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Polyacrylamide (PAAm) hydrogels are widely adopted as 2D‐model soft substrates for investigating cell‐material interactions in a controlled in vitro environment. They offer facile synthesis, tunable physico‐chemical properties, diverse biofunctionalization routes, optical transparency, mouldability in a range of geometries and shapes, and compatibility with living cells. PAAm hydrogels can be engineered to reconstruct physiologically relevant biointerfaces, like cell‐matrix or cell–cell interfaces, featuring biochemical, mechanical, and topographical cues present in the extracellular environment. This Review provides a materials science perspective on PAAm material properties, fabrication, and modification strategies relevant to cell studies, highlighting their versatility and potential to address a wide range of biological questions. Current routes are presented to integrate cell‐instructive features, such as 2D patterns, 2.5D surface topographies, or mechanical stiffness gradients. Finally, the recent advances are emphasized toward dynamic PAAm hydrogels with on‐demand control over hydrogel properties as well as electrically conductive PAAm hydrogels for bioelectronics. [ABSTRACT FROM AUTHOR]

Aims: Insulin (Ins) resistance (IRES) associates to increased cardiovascular risk as observed in metabolic syndrome. Chronic stimulation of beta-adrenergic receptors (betaAR) due to exaggerated sympathetic nervous system activity is involved in the pathogenesis of IRES. The cellular levels of G protein coupled receptor kinase 2 (GRK2) increase during chronic betaAR stimulation, leading to betaAR desensitization. We tested the hypothesis that GRK2 plays a role in betaAR-induced IRES., Methods and Results: We evaluated Ins-induced glucose uptake and signalling responses in vitro in cell overexpressing the beta(2)AR, the GRK2, or the catalytically dead mutant GRK2-DN. In a model of increased adrenergic activity, IRES and elevated cellular GRK2 levels, the spontaneously hypertensive rats (SHR) we performed the intravenous glucose tolerance test load. To inhibit GRK2, we synthesized a peptide based on the catalytical sequence of GRK2 conjugated with the antennapedia internalization sequence (Ant-124). Ins in human kidney embryonic (HEK-293) cells causes rapid accumulation of GRK2, tyrosine phosphorylation of Ins receptor substrate 1 (IRS1) and induces glucose uptake. In the same cell type, transgenic beta(2)AR overexpression causes GRK2 accumulation associated with significant deficit of IRS1 activation and glucose uptake by Ins. Similarly, transgenic GRK2 overexpression prevents Ins-induced tyrosine phosphorylation of IRS1 and glucose uptake, whereas GRK2-DN ameliorates glucose extraction. By immunoprecipitation, GRK2 binds IRS1 but not the Ins receptor in an Ins-dependent fashion, which is lost in HEK-GRK2 cells. Ant-124 improves Ins-induced glucose uptake in HEK-293 and HEK-GRK2 cells, but does not prevent GRK2/IRS1 interaction. In SHR, Ant-124 infusion for 30 days ameliorates IRES and IRS1 tyrosine phosphorylation., Conclusion: Our results suggest that GRK2 mediates adrenergic IRES and that inhibition of GRK2 activity leads to increased Ins sensitivity both in cells and in animal model of IRES.

Aims: We investigated whether exercise training could promote angiogenesis and improve blood perfusion and left ventricular (LV) remodelling of the post-myocardial infarction (MI) failing heart. We also explored the contribution of ameliorated beta-adrenergic receptor signalling and function on the overall improvement of cardiac contractility reserve induced by exercise., Methods and Results: Adult Wistar male rats were randomly assigned to one of four experimental groups. Sham-operated and post-MI heart failure (HF) rats were housed under sedentary conditions or assigned to 10-weeks of a treadmill exercise protocol. At 4 weeks after MI, sedentary HF rats showed LV eccentric hypertrophy, marked increase of LV diameters associated with severely impaired fractional shortening (14 +/- 5%), increased LV end diastolic pressure (20.9 +/- 2.6 mmHg), and pulmonary congestion. In addition, cardiac contractile responses to adrenergic stimulation were significantly blunted. In trained HF rats, exercise was able to (i) reactivate the cardiac vascular endothelial growth factor pathway with a concurrent enhancement of myocardial angiogenesis, (ii) significantly increase myocardial perfusion and coronary reserve, (iii) reduce cardiac diameters, and (iv) improve LV contractility in response to adrenergic stimulation. This latter finding was also associated with a significant improvement of cardiac beta-adrenergic receptor downregulation and desensitization., Conclusions: Our data indicate that exercise favourably affects angiogenesis and improves LV remodelling and contractility reserve in a rat model of severe chronic HF.

Alterations in signal transduction pathway of G-protein-coupled receptors (GPCRs) have been found in the cerebrocortex and in the peripheral cultured tissues of patients with Alzheimer's disease (AD). The G-protein-coupled receptor kinase-2 (GRK2) plays an important role in regulating the GPCRs signaling: its increased expression is associated with receptor desensitization. The aim of this study was to explore GRK2 levels in peripheral lymphocytes of AD patients and to establish a correlation between lymphocyte protein concentrations and the degree of cognitive impairment. GRK2 mRNA and protein expression were evaluated in the lymphocytes of AD patients with mild or moderate/severe cognitive impairment and in age-matched healthy subjects. Both GRK2 mRNA and protein expression were higher in AD patients lymphocytes compared to controls. Furthermore, lymphocyte GRK2 levels were significantly correlated to the degree of cognitive decline. Our preliminary data suggest that GRK2 is involved in GPCRs coupling dysfunction observed in AD patients. Further studies are needed in order to verify whether the lymphocyte GRK2 might be utilized as a novel biomarker in AD diagnosis and clinical monitoring.

