Potential Role Of Autophagy Research Articles

Relationships between endurance exercise training-induced muscle fiber-type shifting and autophagy in slow- and fast-twitch skeletal muscles of mice.

Endurance exercise induces muscle fiber-type shifting and autophagy; however, the potential role of autophagy in muscle fiber-type transformation remains unclear. This study examined the relationship between muscle fiber-type shifting and autophagy in the soleus (SOL) and extensor digitorum longus (EDL) muscles, which are metabolically discrete muscles. Male C57BL/6J mice were randomly assigned to sedentary control (CON) and exercise (EXE) groups. After 1 week of acclimation to treadmill running, the mice in the EXE group ran at 12-15 m/min, 60 min/day, 5 days/week for 6 weeks. All mice were sacrificed 90 min after the last exercise session, and the targeted tissues were rapidly dissected. The right side of the tissues was used for western blot analysis, whereas the left side was subjected to immunohistochemical analysis. Endurance exercise resulted in muscle fiber-type shifting (from type IIa to type I) and autophagy (an increase in LC3-II) in the SOL muscle. However, muscle fiber-type transformation and autophagy were not correlated in the SOL and EDL muscles. Interestingly, in contrast to the canonical autophagy signaling pathways, our study showed that exercise-induced autophagy concurs with enhanced anabolic (increased p-AKTSer473/AKT and p-mTOR/mTORSer2448 ratios) and suppressed catabolic (reduced p-AMPKThr172/AMPK ratio) states. Our findings demonstrate that chronic endurance exercise-induced muscle fiber-type transformation and autophagy occur in a muscle-specific manner (e.g., SOL). More importantly, our study suggests that endurance training-induced SOL muscle fiber-type transition may underlie metabolic modulations caused by the AMPK and AKT/mTOR signaling pathways rather than autophagy.

Potential role of autophagy in the male reproductive system

Autophagy is a highly controlled cellular mechanism that maintains cellular homeostasis by degrading and recycling cellular components. In recent years, there has been a greater concentration on understanding the role of autophagy in the male reproductive system. This review addresses the potential importance of autophagy in many aspects of male reproductive physiology, such as spermatogenesis, sperm maturation, and testicular function. The role of autophagy in male fertility, sperm quality, and response to environmental stressors is explored. Insights into the molecular mechanisms driving autophagy in male reproductive cells cover the groundwork for future research targeted at understanding the complex relationship between autophagy and male reproductive health.

Targeting autophagy for breast cancer prevention and therapy: From classical methods to phytochemical agents.

Breast cancer is a heterogeneous illness comprising diverse biological subtypes, each of which differs in incidence, response to therapies, and prognosis. Despite the presence of novel medications that effectively target vital cellular signaling pathways and their application in clinical practice, breast cancer can still develop resistance to therapies by various mechanisms. Autophagy is a conserved catabolic cellular process that maintains intracellular metabolic homeostasis by removing dysfunctional or unnecessary cellular materials to recycle cytosolic components. This process serves as an adaptive survival response to diverse stress stimuli, thereby contributing to tumor initiation, progression, and drug resistance, leading to restriction of the effectiveness of chemotherapeutic treatments. Regarding this potential role of autophagy, molecular regulation and signal transduction of this process represent an attractive approach to combat cancer development and drug resistance. Among various therapeutic agents, bioactive plant-derived compounds have received significant interest as promising anticancer drugs. A plethora of evidence has shown that phytochemicals with the capacity to modulate autophagy may have the potential to be used as inhibitors of breast cancer growth. In this review, we describe recent findings on autophagy targeting along with conventional methods for breast cancer therapy. Subsequently, we introduce phytochemical compounds with the capacity to modulate autophagy for breast cancer treatment.

