Damaged Organelles Research Articles

Glp-1 Mimetics and Autophagy in Diabetic Milieu: State-of-the-Art.

The diabetic milieu is associated with cascades of pathophysiological pathways that culminate in diabetic complications and tissue injuries. Autophagy is an essential process mandatory for cell survival and tissue homeostasis by degrading damaged organelles and removing injured cells. However, it may turn into a pathological process in an aberrant mode in the diabetic and/or malignant milieu. Moreover, autophagy could serve as a promising therapeutic target for many complications related to tissue injury. Glp-1 mimetics are a class of newer antidiabetic agents that reduce blood glucose through several pathways. However, some evidence suggests that they can provide extra glycemic benefits by modulating autophagy, although there is no complete understanding of this mechanism and its underlying molecular pathways. Hence, in the current review, we aimed to provide new insights on the possible impact of Glp-1 mimetics on autophagy and consequent benefits as well as mediating pathways.

Autophagy in Acute Lung Injury.

Acute lung injury (ALI) is a critical condition marked by rapid-onset respiratory failure due to extensive inflammation and increased pulmonary vascular permeability, often progressing to acute respiratory distress syndrome (ARDS) with high mortality. Autophagy, a cellular degradation process essential for removing damaged organelles and proteins, plays a crucial role in regulating lung injury and repair. This review examines the protective role of autophagy in maintaining cellular function and reducing inflammation and oxidative stress in ALI. It underscores the necessity of precise regulation to fully harness the therapeutic potential of autophagy in this context. We summarize the mechanisms by which autophagy influences lung injury and repair, discuss the interplay between autophagy and apoptosis, and examine potential therapeutic strategies, including autophagy inducers, targeted autophagy signaling pathways, antioxidants, anti-inflammatory drugs, gene editing, and stem cell therapy. Understanding the role of autophagy in ALI could lead to novel interventions for improving patient outcomes and reducing mortality rates associated with this severe condition.

Bimetallic peroxide nanoparticles induce PANoptosis by disrupting ion homeostasis for enhanced immunotherapy.

PANoptosis has recently emerged as a potential approach to improve the immune microenvironment. However, current methods for inducing PANoptosis are limited. Herein, through biological screening, the rational use of the nutrient metal ions Cu2+ and Zn2+ had great potential to induce PANoptosis. Inspired by these findings, we successfully developed hydrazided hyaluronic acid-modified zinc copper oxide (HZCO) nanoparticles as a PANoptosis inducer to potentiate immunotherapy. Bioactive HZCO actively delivered Cu2+ and Zn2+ while disrupting the cellular intrinsic ion metabolism pathway, resulting in double-stranded DNA release and organelle damage in cancer cells. Simultaneously, this process triggered the formation of PANoptosome and the activation of PANoptosis. HZCO-induced PANoptosis inhibited tumor growth and activated potent antitumor immune response, thereby enhancing the effectiveness of anti-programmed cell death 1 therapy. Overall, our work provides an insight into the development of PANoptosis inducers and the design of synergistic immunotherapy strategies.

Autophagy in the nervous system: general principles and specific functions

Autophagy is an intracellular mechanism for the isolation, transport and degradation of macromolecules and organelles. The physiological significance of autophagy lies, firstly, in maintaining the constancy of the intracellular environment through the timely disposal of proteins with a disrupted structure and damaged organelles. Secondly, due to the selective degradation of macromolecules, autophagy supplies the cell with monomers, which are then used by it to synthesize new compounds, which serves to ensure the rearrangement of cellular metabolism in the processes of cell differentiation, ontogenesis and adaptation to environmental challenges. Autophagy is an extremely important mechanism for maintaining normal functioning of postmitotic and differentiated cells, including neurons. Impaired neuronal autophagy leads to the formation of aggregated protein plaques, the accumulation of damaged cellular organelles, defects in the structure of processes and neuronal degeneration, which often accompanies to the progression of some forms of neurodegenerative diseases. In addition, the role of autophagy in synaptic plasticity and memory mechanisms has been established. Since autophagy has a significant impact on cellular metabolism, the study of the regulation and main pathways of this mechanism may be crucial in the elaboration of means and approaches to the treatment and prevention of many pathologies that progress with age. This review describes the basic concepts of the autophagy process, summarizes the key functions of autophagy in cells, and also presents current data on its role in ensuring the normal metabolism and implementation of specific functions of neurons.