Cross-linked poly(N-isopropylacrylamide), a typical representative of smart thermo-responsive polymers, usually shows a broad range of lower critical solution temperature (LCST) of 28–60 °C, which needs to be precisely fine-tuned in a narrow range to widen its applications. This work details the preparation of dual responsive (temperature and pH) flexible graft copolymeric hydrogel films through free radical polymerization of N-isopropylacrylamide (NIPAm) with acrylated epoxidized linseed oil (AELO) derived from linseed oil. The broad LCST of PNIPAm is fine-tuned more precisely to a narrow range of 30–33 °C with an optimized content of AELO. Further, temperature response is clearly demonstrated with the transmittance analysis of swelled gels above and below the LCST, which is also confirmed by dynamic mechanical analysis. Furthermore, different concentrations of curcumin were included in the responsive matrix to impart antioxidant properties and pH-dependent colour-changing abilities. The effect of AELO grafting and inclusion of curcumin on physicochemical properties of copolymeric hydrogel films, namely, swelling, morphology, and tensile strength, is investigated. In vitro cell studies showed that the resultant hydrogel films exhibited desirable biocompatibility with human keratinocyte and fibroblast cell lines. The results presented in this study demonstrate the potential of AELO-co-PNIPAm copolymeric hydrogel films as a viable functional material for medical patches, smart curtains, and other applications. [ABSTRACT FROM AUTHOR]

We recently published the genomic characterization of the STAT5A and STAT5B paralogous genes that are located head to head in the 17q21 chromosome and share large regions of sequence identity. We here demonstrate by transient in vitro transfection that STAT5A and STAT5B promoters are able to direct comparable levels of transcription. The expression of basal promoters is enhanced after Sp1 up-regulation in HeLa and SL2 cells while DNA methylation associated to the recruitment of MeCP2 methyl CpG binding protein down-regulates STAT5A and B promoters by interfering with Sp1-induced transcription. In addition, cross-species sequence comparison identified a bi-directional negative cis-acting regulatory element located in the STAT5 intergenic region.

In this study we examined the ability of Salmonella enterica serovar Typhimurium porins to activate activating protein 1 (AP-1) and nuclear factor kappaB (NF-kappaB) through the mitogen-activated protein kinase (MAPK) cascade, and we identified the AP-1-induced protein subunits. Our results demonstrate that these enzymes may participate in cell signaling pathways leading to AP-1 and NF-kappaB activation following porin stimulation of cells. Raf-1 was phosphorylated in response to the treatment of U937 cells with porins; moreover, the porin-mediated increase in Raf-1 phosphorylation is accompanied by the phosphorylation of MAPK kinase 1/2 (MEK1/2), p38, extracellular-signal-regulated kinase 1/2, and c-Jun N-terminal kinase. We used three different inhibitors of phosphorylation pathways: 2'-amino-3'-methoxyflavone (PD-098059), a selective inhibitor of MEK1 activator and the MAPK cascade; 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580), a specific inhibitor of the p38 pathway; and 7beta-acetoxy-1alpha,6beta,9alpha-trihydroxy-8,13-epoxy-labd-14-en-11-one (forskolin), an inhibitor at the level of Raf-1 kinase. PD-098059 pretreatment of cells decreases AP-1 and NF-kappaB activation by lipopolysaccharide (LPS) but not by porins, and SB203580 pretreatment of cells decreases mainly AP-1 and NF-kappaB activation by porins; in contrast, forskolin pretreatment of cells does not affect AP-1 and NF-kappaB activation following either porin or LPS stimulation. Our data suggest that the p38 signaling pathway mainly regulates AP-1 and NF-kappaB activation in cells treated with S. enterica serovar Typhimurium porins. Antibody electrophoretic mobility shift assays showed that JunD and c-Fos binding is found in cells treated with porins, in cells treated with LPS, and in unstimulated cells. However, by 30 to 60 min of stimulation, a different complex including c-Jun appears in cells treated with porins or LPS, while the Fra-2 subunit is present only after porin stimulation. These data suggest different molecular mechanisms of activation induced by porins or by LPS.

The tunable properties of stimuli-responsive copolymers or hydrogels enable their application in different fields such as biomedical engineering, tissue engineering, or even drug release. Here we introduce a new PNIPAM-based triblock copolymer material comprising a controlled amount of a novel hydrophobic crosslinker 2,40 -diacryloyloxy benzophenone (DABP) and acrylic acid (AAc) to achieve lower critical solution temperature (LCST) between ambient and body temperatures. The dual stimuli-responsive p(NIPAM-coDABP-co-AAc) triblock copolymer material and hydrogel were synthesized, and their temperature and pHresponsive behaviors were systematically investigated. The hydrogel exhibited excellent temperature and pH-responsive properties with an LCST of around 30 1C. Moreover, the synthesized copolymer has been demonstrated to be nontoxic both in vitro and in vivo. When the hydrogel was preloaded with the model drug 5-fluorouracil (5-FU), the designed hydrogel released the drug in a temperature and pH-controlled fashion. It was observed that the prepared hydrogel has the ability to entrap 5-FU, and the loading is more than 85%. In the case of temperature-controlled release, we observed almost complete release of 5-FU at lower temperatures and sustained release behavior at higher temperatures. In addition, the hydrogel matrix was able to retard the release of 5-FU in an acidic environment and selectively release 5-FU in a basic environment. By realizing how the hydrogel properties influence the release of drugs from preloaded hydrogels, it is possible to design new materials with myriad applications in the drug delivery field. [ABSTRACT FROM AUTHOR]