Porphyromonas gingivalis, a periodontal pathogen, impairs post-infarcted myocardium by inhibiting autophagosome–lysosome fusion

While several previous studies have indicated the link between periodontal disease (PD) and myocardial infarction (MI), the underlying mechanisms remain unclear. Autophagy, a cellular quality control process that is activated in several diseases, including heart failure, can be suppressed by Porphyromonas gingivalis (P.g.). However, it is uncertain whether autophagy impairment by periodontal pathogens stimulates the development of cardiac dysfunction after MI. Thus, this study aimed to investigate the relationship between PD and the development of MI while focusing on the role of autophagy. Neonatal rat cardiomyocytes (NRCMs) and MI model mice were inoculated with wild-type P.g. or gingipain-deficient P.g. to assess the effect of autophagy inhibition by P.g. Wild-type P.g.-inoculated NRCMs had lower cell viability than those inoculated with gingipain-deficient P.g. This study also revealed that gingipains can cleave vesicle-associated membrane protein 8 (VAMP8), a protein involved in lysosomal sensitive factor attachment protein receptors (SNAREs), at the 47th lysine residue, thereby inhibiting autophagy. Wild-type P.g.-inoculated MI model mice were more susceptible to cardiac rupture, with lower survival rates and autophagy activity than gingipain-deficient P.g.-inoculated MI model mice. After inoculating genetically modified MI model mice (VAMP8-K47A) with wild-type P.g., they exhibited significantly increased autophagy activation compared with the MI model mice inoculated with wild-type P.g., which suppressed cardiac rupture and enhanced overall survival rates. These findings suggest that gingipains, which are virulence factors of P.g., impair the infarcted myocardium by cleaving VAMP8 and disrupting autophagy. This study confirms the strong association between PD and MI and provides new insights into the potential role of autophagy in this relationship.

The Effect of Intermittent Fasting on Isoproterenol-Induced Myocardial Infarction in Aged Rats: A Potential Role of Autophagy

Background Aging is associated with cardiovascular and metabolic changes, increasing the susceptibility to acute myocardial infarction (MI). Intermittent fasting (IF) was found to reduce the age associated cardiovascular diseases. Aim To investigate the possible protective effect of IF against acute MI induced by isoproterenol (ISO) in old rats and its underlying mechanisms, including autophagy. Methods 50 male Wistar rats were equally divided into five groups: Adult; Old; Old-F (rats were subjected to IF for 4 weeks); Old-ISO (rats subjected to MI by ISO) and Old-F-ISO groups. Results IF significantly reduced troponin-I and creatine kinase (CK-MB), cardiac malondialdehyde (MDA) and TNF- α in Old-F-ISO compared to Old-ISO group. This was associated with a significant decrease in the age-related overall and visceral obesity; and dyslipidemia in Old-F and Old-F-ISO versus Old and Old-ISO groups. IF increases cardiac Atg-5 in Old-F-ISO versus Old group. Also, IF attenuated the age-related diabetic changes and significantly increased the pancreatic Atg-7 in Old-F-ISO versus Old group. Histological studies revealed attenuation of the local inflammatory response in Old-F-ISO versus Old-ISO group. Pancreatic Atg-7 and heart Atg-5 were significantly increased in Old-ISO versus Old rats. Conclusion IF protects against acute MI in old rats, in part, via alleviation of the age-related obesity, diabetic changes, and dyslipidemia. Chronic activation of heart and pancreatic autophagy by IF may possibly afford a cardioprotective effect. Acute activation of both heart and pancreatic autophagy by ISO could have a deleterious effect, augmenting cardiac injury.

974 Decreased epidermal thickening by imiquimod in mice with conditional aryl hydrocarbon receptor ablation in langerhans cells: A potential role of autophagy by dysregulated AhR activation in psoriasis

974 Decreased epidermal thickening by imiquimod in mice with conditional aryl hydrocarbon receptor ablation in langerhans cells: A potential role of autophagy by dysregulated AhR activation in psoriasis

Role of Autophagy in HIV-1 and Drug Abuse-Mediated Neuroinflammaging.

