Biophysical translational paradigm of polymeric nanoparticle: Embarked advancement to brain tumor therapy.

Polymeric nanoparticles have emerged as promising contenders for addressing the intricate challenges encountered in brain tumor therapy due to their distinctive attributes, including adjustable size, biocompatibility, and controlled drug release kinetics. This review comprehensively delves into the latest developments in synthesizing, characterizing, and applying polymeric nanoparticles explicitly tailored for brain tumor therapy. Various synthesis methodologies, such as emulsion polymerization, nanoprecipitation, and template-assisted fabrication, are scrutinized within the context of brain tumor targeting, elucidating their advantages and limitations concerning traversing the blood-brain barrier. Furthermore, strategies pertaining to surface modification and functionalization are expounded upon to augment the stability, biocompatibility, and targeting prowess of polymeric nanoparticles amidst the intricate milieu of the brain microenvironment. Characterization techniques encompassing dynamic light scattering, transmission electron microscopy, and spectroscopic methods are scrutinized to evaluate the physicochemical attributes of polymeric nanoparticles engineered for brain tumor therapy. Moreover, a comprehensive exploration of the manifold applications of polymeric nanoparticles encompassing drug delivery, gene therapy, imaging, and combination therapies for brain tumours is undertaken. Special emphasis is placed on the encapsulation of diverse therapeutics within polymeric nanoparticles, thereby shielding them from degradation and enabling precise targeting within the brain. Additionally, recent advancements in stimuli-responsive and multifunctional polymeric nanoparticles are probed for their potential in personalized medicine and theranostics tailored for brain tumours. In essence, this review furnishes an all-encompassing overview of the recent strides made in tailoring polymeric nanoparticles for brain tumor therapy, illuminating their synthesis, characterization, and multifaceted application.

ExoDS: a versatile exosome-based drug delivery platform to target cancer cells and cancer stem cells.

Chemotherapy drugs like doxorubicin (Dox) are widely used in middle-income countries around the world to treat various types of cancers, including breast cancer. Although they are toxic, they are still widely used to treat cancer. Delivering chemotherapy drugs directly to cancer cells to reduce side effects remains a challenge. Moreover, modern research gave rise to cancer stem cell theory, which implicated cancer stem cells in tumor initiation, progression, and relapse. This makes it imperative to target cancer stem cells to achieve complete remission. Our work highlights the development of an exosome-based targeted drug delivery vehicle. These exosomes were isolated from mature dendritic cells (mDCs) and encapsulated with doxorubicin (ExoDS). Our results showed that ExoDS specifically targeted breast cancer cells and breast cancer stem cells. Further analysis revealed that ExoDS did not induce any significant apoptosis in healthy mammary cells and peripheral blood mononuclear cells (PBMCs) isolated from healthy individuals and breast cancer patients. ExoDS was also found to target circulating tumor cells (CTCs) isolated from patient blood. ExoDS also showed equal efficiency compared to free doxorubicin in vivo. We also observed that ExoDS reduced the expression of cancer stem cell markers in murine tumor tissues. Altogether, this work provides novel insights into how mDC-derived exosomes can be used to specifically target cancer cells and cancer stem cells.

Molecular insights to in vitro biocompatibility of endodontic Pulpotec with macrophages determined by oxidative stress and apoptosis.

Pulp therapy has been emerged as a one of the efficient therapies in the field of endodontics. Among different types of new endodontic materials, pulpotec has been materialized as a recognized material for vital pulp therapy. However, its efficacy has been challenged due to lack of information about its cellular biocompatibility. This study evaluates the mechanistic biocompatibility of pulpotec cement with macrophage cells (RAW 264.7) at cellular and molecular level. The biocompatibility was evaluated using experimental and computational techniques like MTT assay, oxidative stress analysis and apoptosis analysis through flow cytometry and fluorescent microscopy. The results showed concentration-dependent cytotoxicity of pulpotec cement extract to RAW 264.7 cells with an LC 50 of X/10-X/20. The computational analysis depicted the molecular interaction of pulpotec cement extract components with metabolic proteins like Sod1 and p53. The study revealed the effects of Pulpotec cement's extract, showing a concentration-dependent induction of oxidative stress and apoptosis. These effects were due to influential structural and functional abnormalities in the Sod1 and p53 proteins, caused by their molecular interaction with internalized components of Pulpotec cement. The study provided a detailed view on the utility of Pulpotec in endodontic applications, highlighting its biomedical aspects.