Although micron-sized microgels have become important building blocks in regenerative materials, offering decisive interactions with living matter, their chemical composition mostly significantly varies when their network morphology is tuned. Since cell behavior is simultaneously affected by the physical, chemical, and structural properties of the gel network, microgels with variable morphology but chemical equivalence are of interest. This work describes a new method to produce thermoresponsive microgels with defined mechanical properties, surface morphologies, and volume phase transition temperatures. A wide variety of microgels is synthesized by crosslinking monomers or star polymers at different temperatures using thermally assisted microfluidics. The diversification of microgels with different network structures and morphologies but of chemical equivalence offers a new platform of microgel building blocks with the ability to undergo phase transition at physiological temperatures. The method holds high potential to create soft and dynamic materials while maintaining the chemical composition for a wide variety of applications in biomedicine., (© 2024 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Cardiac rehabilitation, a comprehensive exercise-based lifestyle and medical management, is effective in decreasing morbidity and improving life quality in patients with coronary heart disease. Endothelial function, an irreplaceable indicator in coronary heart disease progression, is measured by various methods in traditional cardiac rehabilitation pathways, including medicinal treatment, aerobic training, and smoking cessation. Nevertheless, studies on the effect of some emerging cardiac rehabilitation programs on endothelial function are limited. This article briefly reviewed the endothelium-beneficial effects of different cardiac rehabilitation pathways, including exercise training, lifestyle modification and psychological intervention in patients with coronary heart disease, and related experimental models, and summarized both uncovered and potential cellular and molecular mechanisms of the beneficial roles of various cardiac rehabilitation pathways on endothelial function. In exercise training and some lifestyle interventions, the enhanced bioavailability of nitric oxide, increased circulating endothelial progenitor cells (EPCs), and decreased oxidative stress are major contributors to preventing endothelial dysfunction in coronary heart disease. Moreover, the preservation of endothelial-dependent hyperpolarizing factors and inflammatory suppression play roles. On the one hand, to develop more endothelium-protective rehabilitation methods in coronary heart disease, adequately designed and sized randomized multicenter clinical trials should be advanced using standardized cardiac rehabilitation programs and existing assessment methods. On the other hand, additional studies using suitable experimental models are warranted to elucidate the relationship between some new interventions and endothelial protection in both macro- and microvasculature., Competing Interests: Compliance and ethics. The author(s) declare that they have no conflict of interest., (© 2024. Science China Press.)

Renal tumors comprise ~7% of all malignant pediatric tumors. Approximately 90% of pediatric kidney tumors comprise Wilms tumors, and the remaining 10% include clear cell sarcoma of the kidney, malignant rhabdoid tumor of the kidney, renal cell carcinoma and other rare renal tumors. Over the last 30 years, the role of cytokines and their receptors has been considerably investigated in both cancer progression and anti-cancer therapy. However, more effective immunotherapies require the cytokine profiling of each tumor type and comprehensive understanding of tumor biology. In this study, we aimed to investigate the activation of signaling pathways in response to cytokines in three pediatric kidney tumor cell lines, in WT-CLS1 and WT-3ab cells (both are Wilms tumors), and in G-401 cells (a rhabdoid kidney tumor, formerly classified as Wilms tumor). We observed that interferon-alpha (IFN-α) and interferon-gamma (IFN-γ) very strongly induced the activation of the STAT1 protein, whereas IL-6 and IFN-α activated STAT3 and IL-4 activated STAT6 in all examined tumor cell lines. STAT protein activation was examined by flow cytometry and Western blot using phospho-specific anti-STAT antibodies which recognize only activated (phosphorylated) STAT proteins. Nuclear translocation of phospho-STAT proteins upon activation with specific cytokines was furthermore confirmed by immunofluorescence. Our results also showed that both IFN-α and IFN-γ caused upregulation of major histocompatibility complex (MHC) class I proteins, however, these cytokines did not have any effect on the expression of MHC class II proteins. We also observed that pediatric kidney tumor cell lines exhibit the functional expression of an additional cytokine signaling pathway, the tumor necrosis factor (TNF)-α-mediated activation of nuclear factor kappa B (NF-κB). In summary, our data show that human pediatric renal tumor cell lines are responsive to stimulation with various human cytokines and could be used as in vitro models for profiling cytokine signaling pathways. [ABSTRACT FROM AUTHOR]

The first aim of this study is to develop a photo‐ATRP process using methyl methacrylate (MMA) by employing a novel perylenediimide derivative (PDI) as photoinitiator. The analysis of the MMA photopolymerization process kinetics is performed in solution and in bulk, demonstrating control over the reaction progress even if the polymerizations display a slow initiation step. The photo‐ATRP process for MMA in suspension is also developed and the obtained PMMA particles are further used to reinitiate the ATRP polymerization of thermoresponsive polymers (different molecular weights poly(ethylene glycol) methyl ether methacrylate and poly(N‐isopropylacrylamide)) (PNIPAM) in solution and surface‐initiated processes. The synthesized polymers by surface‐initiated process display a bimodal molecular weight distribution with a clear modification of the signal areas ratio depending on the grafted monomer and on the reaction conditions. The grafting process can take place on the surface of the polymer particles (Mn2), or it can also involve polymer chains located further at the interior of the polymer particles (Mn1). The lower critical solution temperature (LCST) transition is demonstrated for the PNIPAM functionalized polymer particles. [ABSTRACT FROM AUTHOR]

Over the past decades, thermoresponsive polymers are attracted much scientific attention and can be widely used in a wide range of applications. Synthesis of polymers throughCfunctionalization of polysaccharide using synthetic materials paves the way for producing much desirable natural biopolymer‐based copolymers. Therefore, this study reported about synthesis of thermo and pH‐responsive polymers, based on tamarind kernel polysaccharide (TKP) and poly (N‐isopropyl acrylamide) (pNIPAM) through atom transfer radical polymerization (ATRP) with controlled polymer chain length. The chemical structure and surface morphology have been investigated by different characterization techniques. Lower Critical Solution Temperature (LCST) confirmed the thermo‐responsive nature of the copolymer. The self‐aggregation among the polymer chains was found above LCST (34 °C). Rheological characterizations suggested that our prepared copolymers are non‐Newtonian shear thinning in nature. Finally, the developed material shows worthy efficacy towards the thermo‐responsive release of encapsulated dye at pH 7.4 (53 % and 65 % at 37 °C and 25 °C, respectively) suggesting that our prepared material could be a good candidate for therapeutic release in tissue engineering application. [ABSTRACT FROM AUTHOR]