TFEB agonist clomiphene citrate activates the autophagy-lysosomal pathway and ameliorates Alzheimer's disease symptoms in mice

Autophagy is a conserved eukaryotic cellular clearance and recycling process through the lysosome-mediated degradation of damaged organelles and protein aggregates to maintain homeostasis. Impairment of the autophagy-lysosomal pathway is implicated in the pathogenesis of Alzheimer’s disease (AD). Transcription factor EB (TFEB) is a master regulator of autophagy and lysosomal biogenesis. Therefore, activating TFEB and autophagy provides a novel strategy for AD treatment. We previously described that clomiphene citrate (CC) promotes nuclear translocation of TFEB and increases autophagy and lysosomal biogenesis. In this study, 7 and 3-month-old APP/PS1 mice were treated with TFEB agonist CC and assessed. The behavioral tests were performed using Morris water maze and open field test. Additional changes in Aβ pathology, autophagy and inflammatory response were determined. We found that CC activated TFEB and the autophagy-lysosomal pathway in neuronal cells. Moreover, using mouse model of Alzheimer's disease, CC treatment promoted clearance of Aβ plaques and ameliorated cognitive function in both 7 and 3-month-old APP/PS1 mice. The CC-induced activation of TFEB occurs by promoting acetylation of TFEB for nuclear translocation. These findings provide a molecular mechanism for the TFEB-mediated activation of the autophagy-lysosome pathway by CC, which has the potential to be repurposed and applied in the treatment or prevention of AD.

Chondrocyte autophagy mechanism and therapeutic prospects in osteoarthritis.

Osteoarthritis (OA) is the most common type of arthritis characterized by progressive cartilage degradation, with its pathogenesis closely related to chondrocyte autophagy. Chondrocytes are the only cells in articular cartilage, and the function of chondrocytes plays a vital role in maintaining articular cartilage homeostasis. Autophagy, an intracellular degradation system that regulates energy metabolism in cells, plays an incredibly important role in OA. During the early stages of OA, autophagy is enhanced in chondrocytes, acting as an adaptive mechanism to protect them from various environmental changes. However, with the progress of OA, chondrocyte autophagy gradually decreases, leading to the accumulation of damaged organelles and macromolecules within the cell, prompting chondrocyte apoptosis. Numerous studies have shown that cartilage degradation is influenced by the senescence and apoptosis of chondrocytes, which are associated with reduced autophagy. The relationship between autophagy, senescence, and apoptosis is complex. While autophagy is generally believed to inhibit cellular senescence and apoptosis to promote cell survival, recent studies have shown that some proteins are degraded by selective autophagy, leading to the secretion of the senescence-associated secretory phenotype (SASP) or increased SA-β-Gal activity in senescent cells within the damaged region of human OA cartilage. Autophagy activation may lead to different outcomes depending on the timing, duration, or type of its activation. Thus, our study explored the complex relationship between chondrocyte autophagy and OA, as well as the related regulatory molecules and signaling pathways, providing new insights for the future development of safe and effective drugs targeting chondrocyte autophagy to improve OA.

Golgiphagy: a novel selective autophagy to the fore.

The Golgi apparatus is the central hub of the cellular endocrine pathway and plays a crucial role in processing, transporting, and sorting proteins and lipids. Simultaneously, it is a highly dynamic organelle susceptible to degradation or fragmentation under various physiological or pathological conditions, potentially contributing to the development of numerous human diseases. Autophagy serves as a vital pathway for eukaryotes to manage intracellular and extracellular stress and maintain homeostasis by targeting damaged or redundant organelles for removal. Recent research has revealed that autophagy mechanisms can specifically degrade Golgi components, known as Golgiphagy. This review summarizes recent findings on Golgiphagy while also addressing unanswered questions regarding its mechanisms and regulation, aiming to advance our understanding of the role of Golgiphagy in human disease.