Perilous paradigm of graphene oxide and its derivatives in biomedical applications: Insight to immunocompatibility.

With advancements in nanotechnology and innovative materials, Graphene Oxide nanoparticles (GONP) have attracted lots of attention among the diverse types of nanomaterials owing to their distinctive physicochemical characteristics. However, the usage at scientific and industrial level has also raised concern to their toxicological interaction with biological system. Understanding these interactions is crucial for developing guidelines and recommendations for applications of GONP in various sectors, like biomedicine and environmental technologies. This review offers crucial insights and an in-depth analysis to the biological processes associated with GONP immunotoxicity with multiple cell lines including human whole blood cultures, dendritic cells, macrophages, and multiple cancer cell lines. The complicated interactions between graphene oxide nanoparticles and the immune system, are highlighted in this work, which reveals a range of immunotoxic consequences like inflammation, immunosuppression, immunostimulation, hypersensitivity, autoimmunity, and cellular malfunction. Moreover, the immunotoxic effects are also highlighted with respect to in vivo models like mice and zebrafish, insighting GO Nanoparticles' cytotoxicity. The study provides invaluable review for researchers, policymakers, and industrialist to understand and exploit the beneficial applications of GONP with a controlled measure to human health and the environment.

Nanoparticle-mediated metronomic chemotherapy in cancer: A paradigm of precision and persistence.

Current methods of cancer therapy have demonstrated enormous potential in tumor inhibition. However, a high dosage regimen of chemotherapy results in various complications which affect the normal body cells. Tumor cells also develop resistance against the prescribed drugs in the whole treatment regimen increasing the risk of cancer relapse. Metronomic chemotherapy is a modern treatment method that involves administering drugs at low doses continuously, allowing the drug sufficient time to take its effect. This method ensures that the toxicity of the drugs is to a minimum in comparison to conventional chemotherapy. Nanoparticles have shown efficacy in delivering drugs to the tumor cells in various cancer therapies. Combining nanoparticles with metronomic chemotherapy can yield better treatment results. This combination stimulates the immune system, improving cancer cells recognition by immune cells. Evidence from clinical and pre-clinical trials supports the use of metronomic delivery for drug-loaded nanoparticles. This review focuses on the functionalization of nanoparticles for improved drug delivery and inhibition of tumor growth. It emphasizes the mechanisms of metronomic chemotherapy and its conjunction with nanotechnology. Additionally, it explores tumor progression and the current methods of chemotherapy. The challenges associated with nano-based metronomic chemotherapy are outlined, paving the way for prospects in this dynamic field.

The paradigm of miRNA and siRNA influence in Oral-biome.

Short nucleotide sequences like miRNA and siRNA have attracted a lot of interest in Oral-biome investigations. miRNA is a small class of non-coding RNA that regulates gene expression to provide effective regulation of post-transcription. On contrary, siRNA is 21-25 nucleotide dsRNA impairing gene function post-transcriptionally through inhibition of mRNA for homologous dependent gene silencing. This review highlights the application of miRNA in oral biome including oral cancer, dental implants, periodontal diseases, gingival fibroblasts, oral submucous fibrosis, radiation-induced oral mucositis, dental Pulp, and oral lichenoid disease. Moreover, we have also discussed the application of siRNA against the aforementioned disease along with the impact of miRNA and siRNA to the various pathways and molecular effectors pertaining to the dental diseases. The influence of upregulation and downregulation of molecular effector post-treatment with miRNA and siRNA and their impact on the clinical setting has been elucidated. Thus, the mentioned details on application of miRNA and siRNA will provide a novel gateway to the scholars to not only mitigate the long-lasting issue in dentistry but also develop new theragnostic approaches.