Deformation of biological cells, tissues, and similar soft materials is often considered linearly elastic; however, the assumption is only valid in a very limited stress range and often leads to significant errors in mechanical evaluation. We demonstrated the hyper-elastic behavior of ultra-soft poly(N-isopropyl acrylamide) (PNIPAm) microgels (USPNMs) in a converging channel flow, as a representation for biological tissues. The hyper-elasticity of USPNMs in response to a broad range of deformation was characterized at the centerline of the converging flow. We introduced a carrier fluid consisting of baby hydrogels (avg. diameter, 10 μ m) and oil that carried the hydrophilic USPNM sample (avg. diameter, 100 μ m) on the centerline of oil background fluid. By "baby hydrogel," we mean small PNIPAm particles obtained during USPNM synthesis, using which, enabled settling-free flow, prevented wall contact, and enhanced carrier fluid viscosity for increased stresses at lower flowrates. Furthermore, drastic reduction of interfacial tension was observed in the converging area due to contact of baby gels with USPNM particles in the carrier fluid. The shear and elongational stresses were balanced with the elastic stress and interfacial Laplace pressure. As a result, we obtained a stress–strain curve from the microscopic images during flow. The non-linear stress–strain curve was characterized by conventional hyper-elastic models. The elastic modulus of the synthesized USPNM was 24 Pa , which is as low as animal brain tissue. This method holds great potential for implementing in similar hyper-elastic systems, enabling accurate mechanical evaluations in the field of soft materials, biology, and medicine. [ABSTRACT FROM AUTHOR]

Cardiovascular disease is an enormous public health problem, particularly in older populations. Exercise is the most potent cardioprotective intervention identified to date, with exercise in the juvenile period potentially imparting greater protection, given the plasticity of the developing heart. To test the hypothesis that voluntary wheel running early in life would be cardioprotective later in life when risk for disease is high, we provided male and female juvenile (3 wk old) mice access to a running wheel for 2 wk. Mice then returned to a home cage to age to adulthood (4--6 mo) before exposure to isoproterenol (ISO) to induce cardiac stress. Cardiac function and remodeling were compared with sedentary control mice, sedentary mice exposed to ISO, and mice that exercised in adulthood immediately before ISO. Early in life activity protected against ISO-induced stress as evidenced by attenuated cardiac mass, myocyte size, and fibrosis compared with sedentary mice exposed to ISO. ISO-induced changes in cardiac function were ameliorated in male mice that engaged in wheel running, with ejection fraction and fractional shortening reversed to control values. Adrenergic receptor expression was downregulated in juvenile male runners. This suppression persisted in adulthood following ISO, providing a putative mechanism by which exercise in the young male heart provides resilience to cardiac stress later in life. Together, we show that activity early in life induces persistent cardiac changes that attenuate ISO-induced stress in adulthood. Identification of the mechanisms by which early in life exercise is protective will yield valuable insights into how exercise is medicine across the life course. [ABSTRACT FROM AUTHOR]

Diverse extracellular and intracellular cues activate mammalian mitogen-activated protein kinases (MAPKs). Canonically, the activation starts at cell surface receptors and continues via intracellular MAPK components, acting in the host cell nucleus as activators of transcriptional programs to regulate various cellular activities, including proinflammatory responses against bacterial pathogens. For instance, binding host pattern recognition receptors (PRRs) on the surface of intestinal epithelial cells to bacterial pathogen external components trigger the MAPK/NF-κB signaling cascade, eliciting cytokine production. This results in an innate immune response that can eliminate the bacterial pathogen. However, enteric bacterial pathogens evolved sophisticated mechanisms that interfere with such a response by delivering virulent proteins, termed effectors, and toxins into the host cells. These proteins act in numerous ways to inactivate or activate critical components of the MAPK signaling cascades and innate immunity. The consequence of such activities could lead to successful bacterial colonization, dissemination, and pathogenicity. This article will review enteric bacterial pathogens' strategies to modulate MAPKs and host responses. It will also discuss findings attempting to develop anti-microbial treatments by targeting MAPKs. [ABSTRACT FROM AUTHOR]

Background and Objective. Studies have shown that physical activity not only reduces cardiovascular risk factors but also improves cardiac protection against ischemia-reperfusion. One of the protective pathways of the heart against ischemia is mitochondrial function protection, and the role of exercise preconditioning in this mechanism is important. We investigated the exercise pretraining on mitochondrial biogenesis effect, angiogenesis, and cardiac tissue injury in male rats following stroke. Materials and Methods. Twenty-four male rats were divided into 4 groups including MI, Sham, HIIT, and HIIT+MI (N = 6). HIIT and HIIT+MI which underwent high-intensity interval training (HIIT) for 4 weeks (5 days a week). The training protocol included 10 intervals of 1-minute running, with 2 minutes rest between each interval. The training intensity was different every week according to the peak treadmill running speed (v peak) percentage of each rat. Isoproterenol injection was used to induce myocardial infarction (MI). Expressions of creatine kinase-MB (CK-MB), PGC-1α troponin-I, mitochondrial transcription factor A (TFAM), vascular endothelial growth factor (VEGF), and microRNA 126 (miR-126) genes were measured. The variables were measured using biochemical and RT-PCR methods. The significance level (P value≤0.05) was analyzed using ANOVA test. Results. The results showed that 4 weeks of HIIT training led to a significant increase in PGC-1α, TFAm, and VEGF levels in the MI, HIIT, and HIIT+MI groups compared to the sham group (P = 0.001). HIIT exercises increased miR-126 in the different groups compared to the sham group; however, it was not significant. Conclusion. The results obtained showed that HIIT exercise exerts cardio-protective effects to reduce cardiac tissue injury and necrosis against MI. These effects increase mitochondrial biogenesis and angiogenesis by inducing the increased expression of VEGF, TFAM, PGC-1α, and miR-126 genes in the heart tissue. Therefore, HIIT training, as a preconditioning program, was able to protect the cardiac tissue against MI. [ABSTRACT FROM AUTHOR]