Chronic low-grade inflammation remains an essential feature of HIV-1 infection under combined antiretroviral therapy (cART) and contributes to the accelerated cognitive defects and aging in HIV-1 infected populations, indicating cART limitations in suppressing viremia. Interestingly, ~50% of the HIV-1 infected population on cART that develops cognitive defects is complicated by drug abuse, involving the activation of cells in the central nervous system (CNS) and neurotoxin release, altogether leading to neuroinflammation. Neuroinflammation is the hallmark feature of many neurodegenerative disorders, including HIV-1-associated neurocognitive disorders (HAND). Impaired autophagy has been identified as one of the underlying mechanisms of HAND in treated HIV-1-infected people that also abuse drugs. Several lines of evidence suggest that autophagy regulates CNS cells' responses and maintains cellular hemostasis. The impairment of autophagy is associated with low-grade chronic inflammation and immune senescence, a known characteristic of pathological aging. Therefore, autophagy impairment due to CNS cells, such as neurons, microglia, astrocytes, and pericytes exposure to HIV-1/HIV-1 proteins, cART, and drug abuse could have combined toxicity, resulting in increased neuroinflammation, which ultimately leads to accelerated aging, referred to as neuroinflammaging. In this review, we focus on the potential role of autophagy in the mechanism of neuroinflammaging in the context of HIV-1 and drug abuse.

The Polo-Like Kinase 1–Mammalian Target of Rapamycin Axis Regulates Autophagy to Prevent Intestinal Barrier Dysfunction During Sepsis

The intestines play a crucial role in the development of sepsis. The balance between autophagy and apoptosis in intestinal epithelial cells is dynamic and determines intestinal permeability. The present study focused on the potential role of autophagy in sepsis-induced intestinal barrier dysfunction and explored the mechanisms invivo and invitro. Excessive apoptosis in intestinal epithelia and a disrupted intestinal barrier were observed in septic mice. Promoting autophagy with rapamycin reduced intestinal epithelial apoptosis and restored intestinal barrier function, presenting as decreased serum diamine oxidase (DAO) and fluorescein isothiocyanate-dextran 40 (FD40) levels and increased expression of zonula occludens-1 (ZO-1) and Occludin. Polo-like kinase 1 (PLK1) knockdown in mice ameliorated intestinal epithelial apoptosis and the intestinal barrier during sepsis, whereas these effects were reduced with chloroquine and enhanced with rapamycin. PLK1 also promoted cell autophagy and improved lipopolysaccharide-induced apoptosis and high permeability invitro. Moreover, PLK1 physically interacted with mammalian target of rapamycin (mTOR) and participated in reciprocal regulatory crosstalk in intestinal epithelial cells during sepsis. This study provides novel insight into the role of autophagy in sepsis-induced intestinal barrier dysfunction and indicates that the PLK1-mTOR axis may be a promising therapeutic target for sepsis.

P-279 The role of autophagy in the development of mouse preimplantation embryos and morphokinetics