The translational paradigm of nanobiomaterials: Biological chemistry to modern applications.

Recently nanotechnology has evolved as one of the most revolutionary technologies in the world. It has now become a multi-trillion-dollar business that covers the production of physical, chemical, and biological systems at scales ranging from atomic and molecular levels to a wide range of industrial applications, such as electronics, medicine, and cosmetics. Nanobiomaterials synthesis are promising approaches produced from various biological elements be it plants, bacteria, peptides, nucleic acids, etc. Owing to the better biocompatibility and biological approach of synthesis, they have gained immense attention in the biomedical field. Moreover, due to their scaled-down sized property, nanobiomaterials exhibit remarkable features which make them the potential candidate for different domains of tissue engineering, materials science, pharmacology, biosensors, etc. Miscellaneous characterization techniques have been utilized for the characterization of nanobiomaterials. Currently, the commercial transition of nanotechnology from the research level to the industrial level in the form of nano-scaffolds, implants, and biosensors is stimulating the whole biomedical field starting from bio-mimetic nacres to 3D printing, multiple nanofibers like silk fibers functionalizing as drug delivery systems and in cancer therapy. The contribution of single quantum dot nanoparticles in biological tagging typically in the discipline of genomics and proteomics is noteworthy. This review focuses on the diverse emerging applications of Nanobiomaterials and their mechanistic advancements owing to their physiochemical properties leading to the growth of industries on different biomedical measures. Alongside the implementation of such nanobiomaterials in several drug and gene delivery approaches, optical coding, photodynamic cancer therapy, and vapor sensing have been elaborately discussed in this review. Different parameters based on current challenges and future perspectives are also discussed here.

Proximal discrepancy in intrinsic atomic interaction arrests G2/M phase by inhibiting Cyclin B1/CDK1 to infer molecular and cellular biocompatibility of D-limonene.

The quest for different natural compounds for different biomedical applications especially in the treatment of cancer is at a high pace with increasing incidence of severity. D-limonene has been portrayed as one of the effective potential candidate centered to the context of breast cancer. The anticipation of its count as an effective biomedical agent required a detailed understanding of their molecular mechanism of biocompatibility. This study elucidates the mechanistic action of D-limonene channelized by the induction of apoptosis for controlling proliferation in breast cancer cells. The possible mechanism was explored through an experimental and computational approach to estimate cell proliferation inhibition, cell cycle phase distribution, apoptosis analysis using a flow cytometry, western blotting and molecular docking. The results showed reduced dose and time-dependent viability of MCF7 cells. The study suggested the arrest of the cell cycle at G2/M phase leading to apoptosis and other discrepancies of molecular activity mediated via significant alteration in protein expression pattern of anti-apoptotic proteins like Cyclin B1 and CDK1. Computational analysis showed firm interaction of D-limonene with Cyclin B1 and CDK1 proteins influencing their structural and functional integrity indicating the mediation of mechanism. This study concluded that D-limonene suppresses the proliferation of breast cancer cells by inducing G2/M phase arrest via deregulation of Cyclin B1/CDK1.

Emerging trends in the nanomedicine applications of functionalized magnetic nanoparticles as novel therapies for acute and chronic diseases.

High-quality point-of-care is critical for timely decision of disease diagnosis and healthcare management. In this regard, biosensors have revolutionized the field of rapid testing and screening, however, are confounded by several technical challenges including material cost, half-life, stability, site-specific targeting, analytes specificity, and detection sensitivity that affect the overall diagnostic potential and therapeutic profile. Despite their advances in point-of-care testing, very few classical biosensors have proven effective and commercially viable in situations of healthcare emergency including the recent COVID-19 pandemic. To overcome these challenges functionalized magnetic nanoparticles (MNPs) have emerged as key players in advancing the biomedical and healthcare sector with promising applications during the ongoing healthcare crises. This critical review focus on understanding recent developments in theranostic applications of functionalized magnetic nanoparticles (MNPs). Given the profound global economic and health burden, we discuss the therapeutic impact of functionalized MNPs in acute and chronic diseases like small RNA therapeutics, vascular diseases, neurological disorders, and cancer, as well as for COVID-19 testing. Lastly, we culminate with a futuristic perspective on the scope of this field and provide an insight into the emerging opportunities whose impact is anticipated to disrupt the healthcare industry.