A class-A GPCR dopamine D2 receptor (D2R) plays a critical role in the proper functioning of neuronal circuits through the downstream activation of both G-protein- and β-arrestin-dependent signaling pathways. Understanding the signaling pathways downstream of D2R is critical for developing effective therapies with which to treat dopamine (DA)-related disorders such as Parkinson's disease and schizophrenia. Extensive studies have focused on the regulation of D2R-mediated extracellular-signal-regulated kinase (ERK) 1/2 signaling; however, the manner in which ERKs are activated upon the stimulation of a specific signaling pathway of D2R remains unclear. The present study conducted a variety of experimental techniques, including loss-of-function experiments, site-directed mutagenesis, and the determination of protein interactions, in order to investigate the mechanisms underlying β-arrestin-biased signaling-pathway-mediated ERK activation. We found that the stimulation of the D2R β-arrestin signaling pathway caused Mdm2, an E3 ubiquitin ligase, to move from the nucleus to the cytoplasm and interact with tyrosine phosphorylated G-protein-coupled receptor kinase 2 (GRK2), which was facilitated by Src, a non-receptor tyrosine kinase. This interaction led to the ubiquitination of GRK2, which then moved to the plasma membrane and interacted with activated D2R, followed by the phosphorylation of D2R as well as the mediation of ERK activation. In conclusion, Mdm2-mediated GRK2 ubiquitination, which is selectively triggered by the stimulation of the D2R β-arrestin signaling pathway, is necessary for GRK2 membrane translocation and its interaction with D2R, which in turn mediates downstream ERK signaling. This study is primarily novel and provides essential information with which to better understand the detailed mechanisms of D2R-dependent signaling. [ABSTRACT FROM AUTHOR]

Oral wound treatment faces challenges due to the complex oral environment, thus, sealing the wound quickly becomes necessary. Although some materials have achieved adhesion and sterilization, how to effectively solve the contradiction between strong adhesion and on-demand removal remains a challenge. Herein, a reversibly adhesive hydrogel is designed by free radical copolymerization of cationic monomer [2-(acryloyloxy) ethyl] trimethylammonium chloride (ATAC), hydrophobic monomer ethylene glycol phenyl ether acrylate (PEA) and N-isopropylacrylamide (NIPAAm). The cationic quaternary ammonium salts provide electrostatic interactions, the hydrophobic groups provide hydrophobic interactions, and the PNIPAAm chain segments provide hydrogen bonding, leading to strong adhesion. Therefore, the hydrogel obtains an adhesion strength of 18.67 KPa to oral mucosa and can seal wounds fast within 10 s. Furthermore, unlike pure PNIPAAm, the hydrogel has a lower critical solution temperature of 40.3 °C due to the contribution of ATAC and PEA, enabling rapid removal with 40 °C water after treatment. In addition, the hydrogel realizes excellent anti-swelling ratio (≈80%) and antibacterial efficiency (over 90%). Animal experiments prove that the hydrogel effectively reduces inflammation infiltration, promotes collagen deposition and vascular regeneration. Thus, hydrogel as a multi-functional dressing has great application prospects in oral wound management., (© 2024 Wiley‐VCH GmbH.)

Neisseria meningitidis is the most frequent cause of bacterial meningitis and is one of the few bacterial pathogens that can breach the blood-brain barrier (BBB). The 37/67 kDa laminin receptor (LamR) was previously identified as a receptor mediating meningococcal binding to rodent and human brain microvascular endothelial cells, which form part of the BBB. The meningococcal surface proteins PorA and PilQ were identified as ligands for this receptor. Subsequently, the fourth extracellular loop of PorA (PorA-Loop4) was identified as the LamR-binding moiety. Here, we show that PorA-Loop4 targets the 37 kDa laminin receptor precursor (37LRP) on the cell surface by demonstrating that deletion of this loop abrogates the recruitment of 37LRP under meningococcal colonies. Using a circularized peptide corresponding to PorA-Loop4, as well as defined meningococcal mutants, we demonstrate that host cell interaction with PorA-Loop4 results in perturbation of p-CDK4 and Cyclin D1. These changes in cell cycle control proteins are coincident with cellular responses including inhibition of cell migration and a G1 cell cycle arrest. Modulation of the cell cycle of host cells is likely to contribute to the pathogenesis of meningococcal disease. [ABSTRACT FROM AUTHOR]