Abstract Study question Which role does autophagy play in the development of mammalian preimplantation embryos? Summary answer This study suggests the critical role of autophagy in the fertilized oocytes and embryo development. What is known already Cellular nutrition plays an important role in improving reproductive efficiency in all animals. Homeostasis of nutrient metabolism is tightly controlled by a cellular pathway called autophagy, which can recycle nutrients and organelles to allow cells adapting to nutritional stress such as nutrient deficiency or excess. Increasing evidence shows that autophagy is involved in a wide range of cellular events within mammalian reproduction. Since it is known that autophagy has paradoxical functions in many cellular processes, it is still unclear which role autophagy plays in the development of mammalian preimplantation embryos. Study design, size, duration To determine the role of autophagy in the development of mammalian preimplantation embryos, a randomized parallel group study with hybride Bl6CBa/ca mouse embryos was designed. Participants/materials, setting, methods 207 zygotes of Bl6CBAca mice were randomly distributed into two groups. The control embryos were cultured in 2ml GTL media (Vitrolife) supplemented with DMSO (vehicle), while the treatment embryos were cultured in 2ml GTL media supplemented with 100 nM autophagy inhibitor Bafilomycin (Baf). Embryos were non-invasively monitored with a Primovision time-lapse system (Vitrolife) for 5 days. Blastocyst, degeneration rate and morphokinetics were analyzed. Furthermore, confocal microscopy staining of 2PN embryos with autophagy marker LC3 was performed. Main results and the role of chance Our study showed a statistically significant difference in the expanded blastocyst as well as degeneration rate among groups (p < 0.0001). 89,19% of embryos in the control group (non-treated) (N = 111) reached to expanded blastocysts, while most of the embryos in Baf-treated group (N = 96) stopped development at 4C-stage. No embryo in Baf-treated group reached expanded blastocysts (blastocyst rate = 0) and 100% embryos degenerated. However, there is no statistically significant difference in the development time from 2C to 4C stage between non-treated (1330 ± 17.35 min, N = 50) and Baf-treated group (1364 ± 22.20 min, N = 50). Moreover, confocal microscopy staining of 2PN embryos with autophagy marker LC3 showed that non-treated embryos expressed weakly and dispersed LC3 signal in the whole cell. In contrast, LC3 signal in Baf-treated embryos were significantly accumulated and translocated in the cell membranes. The accumulation of autophagy-marker LC3 after treatment with Bafilomycin, an autophagy inhibitor, indicated the high expression of autophagosomal activity during the embryo development. This may explain the toxicity in Baf-treated embryos, which prevent the embryos to develop further than 4C-stage. Altogether our study suggests the critical role of autophagy in the fertilized oocytes and embryo development Limitations, reasons for caution Murine embryos model is widely used for safety testing in assisted reproduction technologies, however human embryos might behave differently. Moreover, although treatment with Bafilomycin is the gold standard in autophagy research in vitro, it might not mimic exactly the autophagy dysfunction in human embryo development. Wider implications of the findings Emergent evidences show that dysfunction of autophagy, which maintains the cellular homeostasis, correlates with metabolic disorders including obesity. In women, obesity causes anovulation and menstrual irregularities. Therefore, we aim to investigate the potential role of autophagy in the obesity, which may help improving the pregnancy rate in the obesity-associated infertility. Trial registration number Not applicable

Repression of autophagy leads to acrosome biogenesis disruption caused by a sub-chronic oral administration of polystyrene nanoparticles

As a new widespread contaminant, nanoplastics (NPs) pose a potential risk to human health. Nevertheless, the adverse effects of NPs on the male reproductive system are poorly understood. In this study, we aimed to determine the effects of polystyrene nanoplastics (PS-NPs) (50 nm) on sperm quality, with a focus on the acrosome defects. After 35 days of intragastric administration, sperm quality was decreased and testicular structures were impaired in mice exposed to PS-NPs in both the medium (1.0 mg/kg) and high dose (10 mg/kg) groups. No significant changes were observed in the low dose (0.2 mg/kg) group. Meanwhile, acrosome parameters including acrosome integrity and acrosome reaction were decreased after the administration of PS-NPs. These findings were consistent with the disruption of acrosome biogenesis, as identified by the changed testicular ultrastructure. Additionally, the findings were further validated using seven marker genes (Gba2, Pick1, Gopc, Hrb, Zpbp1, Spaca1 and Dpy19l2) essential for acrosome formation, which showed that two of these genes (Gopc and Dpy19l2) were significantly down-regulated. Moreover, repressed autophagy was observed in the testes of PS-NPs-exposed mice based on autophagy-related protein expression. This phenomenon was further verified in GC-2spd cells treated with PS-NPs (50 μg/mL, 100 μg/mL, 200 μg/mL for 24 h). The potential role of autophagy in such acrosome defects was explored by using the autophagy inhibitor 3-methyladenine (3-MA), autophagy activator rapamycin or beclin-1 siRNA. The results showed that Golgi-associated vesicle disorganization was exacerbated with the 3-MA and beclin-1 siRNA pretreatments, but decreased with the rapamycin pretreatment, and the expression of GOPC and DPY19L2 was also altered. These results indicated that autophagy might be involved in the PS-NPs-induced acrosome lesions based on the regulation of two key acrosome-formation proteins, GOPC and DPY19L2. Altogether, our results will provide new insights into the PS-NPs-induced male reproductive impairment.

