistant to chemotherapy, owing to the presence of a dense and hypovascularized fibrotic tissue, which is composed of stromal cells and extracellular matrices. Increase deposition and crosslinking of matrices by stromal cells lead to a heterogeneous microenvironment that aids in PDAC development. In the past decade, various hydrogel-based, in vitro tumor models have been developed to mimic and recapitulate aspects of the tumor microenvironment in PDAC. Advances in hydrogel chemistry and engineering should provide a venue for discovering new insights regarding how matrix properties govern PDAC cell growth, migration, invasion, and drug resistance. These engineered hydrogels are ideal for understanding how variation in matrix properties contributes to the progressiveness of cancer cells, including durotaxis, the directional migration of cells in response to a stiffness gradient. This review surveys the various hydrogel-based, in vitro tumor models and the methods to generate gradient stiffness for studying migration and other cancer cell fate processes in PDAC.

Developing a Silk Fibroin Composite Film to Scavenge and Probe H2O2 Associated with UV-Excitable Blue Fluorescence.

A silk fibroin composite film that can simultaneously scavenge and probe H2O2 in situ was developed for possibly examining local concentrations of H2O2 for biomedical applications. A multi-functional composite film (GDES) that consists of graphene oxide (G), a photothermally responsive element that was blended with polydopamine (PDA, D)/horseradish peroxidase (HRP, E) (or DE complex), and then GDE microaggregates were coated with silk fibroin (SF, S), a tyrosine-containing protein. At 37 °C, the H2O2-scavenging ability of a GDES film in solution at approximately 7.5 × 10-3 µmol H2O2/mg film was the highest compared with those of S and GS films. The intensities of UV-excitable blue fluorescence of a GDES film linearly increased with increasing H2O2 concentrations from 4.0 µM to 80 µM at 37 °C. Interestingly, after a GDES film scavenged H2O2, the UV-excitable blue fluorescent film could be qualitatively monitored by eye, making the film an eye-probe H2O2 sensor. A GDES film enabled to heat H2O2-containing samples to 37 °C or higher by the absorption of near-IR irradiation at 808 nm. The good biocompatibility of a GDES film was examined according to the requirements of ISO-10993-5. Accordingly, a GDES film was developed herein to scavenge and eye-probe H2O2 in situ and so it has potential for biomedical applications.

Quantification of cardiac pumping mechanics in rats by using the elastance-resistance model based solely on the measured left ventricular pressure and cardiac output.

The cardiac pumping mechanics can be characterized by both the maximal systolic elastance (Emax) and theoretical maximum flow (Qmax), which are generated using an elastance-resistance model. The signals required to fit the elastance-resistance model are the simultaneously recorded left ventricular (LV) pressure and aortic flow (Qm), followed by the isovolumic LV pressure. In this study, we evaluated a single-beat estimation technique for determining the Emax and Qmax by using the elastance-resistance model based solely on the measured LV pressure and cardiac output. The isovolumic LV pressure was estimated from the measured LV pressure by using a non-linear least-squares approximation technique. The measured Qm was approximated by an unknown triangular flow (Qtri), which was generated by using a fourth-order derivative of the LV pressure. The Qtri scale was calibrated using the cardiac output. Values of EmaxtriQ and QmaxtriQ obtained using Qtri were compared with those of EmaxmQ and QmaxmQ obtained from the measured Qm. Healthy rats and rats with chronic kidney disease or diabetes mellitus were examined. We found that the LV Emax and Qmax can be approximately calculated using the assumed Qtri, and they strongly correlated with the corresponding values derived from Qm (P < 0.0001; n = 78): EmaxtriQ = 51.9133 + 0.8992 × EmaxmQ (r2 = 0.8257; P < 0.0001); QmaxtriQ = 2.4053 + 0.9767 × QmaxmQ (r2 = 0.7798; P < 0.0001). Our findings suggest that the proposed technique can be a useful tool for determining Emax and Qmax by using a single LV pressure pulse together with cardiac output.

Quantification of contractile mechanics in the rat heart from ventricular pressure alone.