Autophagy in oral cancer: Promises and challenges (Review).

Autophagy captures damaged or dysfunctional proteins and organelles through the lysosomal pathway to achieve proper cellular homeostasis. Autophagy possesses distinct characteristics and is given recognized functions in numerous physiological and pathological conditions, such as cancer. Early stage cancer development can be stopped by autophagy. After tumor cells have successfully undergone transformation and progressed to a late stage, the autophagy-mediated system of dynamic degradation and recycling will support cancer cell growth and adaptation to various cellular stress responses while preserving energy homeostasis. In the present study, the dual function that autophagy plays in various oral cancer development contexts and stages, the existing arguments for and against autophagy, and the ways in which autophagy contributes to oral cancer modifications, such as carcinogenesis, drug resistance, invasion, metastasis and self-proliferation, are reviewed. Special attention is paid to the mechanisms and functions of autophagy in oral cancer processes, and the most recent findings on the application of certain conventional drugs or natural compounds as novel agents that modulate autophagy in oral cancer are discussed. Overall, further research is needed to determine the validity and reliability of autophagy promotion and inhibition while maximizing the difficult challenge of increasing cancer suppression to improve clinical outcomes.

The structural features and anti-inflammatory properties of a glucogalactan from Holotrichia diomphalia Bates (Qi Cao)

Ethnopharmacological relevanceThe dried larvae of Holotrichia diomphalia Bates, named Qi Cao, is a traditional Chinese medicine treat for liver diseases and arthritis. Polysaccharides is a principal component in Qi Cao, which exhibiting antioxidant and anti-inflammatory effects. However, the structural characteristics and underlying mechanisms of the polysaccharides remain inadequately elucidated. Aim of the studyTo analyze the primary structure and elucidate the molecular anti-inflammatory mechanisms of the active polysaccharide in Qi Cao. Materials and methodsThe total polysaccharide was extracted by water extraction and alcohol precipitation, and further isolated and purified by DEAE Sephadex A-25 column and Sephadex G-100 column. The anti-inflammatory properties of four major fractions (HDPS-1, HDPS-2, HDPS-3, HDPS-4) and the pure homogeneous polysaccharides (HDPS-1I and HDPS-1II) were assessed using a RAW 264.7 cell model induced by lipopolysaccharide (LPS), and HDPS-1II was identified as the polysaccharide exhibiting significant anti-inflammatory activity in Qi Cao. The structural characteristics of HDPS-1II were subsequently analyzed using high-performance size-exclusion chromatography (HPSEC), fourier-transform infrared spectroscopy (FT-IR), gas chromatography-mass spectrometry (GC-MS), and nuclear magnetic resonance (NMR) spectroscopy. The TLR4, NF-κB, COX-2 and iNOS expressions were determined by Western blot analysis to investigate the anti-inflammatory mechanism of HDPS-1II in vitro. Finally, the in vivo anti-inflammatory activity of HDPS-1II were evaluated by measuring the serum levels of pro-inflammatory factors, inflammatory cell infiltration and organelle damage in the lung tissues of sepsis model mice. ResultsA homogeneous polysaccharide (HDPS-1II) with molecular weight of 1.7 × 104 Da was isolated from Holotrichia diomphalia Bates. HDPS-1II contains a backbone of α-T-Glcp-(1 → 6)-α-Glcp-(1 → 4)-α-Galp-(1 → 4)-α-Galp-(1 → 6)-α-Galp-(1 → 3)-α-Galp-(1 → . It inhibited activation of the TLR4/NF-κB signaling and reduced pro-inflammatory factors and NO in LPS-stimulated macrophage. Moreover, HDPS-1II increased the survival rate, inhibited inflammatory cells infiltration, and ameliorated the lung tissue damage in septic mice. ConclusionsHDPS-1II exhibits anti-inflammatory effects in vitro and in vivo, which is the active polysaccharide components of the anti-inflammatory activity of Qi Cao.

