Search Results (101)

Autophagy, an evolutionarily conserved self-degradation catabolic mechanism, is crucial for recycling breakdown products and degrading intracellular components such as cytoplasmic organelles, macromolecules, and proteins in eukaryotes. The process, which can be selective or non-selective, involves the removal of specific ribosomes, protein aggregates, and organelles. Although the specific mechanisms governing various aspects of selective autophagy have not been fully understood, numerous studies have revealed that the dysregulation of autophagy-related genes significantly influences cellular homeostasis and contributes to a wide range of human diseases, particularly cancers, neurodegenerative disorders and inflammatory diseases. Notably, accumulating evidence highlights the complex, dual role of autophagy in cancer development. Thus, this review systematically summarizes the molecular mechanisms of autophagy and presents the latest research on its involvement in both pro- and anti-tumor progression. Furthermore, we discuss the role of autophagy in cancer development and summarize advancement in tumor therapies targeting autophagy. Full article

Mitochondrial dysfunction is a pivotal driver in the pathogenesis of acute kidney injury (AKI), chronic kidney disease (CKD), and congenital anomalies of the kidney and urinary tract (CAKUT). The kidneys, second only to the heart in mitochondrial density, rely on oxidative phosphorylation to meet the high ATP demands of solute reabsorption and filtration. Disrupted mitochondrial dynamics, such as excessive fission mediated by Drp1, exacerbate tubular apoptosis and inflammation in AKI models like ischemia–reperfusion injury. In CKD, persistent mitochondrial dysfunction drives oxidative stress, fibrosis, and metabolic reprogramming, with epigenetic mechanisms (DNA methylation, histone modifications, non-coding RNAs) regulating genes critical for mitochondrial homeostasis, such as PMPCB and TFAM. Epigenetic dysregulation also impacts mitochondrial–ER crosstalk, influencing calcium signaling and autophagy in renal pathology. Mitophagy, the selective clearance of damaged mitochondria, plays a dual role in kidney disease. While PINK1/Parkin-mediated mitophagy protects against cisplatin-induced AKI by preventing mitochondrial fragmentation and apoptosis, its dysregulation contributes to fibrosis and CKD progression. For instance, macrophage-specific loss of mitophagy regulators like MFN2 amplifies ROS production and fibrotic responses. Conversely, BNIP3/NIX-dependent mitophagy attenuates contrast-induced AKI by suppressing NLRP3 inflammasome activation. In diabetic nephropathy, impaired mitophagy correlates with declining eGFR and interstitial fibrosis, highlighting its diagnostic and therapeutic potential. Emerging therapeutic strategies target mitochondrial dysfunction through antioxidants (e.g., MitoQ, SS-31), mitophagy inducers (e.g., COPT nanoparticles), and mitochondrial transplantation, which mitigates AKI by restoring bioenergetics and modulating inflammatory pathways. Nanotechnology-enhanced drug delivery systems, such as curcumin-loaded nanoparticles, improve renal targeting and reduce oxidative stress. Epigenetic interventions, including PPAR-α agonists and KLF4 modulators, show promise in reversing metabolic reprogramming and fibrosis. These advances underscore mitochondria as central hubs in renal pathophysiology. Tailored interventions—ranging from Drp1 inhibition to mitochondrial transplantation—hold transformative potential to mitigate kidney injury and improve clinical outcomes. Additionally, dietary interventions and novel regulators such as adenogens are emerging as promising strategies to modulate mitochondrial function and attenuate kidney disease progression. Future research should address the gaps in understanding the role of mitophagy in CAKUT and optimize targeted delivery systems for precision therapies. Full article

Acute radiation syndrome (ARS) results from high-dose ionizing radiation (IR) exposure, with bone marrow (BM) being highly susceptible due to its proliferative activity. BM injury causes pancytopenia, leading to infections, anemia, and bleeding. Mesenchymal stem cells (MSCs) hold promise for ARS treatment because of their immunomodulatory, anti-inflammatory, and regenerative properties. However, challenges such as replicative senescence, poor survival, and engraftment in irradiated microenvironments limit their efficacy. This study evaluated rapamycin-preconditioned placenta-derived MSCs (rPD-MSCs) in a mouse ARS model. Rapamycin was selected for preconditioning due to its ability to induce autophagy and modulate cytokine secretion. We assessed rapamycin-dependent modulation of autophagy-related genes and proteins, as well as hematopoietic cytokines secretion in PD-MSCs, and evaluated morphological changes in blood and BM at 7 and 21 days post-irradiation in ICR/CD1 mice. Preconditioning with rapamycin alters the secretion of granulocyte colony-stimulating factor (G-CSF), stem cell factor (SCF), and Fms-related tyrosine kinase 3 ligand (Flt3LG) in PD-MSCs without affecting cell viability. rPD-MSCs better enhance hematopoietic recovery, restore bone marrow cellularity, and increase peripheral blood cell counts by elevating the secretion of hematopoietic cytokines compared to non-preconditioned cells. These results highlight rapamycin preconditioning as a promising strategy to enhance MSCs therapeutic potential for ARS, supporting further preclinical and clinical exploration. Full article