To quantitate the contractile mechanics of the heart, the ventricle is considered an elastic chamber with known end-systolic elastance (Ees ). Ees can be calculated from a single pressure-ejected volume curve, which requires simultaneous records of left ventricular (LV) pressure and the aortic flow (Qm). In clinical settings, it is helpful to evaluate patients' cardiac contractile status by using a minimally invasive approach to physiological signal monitoring, wherever possible, such as by using LV pressure alone. In this study, we evaluated a method for determining Ees on the basis of the measured LV pressure and an assumed aortic flow with a triangular wave shape (Qtri). Qtri was derived using a fourth-order derivative of the LV pressure to approximate its corresponding Qm. Values of EestriQ obtained using Qtri were compared with those of EesmQ obtained from the measured Qm. Healthy rats (NC; n = 28) and rats with type 1 diabetes (DM; n = 26) and chronic kidney disease (CKD; n = 20) were examined. The cardiodynamic conditions in both the DM and CKD groups were characterized by a decline in EesmQ and EestriQ. A significant regression line for Ees was observed (P < 0.0001): EestriQ = 2.6214 + 1.0209 × EesmQ (r2 = 0.9870; n = 74). Our finding indicates that the systolic pumping mechanics of the heart can be derived from a single LV pressure recording together with the assumed Qtri.

Defects in Vascular Mechanics Due to Aging in Rats: Studies on Arterial Wave Properties from a Single Aortic Pressure Pulse.

Changes in vascular mechanics due to aging include elevated vascular impedance, diminished aorta distensibility, and an accelerated return of pulse wave reflection, which may increase the systolic workload on the heart. Classically, the accurate measurement of vascular mechanics requires the simultaneous recording of aortic pressure and flow signals. In practice, it is feasible to estimate arterial wave properties in terms of wave transit time (τw) and wave reflection index (RI) by using aortic pressure signal alone. In this study, we determined the τ w and magnitudes of the forward (∣Pf ∣) and backward (∣Pb ∣) pressure waves in Long-Evans male rats aged 4 (n = 14), 6 (n = 17), 12 (n = 17), and 18 (n = 24) months, based on the measured aortic pressure and an assumed triangular flow (Qtri). The pulsatile pressure wave was the only signal recorded in the ascending aorta by using a high-fidelity pressure sensor. The base of the unknown Qtri was constructed using a duration, which equals to the ejection time. The timing at the peak of the triangle was derived using the fourth-order derivative of the aortic pressure waveform. In the 18-month-old rats, the ratio of τ w to left ventricular ejection time (LVET) decreased, indicating a decline in the distensibility of the aorta. The increased ∣Pb ∣ associated with unaltered ∣Pf ∣ enhanced the RI in the older rats. The augmentation index (AI) also increased significantly with age. A significant negative correlation between the AI and τ w /LVET was observed: AI = -0.7424 - 0.9026 × (τ w /LVET) (r = 0.4901; P < 0.0001). By contrast, RI was positively linearly correlated with the AI as follows: AI = -0.4844 + 2.3634 × RI (r = 0.8423; P < 0.0001). Both the decreased τ w /LVET and increased RI suggested that the aging process may increase the AI, thereby increasing the systolic hydraulic load on the heart. The novelty of the study is that Qtri is constructed using the measured aortic pressure wave to approximate its corresponding flow signal, and that calibration of Qtri is not essential in the analysis.

Investigation of the self-assembly of CS and PCL copolymers with different molecular weights in water solution by coarse-grained molecular dynamics simulation.

Coarse-grained molecular dynamics (CGMD) simulation was employed to investigate how stable chondroitin sulfate-graft-polycaprolactone (CS-PCL, CP) copolymers self-assemble into micelles in an aqueous environment. Three types of CP containing low (2.4%), medium (6.3%), and high (18.7%) PCL contents (denoted L-CP, M-CP, and H-CP, respectively) in which PCL molecules consisting of 63 monomers were grafted onto each CS molecule consisting of 120 monomers were considered. L-CP and M-CP were found to display spheroidal micellar structures, while H-CP presented a rod-like structure, in agreement with previous experimental observations. In addition, the entanglement of the PCL segment increased as its molecular weight was increased. The number density distribution profiles of PCL, CS, and water molecules indicated that there were a few water molecules between the PCL core of the micelle and the water solution surrounding the micelle (in the micelle layer immediately above the core), and the number density of water in the CP micelle increased as the PCL content decreased. Using the radius of gyration, the three-dimensional conformations of the micelles were explored. When the number of CP chains was 3, H-CP adopted a long nanorod form, whereas L-CP and M-CP were roughly nanospherical. When the number of CP chains was increased beyond 3, however, the structure of L-CP changed from a nanosphere to a nanodisk. Finally, the slope of the mean square displacement profile was greatest when the molecular weight of the PCL segment was lowest, indicating that the mobilities of the CS and PCL segments are highest in L-CP. The self-diffusion coefficients of the CS and PCL segments decreased as the number of PCL segments grafted increased. Graphical abstract Morphologies of H-CP micelle.