Apache is a neuronal player in autophagy required for retrograde axonal transport of autophagosomes

Neurons are dependent on efficient quality control mechanisms to maintain cellular homeostasis and function due to their polarization and long-life span. Autophagy is a lysosomal degradative pathway that provides nutrients during starvation and recycles damaged and/or aged proteins and organelles. In neurons, autophagosomes constitutively form in distal axons and at synapses and are trafficked retrogradely to the cell soma to fuse with lysosomes for cargo degradation. How the neuronal autophagy pathway is organized and controlled remains poorly understood. Several presynaptic endocytic proteins have been shown to regulate both synaptic vesicle recycling and autophagy. Here, by combining electron, fluorescence, and live imaging microscopy with biochemical analysis, we show that the neuron-specific protein APache, a presynaptic AP-2 interactor, functions in neurons as an important player in the autophagy process, regulating the retrograde transport of autophagosomes. We found that APache colocalizes and co-traffics with autophagosomes in primary cortical neurons and that induction of autophagy by mTOR inhibition increases LC3 and APache protein levels at synaptic boutons. APache silencing causes a blockade of autophagic flux preventing the clearance of p62/SQSTM1, leading to a severe accumulation of autophagosomes and amphisomes at synaptic terminals and along neurites due to defective retrograde transport of TrkB-containing signaling amphisomes along the axons. Together, our data identify APache as a regulator of the autophagic cycle, potentially in cooperation with AP-2, and hypothesize that its dysfunctions contribute to the early synaptic impairments in neurodegenerative conditions associated with impaired autophagy.

Drug repositioning identifies potential autophagy inhibitors for the LIR motif p62/SQSTM1 protein

Autophagy is a critical cellular process for degrading damaged organelles and proteins under stressful conditions and has casually been shown to contribute to tumor survival and drug resistance. Sequestosome-1 (SQSTM1/p62) is an autophagy receptor that interacts with its binding partners via the LC3-interacting region (LIR). The p62 protein has been a highly researched target for its critical role in selective autophagy. In this study, we aimed to identify FDA-approved drugs that bind to the LIR motif of p62 and inhibit its LIR function, which could be useful targets for modulating autophagy. To this, the homology model of the p62 protein was predicted using biological data, and docking analysis was performed using Molegro Virtual Docker and PyRx softwares. We further assessed the toxicity profile of the drugs using the ProTox-II server and performed dynamics simulations on the effective candidate drugs identified. The results revealed that the kanamycin, velpatasvir, verteporfin, and temoporfin significantly decreased the binding of LIR to the p62 protein. Finally, we experimentally confirmed that Kanamycin can inhibit autophagy-associated acidic vesicular formation in breast cancer MCF-7 and MDA-MB 231 cells. These repositioned drugs may represent novel autophagy modulators in clinical management, warranting further investigation.

Autophagy and the pancreas: Healthy and disease states.

Macroautophagy/autophagy is an intracellular degradation pathway that has an important effect on both healthy and diseased pancreases. It protects the structure and function of the pancreas by maintaining organelle homeostasis and removing damaged organelles. A variety of pancreas-related diseases, such as diabetes, pancreatitis, and pancreatic cancer, are closely associated with autophagy. Genetic studies that address autophagy confirm this view. Loss of autophagy homeostasis (lack or overactivation) can lead to a series of adverse reactions, such as oxidative accumulation, increased inflammation, and cell death. There is growing evidence that stimulating or inhibiting autophagy is a potential therapeutic strategy for various pancreatic diseases. In this review, we discuss the multiple roles of autophagy in physiological and pathological conditions of the pancreas, including its role as a protective or pathogenic factor.