Facile green bio-fabricated silver nanoparticles from Microchaete infer dose-dependent antioxidant and anti-proliferative activity to mediate cellular apoptosis.

With the rapid development of nanotechnology, much has been anticipated with silver nanoparticles (AgNPs) due to their extensive industrial and commercial applications. However, it has raised concerns over environmental safety and human health effects. In this study, AgNPs were bio-fabricated using aqueous extract of Microchaete and their medical applications like antioxidant, anti-proliferative, and apoptosis were done. The biosynthesis of AgNPs was continuously followed by UV-vis spectrophotometric analysis. The physiochemical properties like shape, size, crystallinity, and polydispersity of the nanoparticles were determined by Scanning Electron Microscopy (SEM) along with EDX, Transmission Electron Microscope (TEM), Atomic Force Microscope (AFM), dynamic light scattering (DLS), and X-Ray Diffraction (XRD). Biosynthesized 7.0 nm sized AgNPs with the crystalline structure (crystalline size 4.8 nm) having a hydrodynamic diameter of 38.74 ± 2.6 nm was achieved due to the involvement of reducing agents present in the cyanobacterial extract. The IC50 values of the AgNPs were evaluated as 75 µg/ml and 79.41 µg/ml with HepG2 and MCF-7 cell lines. Different in-vitro cellular assays investigated in the present study exhibited antioxidant, anti-proliferative, and apoptotic activities. Probably delayed apoptosis in HepG2 and MCF-7 is due to better antioxidant activities of Microchaete based AgNPs.

Molecular intrinsic proximal interaction infer oxidative stress and apoptosis modulated in vivo biocompatibility of P.niruri contrived antibacterial iron oxide nanoparticles with zebrafish.

Extensive use of magnetic iron oxide (magnetite) nanoparticles (IONP) has raised concerns about their biocompatibility. It has also stimulated the search for its green synthesis with greater biocompatibility. Addressing the issue, this study investigates the molecular nanotoxicity of IONP with embryonic and adult zebrafish, and reveal novel green fabrication of iron oxide nanoparticles (P-IONP) using medicinal plant extract of Phyllanthus niruri. The synthesized P-IONP was having a size of 42 ± 08 nm and a zeta potential of -38 ± 06 mV with hydrodynamic diameter of 109 ± 09 nm and 90emu/g magnetic saturation value. High antibacterial efficacy of P-IONP was found against E.coli. Comparative in vivo biocompatibility assessment with zebrafish confirmed higher biocompatibility of P-IONP compared to commercial C-IONP in the relevance of mortality rate, hatching rate, heart rate, and morphological abnormalities. LC50 of P-IONP and C-IONP was 202 µg/ml and 126 µg/ml, respectively. Molecular nano-biocompatibility analysis revealed the phenomenon as an effect of induced apoptosis lead by dysregulation of induced oxidative stress due to structural and functional influence of IONP to Sod1 and Tp53 proteins through intrinsic atomic interaction.

Structure-based drug designing and immunoinformatics approach for SARS-CoV-2.

The prevalence of respiratory illness caused by the novel SARS-CoV-2 virus associated with multiple organ failures is spreading rapidly because of its contagious human-to-human transmission and inadequate globalhealth care systems. Pharmaceutical repurposing, an effective drug development technique using existing drugs, could shorten development time and reduce costs compared to those of de novo drug discovery. We carried out virtual screening of antiviral compounds targeting the spike glycoprotein (S), main protease (Mpro), and the SARS-CoV-2 receptor binding domain (RBD)-angiotensin-converting enzyme 2 (ACE2) complex of SARS-CoV-2. PC786, an antiviral polymerase inhibitor, showed enhanced binding affinity to all the targets. Furthermore, the postfusion conformation of the trimeric S protein RBD with ACE2 revealed conformational changes associated with PC786 drug binding. Exploiting immunoinformatics to identify T cell and B cell epitopes could guide future experimental studies with a higher probability of discovering appropriate vaccine candidates with fewer experiments and higher reliability.