The Signal Transducer and Activator of Transcription (STAT)-5 proteins are required in immune regulation and homeostasis and play a crucial role in the development and function of several hematopoietic cells. STAT5b activation is involved in the expression of genes that participate in cell development, proliferation, and survival. STAT5a and STAT5b are paralogs and only human mutations in STAT5B have been identified leading to immune dysregulation and hematopoietic malignant transformation. The inactivating STAT5B mutations cause impaired post-natal growth, recurrent infections and immune dysregulation, whereas gain of function somatic mutations cause dysregulated allergic inflammation. These mutations are rare, and they are associated with a wide spectrum of clinical manifestations which provide a disease model elucidating the biological mechanism of STAT5 by studying the consequences of perturbations in STAT5 activity. Further, the use of Jak inhibitors as therapy for a variety of autoimmune and malignant disorders has increased substantially heading relevant lessons for the consequences of Jak/STAT immunomodulation from the human model. This review summarizes the biology of the STAT5 proteins, human disease associate with molecular defects in STAT5b, and the connection between aberrant activation of STAT5b and the development of certain cancers. [ABSTRACT FROM AUTHOR]

Several researches have demonstrated that synthetic hydrogels can mimic the mechanical and physicochemical properties of native extracellular matrices and act as cell‐scaffold. The biointerface can influence over tissue activities such as adhesion, signaling, cell–cell communications, and proliferation. In this work, the behavior of human embryonic kidney cells (HEK293) in contact with hydrogel surfaces based on poly‐N‐isopropylacrylamide (PNIPAM) and copolymers is studied. Ionic and neutral hydrogel surfaces are synthesized by free radical polymerization and characterized by Fourier‐transform infrared spectroscopy, swelling capacity, and wettability at culture conditions. Viability, proliferation, and bioadhesive capacity are analyzed by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide and Neutral Red assays, [3H]‐thymidine technique, Acridine Orange and Hoechst dye. Noncytotoxic and proliferative effects are observed in all cases. HEK293 cells are mainly adapted and adhered on neutral and low ionic charge surfaces showing typical cell morphology, and normal mitotic rates. While, lower adhesion, abnormal nuclear and cytoplasmic morphologies with mitotic/fragmentation processes are observed after contact with high ionic surfaces. The cellular cycle after cultive on PNIPAM, assessed by flow cytometry, is not affected regarding control surfaces (polystyrene). Therefore, hydrogel surfaces with neutral and low ionic charges can be apt to in vitro tissue development and possible applications of biomedical treatments. [ABSTRACT FROM AUTHOR]

This work reports preparing thermal responsive poly (N-isovinylcaprolactam) (PNVCL) microgel based films for cell growth and detachment. PNVCL microgels of hydrated size ranging from 386 to 815 nm (25 °C) and different crosslinking degree are prepared. The PNVCL microgels can be rapidly and massively deposited on glass by spin coating method. Atomic force microscopy (AFM) and water contact angle (WCA) are used to study the influence of crosslinking degree and particle size on the surface morphology, stability, and hydrophilicity of PNVCL microgel film. The cell activity of the desorbed cells is quantitatively characterized employing human normal lung epithelial cells (BEAS-2B). The results show that BEAS-2B cells can be desorbed quickly from the film in 30 min, and the optical density (OD) value of desorbed cells incubated after 3 d increases by approximately 52% compared to the control group. This study broadens the selection of temperature-sensitive film for cell harvesting, and provides a new tool for the quantitative characterization of desorbed cells., (© 2024 Wiley‐VCH GmbH.)

Recent evidences have shown that exercise training not only plays a necessary role in maintaining cardiac homeostasis, but also promotes cardiac repair after myocardial infarction. Post-myocardial infarction, exercise training has been observed to effectively increase the maximum cardiac output, and protect myocardial cells against necrosis and apoptosis, thus leading to an improved quality of life of myocardial infarction patients. In fact, exercise training has received more attention as an adjunct therapeutic strategy for both treatment and prevention of myocardial infarction. This review summarizes the experimental evidence of the effects of exercise training in ventricular remodeling after myocardial infarction, and tries to provide theoretical basis along with suitable references for the exercise prescription aimed at prevention and therapy of myocardial infarction. [ABSTRACT FROM AUTHOR]

Chitinase-3-like protein 1 (CHI3L1) is a myokine involving tissue remodeling and inflammatory processes. CHI3L1 and its receptor protease-activated receptor 2 (PAR2) are induced by exercise in skeletal muscles. However, it remains unknown if CHI3L1/PAR2 signaling also mediates exercise-induced cardioprotection after myocardial infarction. Twenty-four adult male rats were divided into three groups (n = 8/group), receiving: (1) a sham operation; (2) permanent ligation of left anterior descending coronary artery; and (3) post-MI exercise training with one-week adaptive treadmill exercise for seven days followed by four weeks of aerobic exercise. Left ventricular systolic and end-diastolic pressure indices were measured and cardiac fibrosis, and angiogenesis were examined. Furthermore, HUVEC cells were treated in vitro with AMPK agonist—AICAR (a putative pharmacological memetic of exercise), recombinant human CHI3L1, PAR2 receptor blocker (AZ3451), and PI3K inhibitor (LY294002), respectively. We found that post-MI exercise significantly upregulated CHI3L1, PAR2, pPI3K/PI3K, pAKT/AKT, pERK/ERK, improved cardiac function, and diminished fibrosis. AICAR increased HUVEC tubules formation and upregulated CHI3L1 and PAR2 and these changes were attenuated by PAR2 blocker. In conclusion, post-MI exercise training can effectively activate CHI3L1/PAR2 signaling, which led to the improved myocardial function and enhanced cardiac angiogenesis in the infarcted heart. [ABSTRACT FROM AUTHOR]