Uncoupling as initiating event in mitochondrial dysfunction after diuron exposure

Diuron, a herbicide derived from urea, has been shown to induce urinary bladder urothelial tumors in rodents, leading the U.S. Environmental Protection Agency (USEPA) to designate it as a ‘known/likely’ human carcinogen. In our laboratory, a series of studies investigating the carcinogenic mode of action (MoA) of Diuron have consistently revealed its cytotoxic effects on the urinary bladder urothelium. Prolonged exposure to relatively high doses of Diuron results in urothelial necrosis, regenerative hyperplasia, and eventually, the development of tumors. The hypothesis posited is that Diuron and its metabolites exert toxicity by causing damage to mitochondria, a phenomenon referred to as mitotoxicity. Our research focuses on evaluating how Diuron and its metabolites affect mitochondria isolated from both the urothelium and the liver, the primary organ for Diuron biotransformation. In this context, we present and discuss data pertaining to mitochondria isolated from the liver of Wistar rats exposed to Diuron or its metabolites 3-(3,4-diclorofenil)-1-metilureia (DCPMU) or 3,4-dichloroaniline (DCA) at concentrations ranging from 0.5 to 500 µM in vitro. The findings indicate that, at concentrations of 100 and 500 µM, the tested chemicals induce uncoupling of oxidative phosphorylation, as evidenced by the dissipation of mitochondrial membrane potential and basal oxygen consumption. Notably, at 500 µM, DCA causes mitochondrial swelling, a morphofunctional indicator of severe organelle damage. These outcomes underscore the classification of Diuron and its metabolites, DCA and DCPMU, as mitotoxic to liver cells, given the pronounced mitochondrial dysfunction they induce.

Regulatory Mechanism of Autophagy in Premature Ovarian Failure.

Premature ovarian failure (POF) is intricately linked to cellular fates such as senescence, apoptosis, and impaired granulosa cell (GC) differentiation, each of which contributes to ovarian dysfunction and follicular depletion. Autophagy is essential in preventing POF by maintaining cellular homeostasis through the degradation and recycling of damaged organelles and proteins, thereby preserving ovarian function and preventing follicular depletion. Recent studies have revealed that the targeted regulation and disruption of autophagy through various molecular mechanisms ultimately lead to the pathogenesis of POF. In this review, we provide a comprehensive analysis of the disruption in regulatory mechanisms of autophagy contributing to POF. Specifically, we elucidate the molecular mechanisms that can be targeted to restore autophagy homeostasis, offering therapeutic potential for the treatment of POF.

1,2,4-trihydroxybenzene induces non-apoptotic cell death via the structural damage of intracellular organelles

Benzene occurs naturally and is widely applied in the production process of petrochemical products. It is mainly exposed through the respiratory tract and dermal and metabolized in the liver, leading to systemic health effects, and 1,2,4-trihydroxybenzene (THB) is a benzene metabolite used as a hair dye ingredient in some countries. In an effort to identify a toxic mechanism of THB, we first analyzed the hair of consumers who used a shampoo containing THB, and contrary to our expectations, THB was not persistent in the hair. Following, we treated THB to human keratinocytes and HeLa Chang liver cells. Membrane damage was observed in both cell lines, which was more notable in HeLa Chang liver cells than in keratinocytes. Thus, we decided on HeLa Chang liver cells as target cells for further study. Cell viability decreased sharply between 20 μg/ml and 40 μg/mL, inducing G2/M phase arrest and non-apoptotic cell death. The expression of carcinogenesis-, DNA damage-, and transcriptional dysregulation–related genes were notably up-regulated, and the structure and function of mitochondria were disrupted. The volume of the ER and acidic compartments decreased, and intracellular ROS and calcium ion levels increased. More interestingly, we found that THB formed unique structures within the cells, especially around the nuclear membrane, and that those structures seemed to dig into the nucleus over time. A reverse docking analysis also showed that SULT1A1, CYP2E1, and CAT, known to play a significant role in protecting cells from harmful factors, might be potential target proteins for THB. Taken together, we suggest that THB induces non-apoptotic cell death via structural damage of intracellular organelles, especially the nuclear membrane.