Percutaneous ventricular assist devices are utilized in cases of cardiogenic shock following acute myocardial infarction (AMI). However, the mechanism underlying the beneficial effects of LV unloading in AMI remains unclear. This study aimed to examine the impact of LV unloading on cardiac function, heart failure markers, and protein degradation (autophagy and ubiquitin–proteasome system: UPS) post AMI in rats. Nine-week-old male Lewis rats were randomized into non-AMI, AMI, non-AMI with LV unloading, and AMI with LV unloading groups. LV unloading was achieved through heterotopic heart–lung transplantation. Rats were euthanized 2 and 14 days after the procedure. Cardiac functional assessment was performed using Langendorff heart perfusion. RT-PCR and Western blot analyses were conducted using the LV myocardium. The rate pressure product was comparable between the non-AMI with LV unloading group and the AMI with LV unloading at 14 days. The atrial natriuretic factor tended to be suppressed by LV unloading. LV unloading had reducing effects on the expressions of p62, selectively degraded during autophagy, both 2 and 14 days after AMI. There was no effect on the parameters for the UPS. LV unloading has a mitigating effect on the deterioration of cardiac function following AMI. Autophagy, which was suppressed by AMI, was ameliorated by LV unloading. Full article

In aging, chronic diseases such as obesity accelerate metabolic dysfunction through chronic inflammation and insulin resistance. This review compared three different dietary strategies to evaluate their mechanisms and benefits for metabolic health and longevity. A comprehensive database search was conducted, selecting studies in animal models and in humans with or without obesity which have been published since 2004. Fasting-mimicking diets reduce IGF-1, promote autophagy, and improve insulin sensitivity, although long-term adherence remains a challenge. Time-restricted feeding synchronizes food intake with circadian rhythms, benefiting inflammation, glycemic control, and body composition. Protein and amino acid restriction, particularly methionine and branched-chain amino acids, modulates mTOR and reduces oxidative stress but requires adjustments in older adults. According to the available evidence, each intervention offers a non-invasive and adaptive approach to mitigating the effects of aging, provided it is applied in a personalized manner with appropriate follow-up. Full article

Huntington disease’s (HD) is a neurodegenerative disorder caused by the expansion of a polyglutamine region (PolyQ) within the huntingtin protein (HTT). Mutated huntingtin (mHTT) is cytotoxic, particularly for striatal medium spiny neurons (MSNs), whose degeneration is the hallmark of HD. Autophagy inducers currently available promote the clearance of toxic proteins. However, due to their low selectivity and the possibility that prolonged autophagy hampers essential processes in unaffected cells, researchers have questioned their benefits in neurodegenerative diseases. Since MSNs express dopamine receptors D2 (DRD2) and D3 (DRD3) and DRD2/DRD3 agonists may activate autophagy, here, we explored how healthy and mHTT-challenged cells respond to prolonged DRD2/DRD3 agonist treatment. Autophagy activation and its effects on mHTT/polyQ clearance were studied in R6/1 mice (a genetic model of HD), their wild-type littermates, and DRD2- and DRD3-HEK cells expressing a pathogenic (Q74) and a non-pathogenic (Q23) polyQ fragment of mHTT treated with the DRD2/DRD3 agonist pramipexole. Two forms of DRD3-mediated autophagy were found: a transient mTORC1-dependent in WT mice and Q23-DRD3-HEK cells and a persistent AMPK-ULK1-activated in R6/1 mice and Q74-DRD3-HEK cells. This also promoted a robust clearance of soluble mHTT/polyQ and neuroprotection in striatal neurons and DRD3-HEK cells. The findings indicate that DRD3-induced autophagy may be a safe, disease-modifying intervention in HD patients. Full article

