The impact of nanomaterials on autophagy across health and disease conditions.

Autophagy, a catabolic process integral to cellular homeostasis, is constitutively active under physiological and stress conditions. The role of autophagy as a cellular defense response becomes particularly evident upon exposure to nanomaterials (NMs), especially environmental nanoparticles (NPs) and nanoplastics (nPs). This has positioned autophagy modulation at the forefront of nanotechnology-based therapeutic interventions. While NMs can exploit autophagy to enhance therapeutic outcomes, they can also trigger it as a pro-survival response against NP-induced toxicity. Conversely, a heightened autophagy response may also lead to regulated cell death (RCD), in particular autophagic cell death, upon NP exposure. Thus, the relationship between NMs and autophagy exhibits a dual nature with therapeutic and environmental interventions. Recognizing and decoding these intricate patterns are essential for pioneering next-generation autophagy-regulating NMs. This review delves into the present-day therapeutic potential of autophagy-modulating NMs, shedding light on their status in clinical trials, intervention of autophagy in the therapeutic applications of NMs, discusses the potency of autophagy for application as early indicator of NM toxicity.

Regulation of genes involved in the metabolic adaptation of murine microglial cells in response to elevated HIF-1α mediated activation.

Microglia cells are activated in response to different stress signals. Several metabolic adaptations underlie microglia activation in the brain. Among these, in conditions like ischemic stroke and, hypoxic stress stimuli activate microglia cells. Hypoxic stress is mediated by HIF-1α. Although HIF-1α has been implicated in the alteration of metabolic pathways, changes in microglia lipid metabolism during M1 activation of microglia induced by elevated HIF-1α levels are yet to be understood. This can also merit interest in the development of novel targets to mitigate chronic inflammation. Our study aims to elucidate the transcriptional regulation of metabolic pathways in microglia cells during HIF-1α mediated activation. To study the adaptations in the metabolic pathways we induced microglia activation, by activating HIF-1α. Here, we show that microglia cells activated in response to elevated HIF-1α require ongoing lipogenesis and fatty acid breakdown. Notably, autophagy is activated during the initial stages of microglia activation. Inhibition of autophagy in activated microglia affects their viability and phagocytic activity. Collectively, our study expands the understanding of the molecular link between autophagy, lipid metabolism, and inflammation during HIF-1α mediated microglial activation that can lead to the development of promising strategies for controlling maladaptive activation states of microglia responsible for neuroinflammation. Together, our findings suggest that the role of HIF-1α in regulating metabolic pathways during hypoxia in microglia is beyond optimization of glucose utilization and distinctly regulates lipid metabolism during pro-inflammatory activation.

Exposure to polystyrene nanoplastics impairs lipid metabolism in human and murine macrophages in vitro.

The use of polystyrene micro and nanoplastics in cosmetics and personal care products continues to grow every day. The harmful effects of their biological accumulation in organisms of all trophic levels including humans have been reported by several studies. While we have accumulating evidence on the impact of nanoplastics on different organ systems in humans, only a handful of reports on the impact of polystyrene nanoplastics upon direct contact with the immune system at the cellular level are avialable. The present study offers significant evidence on the cell-specific harmful impact of sulfate-modified nanoplastics (S-NPs) on human macrophages. Here we report that exposure of human macrophages to S-NPs (100 µg/mL) stimulated the accumulation of lipids droplets (LDs) in the cytoplasm resulting in the differentiation of macrophages into foam cells. The observed effect was specific for human and murine macrophages but not for other cell types, especially human keratinocytes, liver, and lung cell models. Furthermore, we found that S-NPs mediated LDs accumulation in human macrophages was accompanied by acute mitochondrial oxidative stress. The accumulated LDs were further delivered and accumulated into lysosomes leading to impaired lysosomal clearance. In conclusion, our study reveals that exposure to polystyrene nanoplastics stabilized with anionic surfactants can be a potent stimulus for dysregulation of lipid metabolism and macrophage foam cell formation, a characteristic feature observed during atherosclerosis posing a serious threat to human health.

Current Understanding on the Role of Lipids in Macrophages and Associated Diseases.