The Interplay between Autophagy and Mitochondria in Cancer.

Besides producing cellular energy, mitochondria are crucial in controlling oxidative stress and modulating cellular metabolism, particularly under stressful conditions. A key aspect of this regulatory role involves the recycling process of autophagy, which helps to sustain energy homeostasis. Autophagy, a lysosome-dependent degradation pathway, plays a fundamental role in maintaining cellular homeostasis by degrading damaged organelles and misfolded proteins. In the context of tumor formation, autophagy significantly influences cancer metabolism and chemotherapy resistance, contributing to both tumor suppression and surveillance. This review focuses on the relationship between mitochondria and autophagy, specifically in the context of cancer progression. Investigating the interaction between autophagy and mitochondria reveals new possibilities for cancer treatments and may result in the development of more effective therapies targeting mitochondria, which could have significant implications for cancer treatment. Additionally, this review highlights the increasing understanding of autophagy's role in tumor development, with a focus on modulating mitochondrial function and autophagy in both pre-clinical and clinical cancer research. It also explores the potential for developing more-targeted and personalized therapies by investigating autophagy-related biomarkers.

Identification and validation of ferroptosis-related hub genes and immune infiltration in liver ischemia-reperfusion injury

Ischemia–reperfusion injury (IRI) is a cumulation of pathophysiological processes that involves cell and organelle damage upon blood flow constraint and subsequent restoration. However, studies on overall immune infiltration and ferroptosis in liver ischemia-reperfusion injury (LIRI) are limited. This study explored immune cell infiltration and ferroptosis in LIRI using bioinformatics and experimental validation. The GSE151648 dataset, including 40 matched pairs of pre- and post- transplant liver samples was downloaded for bioinformatic analysis. Eleven hub genes were identified by overlapping differentially expressed genes (DEGs), iron genes, and genes identified through weighted gene co-expression network analysis (WGCNA). Subsequently, the pathway enrichment, transcription factor-target, microRNA-mRNA and protein-protein interaction networks were investigated. The diagnostic model was established by logistic regression, which was validated in the GSE23649 and GSE100155 datasets and verified using cytological experiments. Moreover, several drugs targeting these genes were found in DrugBank, providing a more effective treatment for LIRI. In addition, the expression of 11 hub genes was validated using quantitative real-time polymerase chain reaction (qRT-PCR) in liver transplantation samples and animal models. The expression of the 11 hub genes increased in LIRI compared with the control. Five genes were significantly enriched in six biological process terms, six genes showed high enrichment for LIRI-related signaling pathways. There were 56 relevant transcriptional factors and two central modules in the protein-protein interaction network. Further immune infiltration analysis indicated that immune cells including neutrophils and natural killer cells were differentially accumulated in the pre- and post-transplant groups, and this was accompanied by changes in immune-related factors. Finally, 10 targeted drugs were screened. Through bioinformatics and further experimental verification, we identified hub genes related to ferroptosis that could be used as potential targets to alleviate LIRI.

Cytoprotective Effect of Growth Factors Derived From Platelets on Corticosteroid-Treated Primary Anterior Cruciate Ligament-Derived Stromal Cells and Chondrocytes.