Background/Objectives: Ovarian aging represents a critically important aspect of female senescence. It not only denotes the loss of fertility but is also accompanied by a series of physiological changes and the aging of other organs. Hydroxytyrosol (HT), a natural polyphenolic phytocompound, has been demonstrated to exhibit remarkable effects in regulating autophagy, inflammation, and the aging process. However, the relationship between HT and ovarian aging, as well as the specific underlying mechanisms, remains poorly understood. Methods: In this study, network pharmacology, molecular docking, and molecular dynamics simulation were employed to explore the regulatory effect of HT on ovarian inflammaging via autophagy-targeted mechanisms. Results: Through network pharmacology analysis, this study successfully identified 10 hub genes associated with ovarian aging regulation. Notably, four out of the top five hub genes were found to be closely related to autophagy regulatory pathways. Further investigation revealed the pivotal role of ATG7: HT may regulate ovarian inflammaging through activating the FIP200 (focal adhesion kinase family interacting protein of 200 kD)-dependent non-canonical selective autophagy pathway. The results of molecular docking indicated that ATG7 has a strong binding ability with HT. Molecular dynamics simulation further verified the binding stability between the two. Conclusions: By analysis, a possible pathway for HT to regulate ovarian inflammaging via non-canonical selective autophagy was explored, providing cues for further research. Full article

The brown planthopper (Nilaparvata lugens) is an insect pest of rice, which mainly feeds on the phloem sap of the leaf sheath. RNA interference (RNAi) has application prospects in pest control, but it is necessary to select target genes and design suitable dsRNA fragments for RNAi so that it can achieve effective pest control and avoid risks to non-target organisms. NlAtg3 is a key protein in the autophagy pathway of N. lugens. Three kinds of dsRNA fragments of the NlAtg3 gene (dsNlAtg3-474×1, dsNlAtg3-138×3 and dsNlAtg3-47×10) were designed to compare the RNAi efficiency and specificity against the target insect N. lugens and non-target organisms through microinjection. The results showed that the fragment dsNlAtg3-474×1 showed strong inhibitory effects on the survival of N. lugens, which resulted in the survival rate decreasing to zero on the fifth day, while the survival rate of a closely related species, Sogatella furcifera, dropped to 2.22%. In contrast, dsNlAtg3-47×10 specifically designed against N. lugens only showed slight or no inhibitory effects on S. furcifera and other non-target organisms such as Drosophila melanogaster, but still showed good lethal effects against N. lugens, with the survival rate dropping to 18.89% on the ninth day. In addition, after being fed N. lugens injected with dsNlAtg3-47×10 fragments, the survival rate of the natural enemies Dolomedes sulfureus and Tytthus chinensis did not show significant change, compared with those treated with the dsGFP control. Our results suggest that the NlAtg3 gene can serve as a potential target for controlling N. lugens. Moreover, by designing suitable RNAi fragments, it is possible to avoid harm to non-target organisms while effectively inhibiting the target insect N. lugens. Full article

Metabolic cardiomyopathy, encompassing diabetic and obese cardiomyopathy, is an escalating global health concern, driven by the rising prevalence of metabolic disorders such as insulin resistance, type 1 and type 2 diabetes, and obesity. These conditions induce structural and functional alterations in the heart, including left ventricular dysfunction, fibrosis, and ultimately heart failure, particularly in the presence of coronary artery disease or hypertension. Autophagy, a critical cellular process for maintaining cardiac homeostasis, is frequently disrupted in metabolic cardiomyopathy. This review explores the role of autophagy in the pathogenesis of high-fat diet (HFD) and streptozotocin (STZ)-induced metabolic cardiomyopathy, focusing on non-selective and selective autophagy pathways, including mitophagy, ER-phagy, and ferritinophagy. Key proteins and genes such as PINK1, Parkin, ULK1, AMPK, mTOR, ATG7, ATG5, Beclin-1, and miR-34a are central to the regulation of autophagy in metabolic cardiomyopathy. Dysregulated autophagic flux impairs mitochondrial function, promotes oxidative stress, and drives fibrosis in the heart. Additionally, selective autophagy processes such as lipophagy, regulated by PNPLA8, and ferritinophagy, modulated by NCOA4, play pivotal roles in lipid metabolism and iron homeostasis. Emerging therapeutic strategies targeting autophagy, including plant extracts (e.g., curcumin, dihydromyricetin), endogenous compounds (e.g., sirtuin 3, LC3), and lipid/glucose-lowering drugs, offer promising avenues for mitigating the effects of metabolic cardiomyopathy. Despite recent advances, the precise mechanisms underlying autophagy in this context remain poorly understood. A deeper understanding of autophagy’s regulatory networks, particularly involving these critical genes and proteins, may lead to novel therapeutic approaches for treating metabolic cardiomyopathy. Full article