The autophagy response during adipogenesis of primary cultured rainbow trout (Oncorhynchus mykiss) adipocytes.

Adipogenesis is a tightly regulated process, and the involvement of autophagy has been recently proposed in mammalian models. In rainbow trout, two well-defined phases describe the development of primary cultured adipocyte cells: proliferation and differentiation. Nevertheless, information on the transcriptional profile at the onset of differentiation and the potential role of autophagy in this process is scarce. In the present study, the cells showed an early and transient induction of several adipogenic transcription factors genes' expression (i.e., cebpa and cebpb) along with the morphological changes (round shape filled with small lipid droplets) typical of the onset of adipogenesis. Then, the expression of various lipid metabolism-related genes involving the synthesis (fas), uptake (fatp1 and cd36), accumulation (plin2) and mobilization (hsl) of lipids, characteristic of the mature adipocyte, increased. In parallel, several autophagy markers (i.e., atg4b, gabarapl1 and lc3b) mirrored the expression of those adipogenic-related genes, suggesting a role of autophagy during in vitro fish adipogenesis. In this regard, the incubation of preadipocytes with lysosomal inhibitors (Bafilomycin A1 or Chloroquine), described to prevent autophagy flux, delayed the process of adipogenesis (i.e., cell remodelling), thus suggesting a possible relationship between autophagy and adipocyte differentiation in trout. Moreover, the disruption of the autophagic flux altered the expression of some key adipogenic genes such as cebpa and pparg. Overall, this study contributes to improve our knowledge on the regulation of rainbow trout adipocyte differentiation, and highlights for the first time in fish the involvement of autophagy on adipogenesis, suggesting a close-fitting connection between both processes.

ATG8 is conserved between Saccharomyces cerevisiae and psychrophilic, polar-collected fungi.

Autophagy is a conserved catabolic process by which eukaryotic cells respond to stress by targeting damaged or unneeded molecules or organelles for sequestration into specialized vesicles known as autophagosomes. Autophagosomes ultimately facilitate the digestion and recycling of their contents by fusing with the degradative organelle of the cell. Studies of the budding yeast Saccharomyces cerevisiae have revealed various types of stress that can regulate autophagy, including starvation and extreme temperatures. While autophagy has not yet been directly shown to confer the ability to survive extreme cold or freeze-thaw stress in yeast, upregulation of autophagy has been directly implicated in the ability of arctic insects to survive cold temperatures. We are interested in investigating the potential role of autophagy in polar habitat survival by cold-loving (psychrophilic) yeast like Mrakia blollopsis. To begin to examine the conservation of Atg machinery in polar-collected yeast, we focused on Atg8, a small, ubiquitin-like protein that plays an important role in autophagy. We report that Atg8 is conserved between S. cerevisiae and polar-collected yeast, using Atg8 from Mrakia blollopsis (strain TGK1-2) as an example. This study represents the first direct examination of autophagy machinery conservation across mesophilic and psychrophilic species of yeast.

FSH Promotes Progesterone Synthesis by Enhancing Autophagy to Accelerate Lipid Droplet Degradation in Porcine Granulosa Cells.