Lipid metabolism is the major intracellular mechanism driving a variety of cellular functions such as energy storage, hormone regulation and cell division. Lipids, being a primary component of the cell membrane, play a pivotal role in the survival of macrophages. Lipids are crucial for a variety of macrophage functions including phagocytosis, energy balance and ageing. However, functions of lipids in macrophages vary based on the site the macrophages are residing at. Lipid-loaded macrophages have recently been emerging as a hallmark for several diseases. This review discusses the significance of lipids in adipose tissue macrophages, tumor-associated macrophages, microglia and peritoneal macrophages. Accumulation of macrophages with impaired lipid metabolism is often characteristically observed in several metabolic disorders. Stress signals differentially regulate lipid metabolism. While conditions such as hypoxia result in accumulation of lipids in macrophages, stress signals such as nutrient deprivation initiate lipolysis and clearance of lipids. Understanding the biology of lipid accumulation in macrophages requires the development of potentially active modulators of lipid metabolism.

Cellular response of THP-1 macrophages to polystyrene microplastics exposure.

Microplastic in the environment have the capability to reach the human immune system via the ingestion, inhalation and direct contact. Polystyrene (PS) is one of the most widely used plastics, which is made up by polymerization of styrene monomers. Mounting evidences on the presence of microplastics in blood clearly indicate their access to macrophages that are major component of the immune system. However, data on the response of macrophages to microplastics exposure are limited. Our study reports the response of human macrophages transformed by PMA (phorbol 12-myristrate 13-acetate) to exposure to PSNPs of size range (≤ 450 nm). The polystyrene particles utilized in this study, were formulated from beads to powder by grinding and filtering the particles to acquire a range of size ≤ 450 nm particles with deionized water. This size variation used in this experiment imitates the size of plastic that humans can ingest plastic particles through food that gets fragmented from plastic cups and plates. Here we report that exposure to PSNPs (50-500 µg/mL) significantly decreased the viability of human macrophages. In addition, PSNPs (500 µg/mL) induced oxidative stress and decrease cell proliferation. Exposure to PSNPs decrease the membrane potential of mitochondria and caused damage to the DNA of macrophages. Overall, our study reports the differential toxic effects of PSNPs on human macrophages, delineating the potential risks of PSNPs exposure to human health.

Polystyrene nanoplastics dysregulate lipid metabolism in murine macrophages in vitro.

Micro and nanoplastics are one of the major emerging environmental contaminants. Their impact on human health is less explored. There are several in vitro studies on their cellular uptake and accumulation, where micro and nanoplastics were mostly reported to be non-cytotoxic. The effects caused by the direct contact of nanoplastics with the immune system, especially at the cellular level is less known. Here we report that RAW 264.7 macrophages undergo differentiation into lipid laden foam cells when exposed to polystyrene nanoplastics (50 µg/mL). We found that exposure of RAW 264.7 macrophages to sulfate-modified polystyrene nanoplastics results in the accumulation of lipid droplets in the cytoplasm leading to foam cell formation. Exposure to high concentration of polystyrene nanoplastics (100 and 200 µg/mL) results in increased reactive oxygen species and impair lysosomes in macrophages. The exposure of BV2 microglial cells to polystyrene nanoplastics (50 µg/mL) induces lipid accumulation. In addition, our results indicate the role of polystyrene nanoplastics in altering the lipid metabolism in murine macrophages in vitro. In the present study we reported that polystyrene nanoplastics stabilized with anionic surfactants can be potent stimuli for lipotoxicity and foam cell formation leading to the pathogenesis of atherosclerosis posing major threat for animal and human health.

Role of PAMAM-OH dendrimers against the fibrillation pathway of biomolecules.

The binding behavior of nanoparticle with proteins determines its biocompatibility. This study reports the interaction of ten different biomolecules (proteins-BSA, HSA, haemoglobin, gamma globulin, transferrin and enzymes-hog and bacillus amylase, lysozyme from chicken and human and laccases from Tramates versicolor) with a surface group hydroxylated Poly AMido AMide dendrimer (PAMAM) of generation 5. The study has utilized various spectroscopic methods like UV-vis spectroscopy, Fluorescence emission, Synchronous, 3-D spectroscopy and Circular Dichroism to detect the binding induced structural changes in biomolecules that occur upon interaction with mounting concentration of the dendrimers. Aggregation of proteins results in the formation of amyloid fibrils causing several human diseases. In this study, fibrillar samples of all ten biomolecules formed in the absence and the presence of dendrimers were investigated with Congo Red absorbance and ThT Assay to detect fibril formation, Trp Emission and 3-D scan to evaluate the effect of fibrillation on aromatic environment of biomolecules, and CD spectroscopy to measure the conformational changes in a quantitative manner. These assays have generated useful information on the role of dendrimers in amyloid fibril formation of biomolecules. The outcomes of the study remain valuable in evaluating the biological safety of PAMAM-OH dendrimers for their biomedical application in vivo.