Selective in vivo molecular and cellular biocompatibility of black peppercorns by piperine-protein intrinsic atomic interaction with elicited oxidative stress and apoptosis in zebrafish eleuthero embryos.

Day to day consumption of black pepper raise concern about the detailed information about their medicinal, pharmaceutical values and knowledge about the biocompatibility with respect to ecosystem. This study investigates the in vivo selective molecular biocompatibility of its seed cover (SC) and seed core (SP) powder extract using embryonic zebrafish model. Gas chromatography mass spectrometry (GCMS) analysis of the extract prepared by grinding showed presence of different components with "piperine" as principle component. Biocompatibility analysis showed dose and time dependent selective effect of SC and SP with LC50 of 30.4 µg/ml and 35.6 µg/ml, respectively on survivability, hatching and heartbeat rate in embryonic zebrafish. Mechanistic investigation elucidated it as effect of accumulation and internalization of black pepper leading to their influence on structure and function of cellular proteins hatching enzyme (he1a), superoxide dismutase (sod1) and tumor protein (tp53) responsible for delayed hatching, oxidative stress induction and apoptosis. The study provided insight to selective biocompatibility of black pepper expedient to produce higher quality spices with respect to pharmaceutical, clinical and environmental aspects.

Targeting exosome-associated human antigen R attenuates fibrosis and inflammation in diabetic heart.

RNA-binding proteins like human antigen R (HuR) are key regulators in post-transcriptional control of gene expression in several pathophysiological conditions. Diabetes adversely affects monocyte/macrophage biology and function. It is not known whether diabetic milieu affects cellular/exosome-HuR and its implications on cardiac inflammation and fibrosis. Here, we evaluate in vitro and in vivo effects of diabetic milieu on macrophage cellular/exosome-HuR, alterations in intercellular cross talk with fibroblasts, and its impact on cardiac remodeling. Human failing hearts show higher HuR levels. Diabetic milieu activates HuR expression in cardiac- and cultured bone marrow-derived macrophages (BMMØ) and stimulates HuR nuclear-to-cytoplasmic translocation and exosome transfer. Exosomes from macrophages exposed to diabetic milieu (high glucose or db/db mice) significantly increase inflammatory and profibrogenic responses in fibroblast (in vitro) and cardiac fibrosis in mice. Intriguingly, Exo-HuR deficiency (HuR knockdown in macrophage) abrogates the above effects. In diabetic mice, macrophage depletion followed by reconstitution with BMMØ-derived HuR-deficient exosomes inhibits angiotensin II-induced cardiac fibrosis response and preserves left ventricle function as compared to control-exosome administration. To the best of our knowledge, this is the first study to demonstrate that diabetes activates BMMØ HuR expression and its transfer into exosome. The data suggest that HuR might be targeted to alleviate macrophage dysfunction and pathological fibrosis in diabetes.

Facile synthesized novel hybrid graphene oxide/cobalt ferrite magnetic nanoparticles based surface coating material inhibit bacterial secretion pathway for antibacterial effect.

Nanomaterial based paints are in current demand in the area of surface protective coatings due to the significant advances made to improve their antibacterial and anticorrosion characteristics. In this work, we have developed magnetic graphene oxide (MGO) paint with the incorporation of cobalt ferrite (CF) and graphene oxide (GO) along with paint materials by using high energy ball milling (HEBM). Morphological, elemental and functional analysis of the MGO paint is studied with ESEM, AFM, Raman, FTIR spectroscopy. EDS and PIXE methods are used for elemental analysis. Thermal analysis shows that the MGO film was stable up to 100 °C. The saturation magnetization of CF MNP is observed as 76 emu/g and it is reduced to 12 emu/g for MGP paint. The detailed antibacterial study of the prepared MGO paint has performed with S. typhimurium and E. coli. The dead-live assessment shows the dead population for S. typhimurium is superior up to 82% whereas it is 20% for E. coli. The morphological damage of bacterial cells is studied using SEM technique. Flow cytometry analysis of reactive oxygen species (ROS) generation experiments and computational analysis supported the proposed mechanism of induced ROS for the damage of bacterial membrane via interaction of GO and CF with bacterial proteins leading to alteration in their functionality. The observed results indicate that the prepared MGO paint could be a better candidate in the area of nano paint for surface protective coatings.