Little is known about the molecular relationships among follicle stimulating hormone (FSH), lipid droplet (LD) degradation, and autophagy. In this study, we aimed to investigate the pathway by which FSH regulates autophagy and the potential role of autophagy in progesterone production. Our results revealed that FSH stimulated progesterone production in mammalian follicular granulosa cells (GCs) through a non-canonical pathway. In porcine secondary follicles cultured in vitro, FSH treatment increased the level of the autophagic marker, LC3-II, as well as increased the number of autophagic vacuoles in GCs. The underlying molecular mechanism and biological functions were then investigated in porcine GCs. Our results demonstrated that FSH could upregulate Beclin1 levels in porcine GCs; however, this effect was blocked by LY294002 (a PI3K/AKT inhibitor) and SP600125 (SAPK/JNK inhibitor). Further research confirmed that the transcriptional factor, c-Jun, was phosphorylated by FSH, then translocated into the nucleus from the cytoplasm and bound to the BECLIN1 promoter region, and that LY294002, SP600125, or c-Jun knockdown prevented the increase in Beclin1 levels induced by FSH. Interestingly, inhibition of autophagy using chloroquine or SP600125 decreased progesterone production in porcine GCs treated with FSH, although the expression of StAR and P450scc was not disturbed. Moreover, FSH treatment reduced the average number and size of LDs in porcine GCs, but these effects were eliminated by knocking down the key autophagy genes, ATG5 and BECLIN1; in addition, the effect of FSH on promoting progesterone secretion by the cells was also reduced significantly. Based on the above results, we concluded that FSH promoted progesterone production by enhancing autophagy through upregulation of Beclin1 via the PI3K/JNK/c-Jun pathway to accelerate LD degradation in porcine GCs, independent of the classical steroidogenic pathway.

Autophagy and its significance in periodontal disease.

Autophagy is an evolutionarily conserved process essential for cellular homeostasis and human health. As a lysosome-dependent degradation pathway, autophagy acts as a modulator of the pathogenesis of diverse diseases. The relationship between autophagy and oral diseases has been explored in recent years, and there is increasing interest in the role of autophagy in periodontal disease. Periodontal disease is a prevalent chronic inflammatory disorder characterized by the destruction of periodontal tissues. It is initiated through pathogenic bacterial infection and interacts with the host immune defense, leading to inflammation and alveolar bone resorption. In this review, we outline the machinery of autophagy and present an overview of work on the significance of autophagy in regulating pathogen invasion, the immune response, inflammation, and alveolar bone homeostasis of periodontal disease. Existing data provide support for the importance of autophagy as a multi-dimensional regulator in the pathogenesis of periodontal disease and demonstrate the importance of future research on the potential roles of autophagy in periodontal disease.

BECN1 promotes radiation-induced G2/M arrest through regulation CDK1 activity: a potential role for autophagy in G2/M checkpoint

Authophagy and G2/M arrest are two important mechanistic responses of cells to ionizing radiation (IR), in particular the IR-induced fibrosis. However, what interplayer and how it links the autophagy and the G2/M arrest remains elusive. Here, we demonstrate that the autophagy-related protein BECN1 plays a critical role in ionizing radiation-induced G2/M arrest. The treatment of cells with autophagy inhibitor 3-methyladenine (3-MA) at 0–12 h but not 12 h postirradiation significantly sensitized them to IR, indicating a radio-protective role of autophagy in the early response of cells to radiation. 3-MA and BECN1 disruption inactivated the G2/M checkpoint following IR by abrogating the IR-induced phosphorylation of phosphatase CDC25C and its target CDK1, a key mediator of the G2/M transition in coordination with CCNB1. Irradiation increased the nuclear translocation of BECN1, and this process was inhibited by 3-MA. We confirmed that BECN1 interacts with CDC25C and CHK2, and which is mediated the amino acids 89–155 and 151–224 of BECN1, respectively. Importantly, BECN1 deficiency disrupted the interaction of CHK2 with CDC25C and the dissociation of CDC25C from CDK1 in response to irradiation, resulting in the dephosphorylation of CDK1 and overexpression of CDK1. In summary, IR induces the translocation of BECN1 to the nucleus, where it mediates the interaction between CDC25C and CHK2, resulting in the phosphorylation of CDC25C and its dissociation from CDK1. Consequently, the mitosis-promoting complex CDK1/CCNB1 is inactivated, resulting in the arrest of cells at the G2/M transition. Our findings demonstrated that BECN1 plays a role in promotion of radiation-induced G2/M arrest through regulation of CDK1 activity. Whether such functions of BECN1 in G2/M arrest is dependent or independent on its autophagy-related roles is necessary to further identify.