Accelerometer-assessed light physical activity is protective of future cognitive ability: A longitudinal study among community dwelling older adults.

OBJECTIVE: Physical activity (PA), especially moderate-to-vigorous intensity, could protect older adults from cognitive impairment. However, most literature is based on self-reported PA which is limited by recall bias. Light PA is popular among older adults, but a paucity of objective longitudinal data has considered the relationship between light PA and cognitive ability. We examined if a higher level of objectively measured light PA, independent of moderate-to-vigorous physical activity (MVPA), was prospectively associated with better cognitive ability in older adults. METHODS: A longitudinal study over 22.12 (±1.46) months including 274 community-dwelling older adults across 14 regions in Taiwan was undertaken. Cognitive ability was obtained using a Chinese version of the Ascertain Dementia 8-item Questionnaire (AD8) and light PA and MVPA captured by 7days accelerometer positioned on waist. Multivariable negative binomial regression adjusted for confounders were undertaken. RESULTS: 274 participants (74.52years, 45.6% male) attended the follow-up (96.1%). Higher light PA, independent from MVPA, was associated with a reduced rate of decline in cognitive ability (rate ratio 0.75 [0.60-0.92]). MVPA, was also associated with a reduced decline in cognitive ability (rate ratio 0.85 [0.75-0.95]). Light PA was protective of cognitive ability in sensitivity analyses removing participants with activities of daily living difficulties, depressive symptoms and cognitive impairment at baseline. CONCLUSION: Our data suggest that light PA may offer a protective influence of future cognitive ability in community dwelling older adults. The promotion of light PA may be a valuable means to maintain cognitive ability in older age.

Determining arterial wave transit time from a single aortic pressure pulse in rats: vascular impulse response analysis.

Arterial wave transit time (τw) in the lower body circulation is an effective biomarker of cardiovascular risk that substantially affects systolic workload imposed on the heart. This study evaluated a method for determining τw from the vascular impulse response on the basis of the measured aortic pressure and an assumed triangular flow (Qtri). The base of the unknown Qtri was constructed with a duration set equal to ejection time. The timing of the peak triangle was derived using a fourth-order derivative of the pressure waveform. Values of τws obtained using Qtri were compared with those obtained from the measure aortic flow wave (Qm). Healthy rats (n = 27), rats with chronic kidney disease (CKD; n = 22), and rats with type 1 (n = 22) or type 2 (n = 11) diabetes were analyzed. The cardiovascular conditions in the CKD rats and both diabetic groups were characterized by a decrease in τws. The following significant relation was observed (P < 0.0001): τwtriQ = -1.5709 + 1.0604 × τwmQ (r2 = 0.9641). Our finding indicates that aortic impulse response can be an effective method for the estimation of arterial τw by using a single pressure recording together with the assumed Qtri.

Spatial pattern of distribution of marine invertebrates within a subtidal community: do communities vary more among patches or plots?

Making links between ecological processes and the scales at which they operate is an enduring challenge of community ecology. Our understanding of ecological communities cannot advance if we do not distinguish larger scale processes from smaller ones. Variability at small spatial scales can be important because it carries information about biological interactions, which cannot be explained by environmental heterogeneity alone. Marine fouling communities are shaped by both the supply of larvae and competition for resources among colonizers-these two processes operate on distinctly different scales. Here, we demonstrate how fouling community structure varies with spatial scale in a temperate Australian environment, and we identify the spatial scale that captures the most variability. Community structure was quantified with both univariate (species richness and diversity) and multivariate (similarity in species composition) indices. Variation in community structure was unevenly distributed between the spatial scales that we examined. While variation in community structure within patch was usually greater than among patch, variation among patch was always significant. Opportunistic taxa that rely heavily on rapid colonization of free space spread more evenly among patches during early succession. In contrast, taxa that are strong adult competitors but slow colonizers spread more evenly among patches only during late succession. Our findings show significant patchiness can develop in a habitat showing no systematic environmental spatial variation, and this patchiness can be mediated through different biological factors at different spatial scales.