Altered electrical properties with controlled copper doping in ZnO nanoparticles infers their cytotoxicity in macrophages by ROS induction and apoptosis.

The present study reports the regulation of cytotoxicity of Cu doped ZnO nanoparticles in macrophages (RAW 264.7) due to altered physiochemical properties changes like electrical properties by controlled doping of Cu in ZnO. Cu-doped ZnO nanoparticles were prepared by High Energy Ball Milling technique (HEBM) and formed single phase Zn1-xCuxO (x = 0.0, 0.01, 0.02, 0.03) were called as pure ZnO, Cu1%, 2%, 3% respectively. Hexagonal wurtzite structure with size range of 22-26 nm was verified. FE-SEM with EDX analysis indicated the Cu doping effect on the surface morphology of ZnO. Zeta potential of Zn1-xCuxO was found to be elevated with increase in doping percentage of Cu (-36.6 mV to +18.2 mV). Dielectric constant was found to be decreased with increasing doping percentage. Increase in doping percentage enhanced cytotoxicity of Zn1-xCuxO in macrophages with LC50 of 62 µg/ml, 51 µg/ml, 40 µg/ml, 32 µg/ml. Granularity change of macrophages suggested doping influenced cellular uptake as consequence of zeta potential and dielectric properties changes. 3% Cu doped ZnO shown a higher ROS signal and apoptosis than 2% and 1% Cu doping with exhibition of ROS scavenging nature leading to apoptosis of prepared Cu doped ZnO nanoparticles. Our findings revealed mechanism of cytotoxicity of Zn1-xCuxO as a consequence of alteration in electric properties eliciting ROS scavenging leading to higher apoptosis with increasing doping percentage of Cu in ZnO.

Mechanistic Insight into Size-Dependent Enhanced Cytotoxicity of Industrial Antibacterial Titanium Oxide Nanoparticles on Colon Cells Because of Reactive Oxygen Species Quenching and Neutral Lipid Alteration.

This study evaluates the impact of industrially prepared TiO2 nanoparticles on the biological system by using an in vitro model of colon cancer cell lines (HCT116). Industrial synthesis of titanium oxide nanoparticles was mimicked on the lab scale by the high-energy ball milling method by milling bulk titanium oxide particles for 5, 10, and 15 h in an ambient environment. The physiochemical characterization by field emission scanning electron microscopy, dynamic light scattering, and UV-visible spectroscopy revealed alteration in the size and surface charge with respect to increase in the milling time. The size was found to be reduced to 82 ± 14, 66 ± 12, and 42 ± 10 nm in 5, 10, and 15 h milled nano TiO2 from 105 ± 12 nm of bulk TiO2, whereas the zeta potential increased along with the milling time in all biological media. Cytotoxicity and genotoxicity assays performed with HCT116 cell lines by MTT assay, oxidative stress, intracellular lipid analysis, apoptosis, and cell cycle estimation depicted cytotoxicity as a consequence of reactive oxygen species quenching and lipid accumulation, inducing significant apoptosis and genotoxic cytotoxicity. In silico analysis depicted the role of Sod1, Sod2, p53, and VLDR proteins-TiO2 hydrogen bond interaction having a key role in determining the cytotoxicity. The particles exhibited significant antibacterial activities against Escherichia coli and Salmonella typhimurium.

Interleukin-10 Inhibits Bone Marrow Fibroblast Progenitor Cell-Mediated Cardiac Fibrosis in Pressure-Overloaded Myocardium.