BET Protein Inhibition Prolongs Cardiac Transplant Survival via Enhanced Myocardial Autophagy.

Graft rejection continues to be a major barrier to long-term engraftment after transplantation. Autophagy plays an important role in cardiac injury pathogenesis. The bromodomain and extraterminal protein inhibitor (S)-tert-butyl2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate (JQ1) inhibits inflammatory responses. However, the beneficial effect of JQ1 on transplant and the potential role of autophagy in the protective effect of graft survival are yet to be investigated. Syngeneic or allogeneic heterotopic heart transplantation was performed using C57BL/6 or BALB/c donors for C57BL/6 recipients through different treatments. Some mice were used to observe the survival of the grafts. The other mice were euthanized on the third, fifth, and seventh days after surgery. The graft samples were taken for cytokines and autophagy pathway analyses. Our study revealed that JQ1 treatment prolonged cardiac allograft survival. JQ1 increased the expression levels of liver kinase beta 1, autophagy-specific gene 5, and microtubule-associated protein light chain3-II (LC3-II) and potentiated the phosphorylation of AMP-activated protein kinase, unc-51-like kinase 1 (ULK1), and autophagy-specific gene 14 in allografts. A conditional autophagy-specific gene 5 deletion donor was utilized to abrogate the effect induced by JQ1. The combined use of JQ1 with bafilomycin A1 partially reversed the effect of JQ1, suggesting that autophagy is involved in the signaling pathway in graft survival. JQ1 downregulated the expression of inflammatory cytokines, such as interleukin-6, interleukin-1β, tumor necrosis factor-α, and interferon-γ, which was abrogated when autophagy was inhibited. JQ1 prolonged cardiac allograft survival by potentiating myocardial autophagy through the liver kinase beta 1-AMP-activated protein kinase-ULK1 signaling pathway and inhibiting the subsequent release of inflammatory cytokines. This result might provide novel insights for extending transplant survival.

Self-eating: friend or foe? The emerging role of autophagy in fibrotic diseases

Fibrosis occurs in most human organs including the liver, lung, heart and kidney, and is crucial for the progression of most chronic diseases. As an indispensable catabolic process for intracellular quality control and homeostasis, autophagy occurs in most mammalian cells and is implicated in many biological processes including fibrogenesis. Although advances have been made in understanding autophagy process, the potential role of autophagy in fibrotic diseases remains controversial and has recently attracted a great deal of attention. In the current review, we summarize the commonalities of autophagy affecting different types of fibrosis in different organs, including the liver, lung, heart, and kidney as well as in cystic fibrosis, systematically outline the contradictory results and highlight the distinct role of autophagy during the various stages of fibrosis. In summary, the exact role autophagy plays in fibrogenesis depends on specific cell types and different stimuli, and identifying and evaluating the pathogenic contribution of autophagy in fibrogenesis will promote the discovery of novel therapeutic strategies for the clinical management of these fibrotic diseases.

Simultaneous and Positively Correlated NET Formation and Autophagy in Besnoitia besnoiti Tachyzoite-Exposed Bovine Polymorphonuclear Neutrophils.