Background and Objective: Diffuse large B-cell lymphoma (DLBCL), a subtype of non-Hodgkin’s lymphoma, is the most common lymphoid malignancy in the Western world. Treatment of DLBCL has been greatly improved in recent years with the addition of the monoclonal antibody Rituximab to the gold standard CHOP (cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone) chemotherapy regimen, but these treatments are often ineffective in patients with highly aggressive disease or patients of advanced age. While CAR-T cells have further advanced the treatment landscape of DLBCL, these often come at significant costs such as toxicity and financial costs for patients. Thus, research has recently focused on natural products that can selectively target malignant lymphomas while displaying a reduced host toxicity profile. Methods: In vitro cellular and biochemical approaches were used to analyze the effects of a natural extract from the Ganoderma lucidum mushroom (GA-DM) on autophagy and apoptosis in human and mouse B-cell lymphoma lines. In addition, in vivo approaches were applied to determine the effect of GA-DM on tumor growth and metastasis in a mouse model of B-cell lymphoma. Results: Here, we report, for the first time, that GA-DM induces apoptosis in the human B-cell lymphoma cell lines DB and Toledo, and orchestrates autophagy and apoptosis in the murine B-cell lymphoma cell line A20. While GA-DM differentially induced autophagy and apoptosis in mouse and human B-cell lymphomas, blocking apoptosis by the caspase inhibitor Z-VAD-FM reduced anti-proliferative activity in human B-cell lymphoma cells (DB: 71.6 ± 6.2% vs. 56.7 ± 2.4%; Toledo: 53.1 ± 10.6% vs. 14.6 ± 9.3%) in vitro. Antitumor efficacy of GA-DM was also investigated in vivo in a murine B-cell lymphoma model using the A20 cell line, where GA-DM treatment reduced both the number of tumor metastases (control: 5.5 ± 3.2 vs. GA-DM: 1.6 ± 0.87) and the overall tumor burden (control: 3.2 g ± 1.9 vs. GA-DM: 1.70 g ± 0.2) in diseased mice. Conclusions: These findings support the potential use of GA-DM as a novel chemotherapeutic in the treatment of DLBCL and could improve the treatment of higher-risk patients with advanced disease who cannot tolerate current chemotherapy treatments. Full article

Cold atmospheric plasma (CAP) has gained attention as a non-invasive therapeutic option in oncology due to its selective cytotoxicity against cancer cells. CAP produces a complex mixture of reactive oxygen and nitrogen species (RONS), which induce oxidative stress, leading to various forms of cell death, including apoptosis, necrosis, autophagy, and ferroptosis. These mechanisms allow CAP to target cancer cells effectively while sparing healthy tissue, making it a versatile tool in cancer treatment. This review explores the molecular pathways modulated by CAP, including PI3K/AKT, MAPK/ERK, and p53, which are crucial in the regulation of cell survival and proliferation. Additionally, in vivo, in vitro, and clinical studies supporting the efficacy of CAP are collected, providing additional evidence on its potential in oncological therapy. Full article

Glycogen, a branched polysaccharide organized into glycogen granules (GGs), is delivered from the cytoplasm to the lysosomes of hepatocytes by STBD1-driven selective autophagy (glycophagy). Recently, we developed Komagataella phaffii yeast as a simple model of GG autophagy and found that it proceeds non-selectively under nitrogen starvation conditions. However, another group, using Saccharomyces cerevisiae as a model, found that glycogen is a non-preferred cargo of nitrogen starvation-induced bulk autophagy. To clarify cargo characteristics of K. phaffii GGs, we used the same glycogen synthase-based reporter (Gsy1-GFP) of GG autophagy in K. phaffii as was used in S. cerevisiae. The K. phaffii Gsy1-GFP marked the GGs and reported on their autophagic degradation during nitrogen starvation, as expected. However, unlike in S. cerevisiae, glycogen synthase-marked GGs were delivered to the vacuole and degraded there with the same efficiency as a cytosolic glycogen synthase in glycogen-deficient cells, suggesting that glycogen is a neutral cargo of bulk autophagy in K. phaffii. We verified our findings with a new set of reporters based on the glycogen-binding CBM20 domain of human STBD1. The GFP-CBM20 and mCherry-CBM20 fusion proteins tagged GGs, reported about the autophagy of GGs, and confirmed that GGs in K. phaffii are neither preferred nor non-preferred substrates of bulk autophagy. They are its neutral substrates. Full article