Prey size diversity hinders biomass trophic transfer and predator size diversity promotes it in planktonic communities.

Body size exerts multiple effects on plankton food-web interactions. However, the influence of size structure on trophic transfer remains poorly quantified in the field. Here, we examine how the size diversity of prey (nano-microplankton) and predators (mesozooplankton) influence trophic transfer efficiency (using biomass ratio as a proxy) in natural marine ecosystems. Our results support previous studies on single trophic levels: transfer efficiency decreases with increasing prey size diversity and is enhanced with greater predator size diversity. We further show that communities with low nano-microplankton size diversity and high mesozooplankton size diversity tend to occur in warmer environments with low nutrient concentrations, thus promoting trophic transfer to higher trophic levels in those conditions. Moreover, we reveal an interactive effect of predator and prey size diversities: the positive effect of predator size diversity becomes influential when prey size diversity is high. Mechanistically, the negative effect of prey size diversity on trophic transfer may be explained by unicellular size-based metabolic constraints as well as trade-offs between growth and predation avoidance with size, whereas increasing predator size diversity may enhance diet niche partitioning and thus promote trophic transfer. These findings provide insights into size-based theories of ecosystem functioning, with implications for ecosystem predictive models.

Systolic aortic pressure-time area is a useful index describing arterial wave properties in rats with diabetes.

The accurate measurement of arterial wave properties in terms of arterial wave transit time (τw) and wave reflection factor (Rf) requires simultaneous records of aortic pressure and flow signals. However, in clinical practice, it will be helpful to describe the pulsatile ventricular afterload using less-invasive parameters if possible. We investigated the possibility of systolic aortic pressure-time area (PTAs), calculated from the measured aortic pressure alone, acting as systolic workload imposed on the rat diabetic heart. Arterial wave reflections were derived using the impulse response function of the filtered aortic input impedance spectra. The cardiovascular condition in the rats with either type 1 or type 2 diabetes was characterized by (1) an elevation in PTAs; and (2) an increase in Rf and decrease in τw. We found that an inverse linear correlation between PTAs and arterial τw reached significance (τw = 38.5462 - 0.0022 × PTAs; r = 0.7708, P < 0.0001). By contrast, as the PTAs increased, the reflection intensity increased: Rf = -0.5439 + 0.0002 × PTAs; r = 0.8701; P <0 .0001. All these findings suggested that as diabetes stiffened aortas, the augmented aortic PTAs might act as a useful index describing the diabetes-related deterioration in systolic ventricular workload.

Methylprednisolone Protects Cardiac Pumping Mechanics from Deteriorating in Lipopolysaccharide-Treated Rats.

It has been shown that a prolonged low-dose corticosteroid treatment attenuates the severity of inflammation and the intensity and duration of organ system failure. In the present study, we determined whether low-dose methylprednisolone (a synthetic glucocorticoid) can protect male Wistar rats against cardiac pumping defects caused by lipopolysaccharide-induced chronic inflammation. For the induction of chronic inflammation, a slow-release ALZET osmotic pump was subcutaneously implanted to infuse lipopolysaccharide (1 mg kg(-1) d(-1)) for 2 weeks. The lipopolysaccharide-challenged rats were treated on a daily basis with intraperitoneal injection of methylprednisolone (5 mg kg(-1) d(-1)) for 2 weeks. Under conditions of anesthesia and open chest, we recorded left ventricular (LV) pressure and ascending aortic flow signals to calculate the maximal systolic elastance (E max) and the theoretical maximum flow (Q max), using the elastance-resistance model. Physically, E max reflects the contractility of the myocardium as an intact heart, whereas Q max has an inverse relationship with the LV internal resistance. Compared with the sham rats, the cardiodynamic condition was characterized by a decline in E max associated with the increased Q max in the lipopolysaccharide-treated rats. Methylprednisolone therapy increased E max, which suggests that the drug may have protected the contractile status from deteriorating in the inflamed heart. By contrast, methylprednisolone therapy considerably reduced Q max, indicating that the drug may have normalized the LV internal resistance. In parallel, the benefits of methylprednisolone on the LV systolic pumping mechanics were associated with the reduced cardiac levels of negative inotropic molecules such as peroxynitrite, malondialdehyde, and high-mobility group box 1 protein. Based on these data, we suggested that low-dose methylprednisolone might prevent lipopolysaccharide-induced decline in cardiac intrinsic contractility and LV internal resistance, possibly through its ability to reduce the aforementioned myocardial depressant substances. However, since our results were obtained in anesthetized open-chest rats, extrapolation to what may occur in conscious intact animals should be done with caution.