Given that B. besnoiti tachyzoites infect host endothelial cells of vessels in vivo, they become potential targets for professional phagocytes [e.g., polymorphonuclear neutrophils (PMN)] when in search for adequate host cells or in case of host cell lysis. It was recently reported that B. besnoiti-tachyzoites can efficiently be trapped by neutrophil extracellular traps (NETs) released by bovine PMN. So far, the potential role of autophagy in parasite-triggered NET formation is unclear. Thus, we here analyzed autophagosome formation and activation of AMP-activated protein kinase α (AMPKα) in potentially NET-forming innate leukocytes being exposed to B. besnoiti tachyzoites. Blood was collected from healthy adult dairy cows, and bovine PMN were isolated via density gradient centrifugation. Scanning electron microscopy confirmed PMN to undergo NET formation upon contact with B. besnoiti tachyzoites. Nuclear area expansion (NAE) analysis and cell-free and anchored NETs quantification were performed in B. besnoiti-induced NET formation. Interestingly, tachyzoites of B. besnoiti additionally induced LC3B-related autophagosome formation in parallel to NET formation in bovine PMN. Notably, both rapamycin- and wortmannin-treatments failed to influence B. besnoiti-triggered NET formation and autophagosome formation. Also, isolated NETs fail to induce autophagy suggesting independence between both cellular processes. Finally, enhanced phosphorylation of AMP activated kinase α (AMPKα), a key regulator molecule of autophagy, was observed within the first minutes of interaction in tachyzoite-exposed PMN thereby emphasizing that B. besnoiti-triggered NET formation indeed occurs in parallel to autophagy.

Targeting autophagy using natural compounds for cancer prevention and therapy.

Autophagy, also known as macroautophagy, is a tightly regulated process involved in the stress responses, such as starvation. It is a vacuolar, lysosomal pathway for the degradation of damaged proteins and organelles in eukaryotic cells. Autophagy also plays a key role in various tissue processes and immune responses and in the regulation of inflammation. Over the past decade, three levels of autophagy regulation have been identified in mammalian cells: 1) signaling, 2) autophagosome formation, and 3) autophagosome maturation and lysosomal degradation. Any deregulation of the autophagy processes can lead to the development of diverse chronic diseases, such as diabetes, obesity, cardiovascular disease, neurodegenerative disease, and malignancies. However, the potential role of autophagy in cancer is rather complex and has been associated with both the induction and the inhibition of neoplasia. Several synthetic autophagy modulators have been identified as promising candidates for cancer therapy. In addition, diverse phytochemicals derived from natural sources, such as curcumin, ursolic acid, resveratrol, thymoquinone, and γ-tocotrienol, also have attracted attention as promising autophagy modulators with minimal side effects. In this review, the authors discuss the importance of autophagy regulators and various natural compounds that induce and/or inhibit autophagy in the prevention and therapy of cancer.

Modifications of autophagy influenced the Alzheimer-like changes in SH-SY5Y cells promoted by ultrafine black carbon

Ambient ultrafine black carbon (uBC) can potentially cross blood-brain barrier, however, very little is currently known about the effects they may have on central nervous system. This study aimed to explore the roles of autophagy in Alzheimer-like pathogenic changes promoted by uBC in SH-SY5Y cells. We firstly found uBC could cause cytotoxicity and oxidative stress in SH-SY5Y cells. Additionally we found uBC initiated progressive development of Alzheimer's disease (AD) associated features, mainly including neuro-inflammation and phosphorylation of tau protein (p-Tau) accumulation. Meanwhile, autophagy process was activated by uBC probably through phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway. RNA interference and autophagosome-lysosome fusion inhibitor were applied to block autophagy process at different stages. Autophagy dysfunction at the initial membrane expansion stage could aggravate p-Tau accumulation and other Alzheimer-like changes in SH-SY5Y cells promoted by uBC. However, autophagy inhibition at the final stage could alleviate p-Tau accumulation caused by uBC. This suggested that inhibition of the infusion of autophagosome and lysosome could possibly activate ubiquitination degradation pathway to regulate p-Tau equilibrium in SH-SY5Y cells. Our findings further raise the concerns about the effects of uBC on the risk of AD and indicate potential roles of autophagy in early Alzheimer-like pathogenic changes caused by ambient uBC.