Background The use of corticosteroids, such as methylprednisolone, for pain management is a common clinical practice. However, it is well known that corticosteroids induce toxicity in anterior cruciate ligament (ACL)-derived stromal cells and chondrocytes. Growth factors from platelets have anti-inflammatory effects that can potentially limit the cytotoxic effects of corticosteroids. In this study, we explored the role of growth factors obtained from the OssinextTM kit (commercially available Wockhardt growth factor concentrate (GFC) kit) in recovering methylprednisolone-induced cell damage. Methodology Primary ACL-derived stromal cells and chondrocytes were isolated from human ligament tissue and articular cartilage, respectively, and characterized by immunophenotyping, gene expression analysis, and immunostaining. GFC obtained from OssinextTM kit was used for the experiments. The ACL-derived stromal cells and chondrocytes were treated with methylprednisolone, alone or in combination with GFC. Cell viability was measured by the neutral red uptake assay. Changes in cell morphology and collagen pattern were observed microscopically by H&E staining and immunostaining, respectively. Cell proliferation was assessed by cell migration assay, and the cell ultra-structure was analyzed using transmission electron microscopy. Results Methylprednisolone was found to induce cytotoxicity, altered cell morphology, reduced cell proliferation, and organelle damage in both ACL-derived stromal cells and chondrocytes. GFC obtained from the OssinextTM kit was able to restore cell viability and reverse the cell structure damages induced by methylprednisolone. GFC was found to recover and protect the cells, both when used in combination with steroids and when used after the steroid treatment. Conclusions The results indicate that GFC may be clinically beneficial when used in combination with steroids to mitigate their adverse effects.

Role of ATG4 Autophagy-Related Protein Family in the Lower Airways of Patients with Stable COPD.

Autophagy is a complex physiological pathway mediating homeostasis and survival of cells degrading damaged organelles and regulating their recycling. Physiologic autophagy can maintain normal lung function, decrease lung cellular senescence, and inhibit myofibroblast differentiation. It is well known that autophagy is activated in several chronic inflammatory diseases; however, its role in the pathogenesis of chronic obstructive pulmonary disease (COPD) and the expression of autophagy-related genes (ATGs) in lower airways of COPD patients is still controversial. The expression and localization of all ATG proteins that represented key components of the autophagic machinery modulating elongation, closure, and maturation of autophagosome membranes were retrospectively measured in peripheral lungs of patients with stable COPD (n = 10), control smokers with normal lung function (n = 10), and control nonsmoking subjects (n = 8) using immunohistochemical analysis. These results show an increased expression of ATG4 protein in alveolar septa and bronchiolar epithelium of stable COPD patients compared to smokers with normal lung function and non-smoker subjects. In particular, the genes in the ATG4 protein family (including ATG4A, ATG4B, ATG4C, and ATG4D) that have a key role in the modulation of the physiological autophagic machinery are the most important ATGs increased in the compartment of lower airways of stable COPD patients, suggesting that the alteration shown in COPD patients can be also correlated to impaired modulation of autophagic machinery modulating elongation, closure, and maturation of autophagosomes membranes. Statistical analysis was performed by the Kruskal-Wallis test and the Mann-Whitney U test for comparison between groups. A statistically significant increased expression of ATG4A (p = 0.0047), ATG4D (p = 0.018), and ATG5 (p = 0.019) was documented in the bronchiolar epithelium as well in alveolar lining for ATG4A (p = 0.0036), ATG4B (p = 0.0054), ATG4C (p = 0.0064), ATG4D (p = 0.0084), ATG5 (p = 0.0088), and ATG7 (p = 0.018) in patients with stable COPD compared to control groups. The ATG4 isoforms may be considered as additional potential targets for the development of new drugs in COPD.

Advances in Polymeric Nanomaterial-mediated Autophagy for Cancer Therapy.

Autophagy is an important biological mechanism for eukaryotic cells to regulate growth, death, and energy metabolism, and plays an important role in removing damaged organelles, misfolded or aggregated proteins, and clearing pathogens. It has been found that autophagy is closely related to cell survival and death, and is of great significance in cancerigenesis and development, playing a bidirectional role in cancer inhibition and cancer promotion. Therefore, treating cancers by regulating autophagy has attracted much attention. A large amount of research evidence indicates that polymeric nanomaterials are able to regulate cellular autophagy, and their good biocompatibility, degradability, and functionalizable modification open up a broad application prospect for improving the therapeutic effect of cancers. This review provides an overview of the research progress of polymeric nanomaterials for modulating autophagy in the treatment of cancers.