Pyridoxamine protects against mechanical defects in cardiac ageing in rats: studies on load dependence of myocardial relaxation.

Our team demonstrated in the past that pyridoxamine attenuated arterial stiffening by targeting the pathogenic formation of glycated collagen cross-links in aged rats. Herein, we examined whether pyridoxamine therapy can protect against mechanical defects in myocardial relaxation by improving arterial wave properties and cardiac contractile performance in senescent animals. Fifteen-month-old male Fisher 344 rats were treated daily with pyridoxamine (1 g l(-1) in drinking water) for 5 months and compared with age-matched untreated control animals (20 months old). Arterial wave properties were characterized by wave transit time (τw) and wave reflection factor (Rf). We measured the contractile status of the myocardium in an intact heart as the left ventricular (LV) end-systolic elastance (Ees). Myocardial relaxation was described according to the time constant of the LV isovolumic pressure decay (τe). Pyridoxamine therapy prevented the age-associated prolongation in LV τe and the diminished Ees in senescent rats. The drug also attenuated the age-related augmentation in afterload imposed on the heart, as evidenced by the increased τw and decreased Rf. We found that the LV τe was significantly influenced by both the arterial τw and Rf (τe = 16.3902 + 8.3123 × Rf - 0.4739 × τw; r = 0.7048, P < 0.005). In the meantime, the LV τe and the LV Ees showed a significant inverse linear correlation (τe = 13.9807 - 0.0068 × Ees; r = 0.6451, P < 0.0005). All these findings suggested that long-term treatment with pyridoxamine might ameliorate myocardial relaxation rate, at least partly through its ability to enhance myocardial contractile performance, increase wave transit time and decrease wave reflection factor in aged rats.

Prevention of arterial stiffening by using low-dose atorvastatin in diabetes is associated with decreased malondialdehyde.

INTRODUCTION: Without affecting the lipid profile, a low-dose treatment with atorvastatin contributes to the reduction of oxidative stress, inflammation, and adverse cardiovascular events in diabetes. In this study, we investigated whether low-dose atorvastatin exerts any beneficial effect on vascular dynamics in streptozotocin (STZ)-induced diabetes in male Wistar rats. METHODS: Diabetes was induced using a single tail-vein injection of STZ at 55 mg kg-1. The diabetic rats were treated daily with atorvastatin (10 mg kg-1 by oral gavage) for 6 weeks. They were also compared with untreated age-matched diabetic controls. Arterial wave reflection was derived using the impulse response function of the filtered aortic input impedance spectra. A thiobarbituric acid reactive substances measurement was used to estimate the malondialdehyde content. RESULTS: The high plasma level of total cholesterol in the diabetic rats did not change in response to this low-dose treatment with atorvastatin. Atorvastatin resulted in a significant increase of 15.4% in wave transit time and a decrease of 33.5% in wave reflection factor, suggesting that atorvastatin may attenuate the diabetes-induced deterioration in systolic loads imposed on the heart. This was in parallel with its lowering of malondialdehyde content in plasma and aortic walls in diabetes. Atorvastatin therapy also prevented the diabetes-related cardiac hypertrophy, as evidenced by the diminished ratio of left ventricular weight to body weight. CONCLUSION: These findings indicate that low-dose atorvastatin might protect diabetic vasculature against diabetes-associated deterioration in aorta stiffness and cardiac hypertrophy, possibly through its decrease of lipid oxidation-derived malondialdehyde.