Immobilised antimicrobial peptides in downregulation of biofilm.

Colonisation of sessile bacterial species on biotic and abiotic surfaces is responsible for the development of various infections in humans. At present, biofilm-associated chronic infections have been a prime concern among the healthcare practitioners since they are impermeable to drugs, resulting in the development of antibiotic resistance or multi-drug resistance. For a few decades, a lot of research activity has been performed in the development of alternative therapeutics to combat biofilm-associated chronic infections. The presence of extracellular polymeric substance (EPS) prevents the permeation of most of the drugs rendering drug failures. The use of small molecules has been necessary to penetrate easily through the EPS and act on the targeted cells. In present days, the use of antimicrobial peptides (AMPs) has gained immense importance as alternative therapeutics since they exhibit a novel class of antibiotics exhibiting a wide spectrum of activity and possess a low rate of development of resistance. In the last few decades, a large number of AMPs have been identified from varied groups of organisms as effector molecules for innate immune system acting as an important line of defence. In this review, we will discuss the use of AMPs as effective agents to combat various biofilm-associated chronic infections.

Antibiofilm activity of mesoporous silica nanoparticles against the biofilm associated infections.

In pharmaceutical industries, various chemical carriers are present which are used for drug delivery to the correct target sites. The most popular and upcoming drug delivery carriers are mesoporous silica nanoparticles (MSN). The main reason for its popularity is its ability to be specific and optimize the drug delivery process in a controlled manner. Nowadays, MSNs are widely used to eradicate various microbial infections, especially the ones related to biofilms. Biofilms are sessile groups of cells that live by forming a consortium and exhibit antibacterial resistance (AMR). They exhibit AMR by extracellular polymeric substances (EPS) and various quorum sensing (QS) signaling molecules. Usually, bacterial and fungal cells are capable of forming biofilms. These biofilms are pathogenic. In the majority of the cases, biofilms cause nosocomial diseases. This review will focus on the antibiofilm activities of MSN, its mechanism of target-specific drug delivery, and its ability to disrupt the bacterial biofilms inhibiting the infection. The review will also discuss various mechanisms for the delivery of pharmaceutical molecules by the MSNs to inhibit the bacterial biofilms, and lastly, we will talk about the different types of MSNs and their antibiofilm activities.

Muscle mitochondrial transplantation can rescue and maintain cellular homeostasis.

Mitochondria control cellular functions through their metabolic role. Recent research that has gained considerable attention is their ability to transfer between cells. This has the potential of improving cellular functions in pathological or energy-deficit conditions, but little is known about the role of mitochondrial transfer in sustaining cellular homeostasis. Few studies have investigated the potential of skeletal muscle as a source of healthy mitochondria that can be transferred to other cell types. Thus, we isolated intermyofibrillar mitochondria from murine skeletal muscle and incubated them with host cells. We observed dose- and time-dependent increases in mitochondrial incorporation into myoblasts. This resulted in elongated mitochondrial networks and an enhancement of bioenergetic profile of the host cells. Mitochondrial donation also rejuvenated the functional capacities of the myoblasts when respiration efficiency and lysosomal function were inhibited by complex I inhibitor rotenone and bafilomycin A, respectively. Mitochondrial transfer was accomplished via tunneling nanotubes, extracellular vesicles, gap junctions, and by macropinocytosis internalization. Murine muscle mitochondria were also effectively transferred to human fibroblast cells having mitochondrial DNA mutations, resulting in augmented mitochondrial dynamics and metabolic functions. This improved cell function by diminishing reactive oxygen species (ROS) emission in the diseased cells. Our findings suggest that mitochondria from donor skeletal muscle can be integrated in both healthy and functionally compromised host cells leading to mitochondrial structural refinement and respiratory boost. This mitochondrial trafficking and bioenergetic reprogramming to maintain and revitalize tissue homeostasis could be a useful therapeutic strategy in treating diseases.NEW & NOTEWORTHY In our study, we have shown the potential of mouse skeletal muscle intermyofibrillar mitochondria to be transplanted in myoblasts and human fibroblast cells having mitochondrial DNA mutations. This resulted in an augmentation of mitochondrial dynamics and enhancement of bioenergetic profile in the host cells. Our findings suggest that mitochondria from donor skeletal muscle can be integrated into both healthy and functionally compromised host cells leading to mitochondrial structural refinement and respiratory boost.

Denervation induces mitochondrial decline and exacerbates lysosome dysfunction in middle-aged mice.

With age, skeletal muscle undergoes a progressive decline in size and quality. Imbalanced mitochondrial turnover and the resultant dysfunction contribute to these phenotypic alterations. Motor neuron denervation (Den) is a contributor to the etiology of muscle atrophy associated with age. Further, aged muscle exhibits reduced plasticity to both enhanced and suppressed contractile activity. It remains unclear when the onset of this blunted response occurs, and how middle-aged muscle adapts to denervation. The purpose of this study was to compare mitochondrial turnover pathways in young (Y, ~5months) and middle-aged (MA, ~15months) mice, and determine the influence of Den. Transgenic mt-Keima mice were subjected to 1,3 or 7 days of Den. Muscle mass, mitochondrial content, and PGC-1α protein were not different between Y and MA mice. However, indications of enhanced mitochondrial fission and mitophagy were evident in MA muscle which were supported by a greater abundance of lysosome proteins. Den resulted in muscle atrophy and reductions in mitochondrial protein content by 7-days. These changes occurred concomitant with modest decreases in PGC-1α protein, but without further elevations in mitophagy. Although both autophagosomal and lysosomal proteins were elevated, evidence of lysosome dysfunction was present following Den in MA mice. These data suggest that increases in fission drive an acceleration of mitophagy in muscle of MA mice to preserve mitochondrial quality. Den exacerbates the aging phenotype by reducing biogenesis in the absence of a change in mitophagy, perhaps limited by lysosomal capacity, leading to an accumulation of dysfunctional mitochondria with an age-related loss of neuromuscular innervation.

p107 mediated mitochondrial function controls muscle stem cell proliferative fates.