This study presents a comprehensive survey of microgel‐coated materials and their functional behavior, describing the complex interplay between the physicochemical and mechanical properties of the microgels and the chemical and morphological features of substrates. The cited literature is articulated in four main sections: i) properties of 2D and 3D substrates, ii) synthesis, modification, and characterization of the microgels, iii) deposition techniques and surface patterning, and iv) application of microgel‐coated surfaces focusing on separations, sensing, and biomedical applications. Each section discusses – by way of principles and examples – how the various design parameters work in concert to deliver functionality to the composite systems. The case studies presented herein are viewed through a multi‐scale lens. At the molecular level, the surface chemistry and the monomer make‐up of the microgels endow responsiveness to environmental and artificial physical and chemical cues. At the micro‐scale, the response effects shifts in size, mechanical, and optical properties, and affinity towards species in the surrounding liquid medium, ranging from small molecules to cells. These phenomena culminate at the macro‐scale in measurable, reversible, and reproducible effects, aiming in a myriad of directions, from lab‐scale to industrial applications. [ABSTRACT FROM AUTHOR]

Purpose: Physical activity (PA) represents the first line of defence against diseases characterised by increased inflammation status, such as metabolic and infectious diseases. Conversely, a sedentary lifestyle—associated with obesity, type 2 diabetes and cardiovascular disorders—negatively impacts on general health status, including susceptibility to infections. At a time of a pandemic SARS-CoV2 infection, and in the context of the multiorgan crosstalk (widely accepted as a mechanism participating in the pathophysiology of all organs and systems), we examine the complex interplay mediated by skeletal muscle contraction involving the immune system and how this contributes to control health status and to counteract viral infections. In so doing, we review the molecular mechanisms and expression of molecules modulated by PA, able to provide the proper molecular equipment against viral infections such as the current SARS-CoV2. Methods: A critical review of the literature was performed to elucidate the molecular mechanisms and mediators induced by PA that potentially impact on viral infections such as SARS-CoV2. Results: We showed the effects mediated by regular moderate PA on viral adverse effects through the regulation of biological processes involving the crosstalk between skeletal muscle, the immune system and adipose tissue. Evidence was provided of the effects mediated by modulation of the expression of inflammation markers. Conclusion: A tigth association between PA and reduction in inflammation status allows effective counteracting of SARS-CoV2 infection. It is therefore essential to persuade people to keep active. [ABSTRACT FROM AUTHOR]

Due to their mechanical and structural similarity to native tissues, hydrogel biomaterials have gained tremendous popularity for applications in 3D tissue culture, therapeutic screening, disease modeling, and regenerative medicine. Recent advances in pre‐ and post‐synthetic processing have afforded anisotropic manipulation of the biochemical, mechanical, and topographical properties of biocompatible gels, increasingly in a dynamic and heterogeneous fashion that mimics natural processes in vivo. Herein, the current state of hydrogel surface patterning to investigate cellular interactions with the surrounding matrix is reviewed, both in techniques utilized and biological findings explored, and the perspective on proposed future directions for the field is offered. [ABSTRACT FROM AUTHOR]

BACKGROUND: Systemic inflammatory biomarkers reflect level of inflammatory response, which have been suggested as prognostic factors in cancer patients. OBJECTIVE: To estimate the prognostic value of inflammatory biomarkers in 149 patients with head and neck soft tissue sarcoma (HNSTS). METHODS: Pre-treatment neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index (SII), neutrophil-platelet score (NPS) and Aarhus Composite Biomarker Score (ACBS) were analyzed for association with overall survival (OS) and progression-free survival (PFS). Nomograms were consisted of independent predictors for OS and PFS, and evaluated by calibration curve and concordance index (C-index). RESULTS: In multivariate analysis, LMR (HR = 0.42, 95% CI: 0.19–0.94, P = 0.035), ACBS (HR = 2.05, 95% CI: 1.02–4.12, P = 0.045) and AJCC stage were independent prognostic markers of OS. Moreover, high NLR (HR = 1.78, 95% CI: 1.07–2.94, P = 0.024) and advanced AJCC stage were independently related with worse PFS. Calibration curves reflected good discriminative ability of prognosis. The nomograms showed better accuracy of predicting OS (C-index: 0.748 vs. 0.690, P = 0.009) and PFS (C-index: 0.644 vs. 0.612, P = 0.028) than stage. CONCLUSIONS: Pre-treatment LMR, ACBS and AJCC stage were effective predictor of OS. The NLR and AJCC stage could independently predict PFS. The nomogram might act as a promising prognostic model for OS and PFS in HNSTS. [ABSTRACT FROM AUTHOR]

Aims: The effects of GRK2 inhibition on myocardial metabolism in heart failure (HF) are unchartered. In this work, we evaluated the impact of pharmacological inhibition of GRK2 by a cyclic peptide, C7, on metabolic, biochemical, and functional phenotypes in experimental HF. Methods and results: C7 was initially tested on adult mice ventricular myocyte from wild type and GRK2 myocardial deficient mice (GRK2‐cKO), to assess the selectivity on GRK2 inhibition. Then, chronic infusion of 2 mg/kg/day of C7 was performed in HF mice with cryogenic myocardial infarction. Cardiac function in vivo was assessed by echocardiography and cardiac catheterization. Histological, biochemical, and metabolic studies were performed on heart samples at time points. C7 induces a significant increase of contractility in wild type but not in adult ventricle myocytes from GRK2‐cKO mice, thus confirming C7 selectivity for GRK2. In HF mice, 4 weeks of treatment with C7 improved metabolic features, including mitochondrial organization and function, and restored the biochemical and contractile responses. Conclusions: GRK2 is a critical molecule in the physiological regulation of cardiac metabolism. Its alterations in the failing heart can be pharmacologically targeted, leading to the correction of metabolic and functional abnormalities observed in HF. [ABSTRACT FROM AUTHOR]