BACKGROUND: Activated fibroblasts (myofibroblasts) play a critical role in cardiac fibrosis; however, their origin in the diseased heart remains unclear, warranting further investigation. Recent studies suggest the contribution of bone marrow fibroblast progenitor cells (BM-FPCs) in pressure overload-induced cardiac fibrosis. We have previously shown that interleukin-10 (IL10) suppresses pressure overload-induced cardiac fibrosis; however, the role of IL10 in inhibition of BM-FPC-mediated cardiac fibrosis is not known. We hypothesized that IL10 inhibits pressure overload-induced homing of BM-FPCs to the heart and their transdifferentiation to myofibroblasts and thus attenuates cardiac fibrosis. METHODS: Pressure overload was induced in wild-type (WT) and IL10 knockout (IL10KO) mice by transverse aortic constriction. To determine the bone marrow origin, chimeric mice were created with enhanced green fluorescent protein WT mice marrow to the IL10KO mice. For mechanistic studies, FPCs were isolated from mouse bone marrow. RESULTS: Pressure overload enhanced BM-FPC mobilization and homing in IL10KO mice compared with WT mice. Furthermore, WT bone marrow (from enhanced green fluorescent protein mice) transplantation in bone marrow-depleted IL10KO mice (IL10KO chimeric mice) reduced transverse aortic constriction-induced BM-FPC mobilization compared with IL10KO mice. Green fluorescent protein costaining with α-smooth muscle actin or collagen 1α in left ventricular tissue sections of IL10KO chimeric mice suggests that myofibroblasts were derived from bone marrow after transverse aortic constriction. Finally, WT bone marrow transplantation in IL10KO mice inhibited transverse aortic constriction-induced cardiac fibrosis and improved heart function. At the molecular level, IL10 treatment significantly inhibited transforming growth factor-ß-induced transdifferentiation and fibrotic signaling in WT BM-FPCs in vitro. Furthermore, fibrosis-associated microRNA (miRNA) expression was highly upregulated in IL10KO-FPCs compared with WT-FPCs. Polymerase chain reaction-based selective miRNA analysis revealed that transforming growth factor-ß-induced enhanced expression of fibrosis-associated miRNAs (miRNA-21, -145, and -208) was significantly inhibited by IL10. Restoration of miRNA-21 levels suppressed the IL10 effects on transforming growth factor-ß-induced fibrotic signaling in BM-FPCs. CONCLUSIONS: Our findings suggest that IL10 inhibits BM-FPC homing and transdifferentiation to myofibroblasts in pressure-overloaded myocardium. Mechanistically, we show for the first time that IL10 suppresses Smad-miRNA-21-mediated activation of BM-FPCs and thus modulates cardiac fibrosis.

Therapeutic inhibition of miR-375 attenuates post-myocardial infarction inflammatory response and left ventricular dysfunction via PDK-1-AKT signalling axis.

AIMS: Increased miR-375 levels has been implicated in rodent models of myocardial infarction (MI) and with patients with heart failure. However, no prior study had established a therapeutic role of miR-375 in ischemic myocardium. Therefore, we assessed whether inhibition of MI-induced miR-375 by LNA anti-miR-375 can improve recovery after acute MI. METHODS AND RESULTS: Ten weeks old mice were treated with either control or LNA anti miR-375 after induction of MI by LAD ligation. The inflammatory response, cardiomyocyte apoptosis, capillary density and left ventricular (LV) functional, and structural remodelling changes were evaluated. Anti-miR-375 therapy significantly decreased inflammatory response and reduced cardiomyocyte apoptosis in the ischemic myocardium and significantly improved LV function and neovascularization and reduced infarct size. Repression of miR-375 led to the activation of 3-phosphoinositide-dependent protein kinase 1 (PDK-1) and increased AKT phosphorylation on Thr-308 in experimental hearts. In corroboration with our in vivo findings, our in vitro studies demonstrated that knockdown of miR-375 in macrophages modulated their phenotype, enhanced PDK-1 levels, and reduced pro-inflammatory cytokines expression following LPS challenge. Further, miR-375 levels were elevated in failing human heart tissue. CONCLUSION: Taken together, our studies demonstrate that anti-miR-375 therapy reduced inflammatory response, decreased cardiomyocyte death, improved LV function, and enhanced angiogenesis by targeting multiple cell types mediated at least in part through PDK-1/AKT signalling mechanisms.