Muscle diseases and aging are associated with impaired myogenic stem cell self-renewal and fewer proliferating progenitors (MPs). Importantly, distinct metabolic states induced by glycolysis or oxidative phosphorylation have been connected to MP proliferation and differentiation. However, how these energy-provisioning mechanisms cooperate remain obscure. Herein, we describe a mechanism by which mitochondrial-localized transcriptional co-repressor p107 regulates MP proliferation. We show p107 directly interacts with the mitochondrial DNA, repressing mitochondrial-encoded gene transcription. This reduces ATP production by limiting electron transport chain complex formation. ATP output, controlled by the mitochondrial function of p107, is directly associated with the cell cycle rate. Sirt1 activity, dependent on the cytoplasmic glycolysis product NAD+, directly interacts with p107, impeding its mitochondrial localization. The metabolic control of MP proliferation, driven by p107 mitochondrial function, establishes a cell cycle paradigm that might extend to other dividing cell types.

Mitochondrial Function in Muscle Stem Cell Fates.

Mitochondria are crucial organelles that control cellular metabolism through an integrated mechanism of energy generation via oxidative phosphorylation. Apart from this canonical role, it is also integral for ROS production, fatty acid metabolism and epigenetic remodeling. Recently, a role for the mitochondria in effecting stem cell fate decisions has gained considerable interest. This is important for skeletal muscle, which exhibits a remarkable property for regeneration following injury, owing to satellite cells (SCs), the adult myogenic stem cells. Mitochondrial function is associated with maintaining and dictating SC fates, linked to metabolic programming during quiescence, activation, self-renewal, proliferation and differentiation. Notably, mitochondrial adaptation might take place to alter SC fates and function in the presence of different environmental cues. This review dissects the contribution of mitochondria to SC operational outcomes, focusing on how their content, function, dynamics and adaptability work to influence SC fate decisions.

Metabolic Regulation of Epithelial to Mesenchymal Transition: Implications for Endocrine Cancer.

The last few decades have witnessed an outstanding advancement in our understanding of the hallmarks of endocrine cancers. This includes the epithelial to mesenchymal transition (EMT), a process that alters the morphology and functional characteristics of carcinoma cells. The mesenchymal stem cell like phenotype produced by EMT allows the dislocation of cancer cells from the primary tumor site with inheritance of motility, metastatic and invasive properties. A fundamental driver thought to initiate and propagate EMT is metabolic reprogramming that occur during these transitions. Though there remains a paucity of data regarding the alterations that occur during EMT in endocrine cancers, the contribution of deregulated metabolism is a prominent feature. This mini review focuses on metabolic reprogramming events that occur in cancer cells and in particular those of endocrine origin. It highlights the main metabolic reprogramming outcomes of EMT, encompassing glycolysis, mitochondria oxidative phosphorylation and function, glutamine and lipid metabolism. Comprehending the metabolic changes that occur during EMT will help formulate potential bioenergetic targets as therapies for endocrine cancer metastasis.

Decreased transcriptional corepressor p107 is associated with exercise-induced mitochondrial biogenesis in human skeletal muscle.

Increased mitochondrial content is a hallmark of exercise-induced skeletal muscle remodeling. For this process, considerable evidence underscores the involvement of transcriptional coactivators in mediating mitochondrial biogenesis. However, our knowledge regarding the role of transcriptional corepressors is lacking. In this study, we assessed the association of the transcriptional corepressor Rb family proteins, Rb and p107, with endurance exercise-induced mitochondrial adaptation in human skeletal muscle. We showed that p107, but not Rb, protein levels decrease by 3 weeks of high-intensity interval training. This is associated with significant inverse association between p107 and exercise-induced improved mitochondrial oxidative phosphorylation. Indeed, p107 showed significant reciprocal correlations with the protein contents of representative markers of mitochondrial electron transport chain complexes. These findings in human skeletal muscle suggest that attenuated transcriptional repression through p107 may be a novel mechanism by which exercise stimulates mitochondrial biogenesis following exercise.

p107 Determines a Metabolic Checkpoint Required for Adipocyte Lineage Fates.

We show that the transcriptional corepressor p107 orchestrates a metabolic checkpoint that determines adipocyte lineage fates for non-committed progenitors. p107 accomplishes this when stem cell commitment would normally occur in growth arrested cells. p107-deficient embryonic progenitors are characterized by a metabolic state resembling aerobic glycolysis that is necessary for their pro-thermogenic fate. Indeed, during growth arrest they have a reduced capacity for NADH partitioning between the cytoplasm and mitochondria. Intriguingly, this occurred despite an increase in the capacity for mitochondrial oxidation of non-glucose substrates. The significance of metabolic reprogramming is underscored by the disruption of glycolytic capacities in p107-depleted progenitors that reverted their fates from pro-thermogenic to white adipocytes. Moreover, the manipulation of glycolytic capacity on nonspecified embryonic and adult progenitors forced their beige fat commitment. These innovative findings introduce a new approach to increase pro-thermogenic adipocytes based on simply promoting aerobic glycolysis to manipulate nonspecified progenitor fate decisions. Stem Cells 2017;35:1378-1391.