Exercise training is known to prolong the ventricular cardiomyocyte action potential duration (APD), increasing Ca2+ influx and contractility. The prolonged APD is caused, in part, by a decreased responsiveness to β-adrenergic agonists. The study’s aims were to elucidate the mechanisms by which exercise training alters -adrenergic regulation and to determine the involvement of delayed rectifier potassium channels (lKr and lKs) in the response. Rats were randomly assigned to wheel running-trained (TRN) or sedentary (SED) groups. After 6 – 8 wk of training, myocytes were isolated from the apex and base regions of the left ventricle, and current–voltage relationships of lKr and lKs were measured. Myocytes from SED and TRN rats exhibit lower lKr current compared with lKs, and a regional difference in lKs was observed, with higher current in apex compared with base myocytes. Wheel running decreased lKs at positive voltages and reduced lKs responsiveness to β-agonist. lKs channel subunit KCNQ1 content was higher in apex compared with base, and exercise training decreased KCNQ1 and KCNE1 subunit content in both regions. Exercise training had no effect on β1-adrenergic receptor content but reduced the kinase anchoring protein yotiao and β-adrenergic receptor kinase GRK2 compared with SED rats. The reduced KCNQ1, KCNE1, and yotiao provide a mechanism underlying the training-induced decrease in lKs current, while downregulation of GRK2 would reduce inactivation of the β1-AR, maintaining adrenergic stimulation of contractility. Collectively, these membrane protein changes in response to TRN provide a mechanism for prolonging the APD, increasing myocyte efficiency in low stress conditions, while increasing contractility. NEW & NOTEWORTHY Results demonstrate that exercise training (TRN) downregulates ventricular lKs channel current and the channel’s responsiveness to -agonist factors mediated by TRN-induced decline in channel subunits KCNQ1 and KCNE1 and the A-kinase anchoring protein yotiao. The reduced lKs current helps explain the TRN-induced prolongation of the action potential in basal conditions and, coupled with previously reported upregulation of the KATP channel, results in a more efficient heart that is better able to respond to beat-by-beat changes in metabolism. [ABSTRACT FROM AUTHOR]

Aims: We assessed the effects of a short-term exercise training on cardiac function, oxidative stress markers, and type 3 iodothyronine deiodinase (D3) activity in cardiac tissue of spontaneously hypertensive rats (SHR) following experimental myocardial infarction (MI). Methods: Twenty-four SHR (aged 3 months) were allocated to 4 groups: sham+sedentary, sham+trained, MI+sedentary and MI+trained. MI was performed by permanent ligation of the coronary artery. Exercise training (treadmill) started 96 hours after MI and lasted for 4 weeks (~60% maximum effort, 4x/week and 40 min/day). Cardiac function (echocardiography), thioredoxin reductase (TRx), total carbonyl levels, among other oxidative stress markers and D3 activity were measured. A Generalized Estimating Equation was used, followed by Bonferroni’s test (p<0.05). Results: MI resulted in an increase in left ventricular mass (p = 0.002) with decreased cardiac output (~22.0%, p = 0.047) and decreased ejection fraction (~41%, p = 0.008) as well as an increase in the carbonyl levels (p = 0.001) and D3 activity (~33%, p<0.001). Exercise training resulted in a decrease in left ventricular mass, restored cardiac output (~34%, p = 0.048) and ejection fraction (~20%, p = 0.040), increased TRx (~85%, p = 0.007) and reduced carbonyl levels (p<0.001) and D3 activity (p<0.001). Conclusions: Our short-term exercise training helped reverse the effects of MI on cardiac function. These benefits seem to derive from a more efficient antioxidant response and lower D3 activity in cardiac tissue. [ABSTRACT FROM AUTHOR]

Impairment of the myogenic response can affect capillary hydrostatic pressure and contribute to peripheral edema and exercise intolerance, which are markers of heart failure (HF). The aim of this study was to assess the effects of exercise training (ET) on myogenic response in skeletal muscle resistance arteries and peripheral edema in HF rats, focusing on the potential signaling pathways involved in these adjustments. Male Wistar rats were submitted to either coronary artery occlusion or a sham-operated surgery. After 4 wk, an exercise test was performed, and the rats were divided into the following groups: untrained normal control (UNC) and untrained HF (UHF) and exercise-trained (on treadmill, 50-60% of maximal capacity) NC (TNC) and exercise-trained HF (THF). Caudal tibial artery (CTA) myogenic response was impaired in UHF compared with UNC, and ET restored this response in THF to NC levels and increased it in TNC. Rho kinase (ROCK) inhibitor abolished CTA myogenic response in the untrained and blunted it in exercise-trained groups. CTA-stored calcium (Ca2+) mobilization was higher in exercise-trained rats compared with untrained rats. The paw volume was higher in UHF rats, and ET decreased this response compared with UNC. Myogenic constriction was positively correlated with maximal running distance and negatively correlated with paw volume. The results demonstrate, for the first time, that HF impairs the myogenic response in skeletal muscle arteries, which contributes to peripheral edema in this syndrome. ET restores the myogenic response in skeletal muscle arteries improving Ca2+ sensitization and handling. Additionally, this paradigm also improves peripheral edema and exercise intolerance. [ABSTRACT FROM AUTHOR]

Mitochondrial regulation of energy production, calcium homeostasis, and cell death are critical for cardiac function. Accordingly, the structural and functional abnormalities of these organelles (mitochondrial dysfunction) contribute to developing cardiovascular diseases and heart failure. Therefore the preservation of mitochondrial integrity is essential for cardiac cell survival. Mitochondrial function is regulated by several proteins, including GRK2 and β-arrestins which act in a GPCR independent manner to orchestrate intracellular signaling associated with key mitochondrial processes. It is now ascertained that GRK2 is able to recover mitochondrial function in response to insults. β-arrestins affect several intracellular signaling pathways within the cell which in turn are involved in the regulation of mitochondrial function, but a direct regulation of mitochondria needs further investigations. In this review, we discuss the recent acquisitions on the role of GRK2 and β-arrestins in the regulation of mitochondrial function. [ABSTRACT FROM AUTHOR]