Background and Objectives: Metabolic syndrome (MetS) is a condition marked by a complex array of physiological, biochemical, and metabolic abnormalities, including central obesity, insulin resistance, high blood pressure, and dyslipidemia (characterized by elevated triglycerides and reduced levels of high-density lipoproteins). The pathogenesis develops from the accumulation of lipid droplets in the hepatocyte (steatosis). This accumulation, in genetically predisposed subjects and with other external stimuli (intestinal dysbiosis, high caloric diet, physical inactivity, stress), activates the production of pro-inflammatory molecules, alter autophagy, and turn on the activity of hepatic stellate cells (HSCs), provoking the low grade chronic inflammation and the fibrosis. This syndrome is associated with a significantly increased risk of developing type 2 diabetes mellitus (T2D), cardiovascular diseases (CVD), vascular, renal, pneumologic, rheumatological, sexual, cutaneous syndromes and overall mortality, with the risk rising five- to seven-fold for T2DM, three-fold for CVD, and one and a half–fold for all-cause mortality. The purpose of this narrative review is to examine metabolic syndrome as a “systemic disease” and its interaction with major internal medicine conditions such as CVD, diabetes, renal failure, and respiratory failure. It is essential for internal medicine practitioners to approach this widespread condition in a “holistic” rather than a fragmented manner, particularly in Western countries. Additionally, it is important to be aware of the non-invasive tools available for assessing this condition. Materials and Methods: We conducted an exhaustive search on PubMed up to July 2024, focusing on terms related to metabolic syndrome and other pathologies (heart, Lung (COPD, asthma, pulmonary hypertension, OSAS) and kidney failure, vascular, rheumatological (osteoarthritis, rheumatoid arthritis), endocrinological, sexual pathologies and neoplastic risks. The review was managed in accordance with the PRISMA statement. Finally, we selected 300 studies (233 papers for the first search strategy and 67 for the second one). Our review included studies that provided insights into metabolic syndrome and non-invasive techniques for evaluating liver fibrosis and steatosis. Studies that were not conducted on humans, were published in languages other than English, or did not assess changes related to heart failure were excluded. Results: The findings revealed a clear correlation between metabolic syndrome and all the pathologies above described, indicating that non-invasive assessments of hepatic fibrosis and steatosis could potentially serve as markers for the severity and progression of the diseases. Conclusions: Metabolic syndrome is a multisystem disorder that impacts organs beyond the liver and disrupts the functioning of various organs. Notably, it is linked to a higher incidence of cardiovascular diseases, independent of traditional cardiovascular risk factors. Non-invasive assessments of hepatic fibrosis and fibrosis allow clinicians to evaluate cardiovascular risk. Additionally, the ability to assess liver steatosis may open new diagnostic, therapeutic, and prognostic avenues for managing metabolic syndrome and its complications, particularly cardiovascular disease, which is the leading cause of death in these patients. Full article

Lung cancer remains a formidable health challenge due to its high mortality and morbidity rates. Non-small cell lung cancer (NSCLC) constitutes approximately 85% of all lung cancer cases, with small cell lung cancer (SCLC) accounting for the remainder. Both NSCLC and SCLC cells express receptor tyrosine kinases, which may be overexpressed or mutated in lung cancer, leading to increased activation. The c-Met receptor tyrosine kinase, crucial for cell transformation and tumor growth, invasion, and metastasis, became the focus of our study. We used an E1B55KD-deleted, replication-selective oncolytic adenovirus (Ad.What), driven by the c-Met promoter, targeting lung cancer cells with c-Met overexpression, thus sparing normal cells. Previous studies have shown the enhanced antitumor efficacy of oncolytic adenoviruses when combined with chemotherapeutic agents. We explored combining rapamycin, a selective mTOR inhibitor with promising clinical trial outcomes for various cancers, with Ad.What. This combination increased infectivity by augmenting the expression of coxsackievirus and adenovirus receptors and αV integrin on cancer cells and induced autophagy. Our findings suggest that combining a c-Met promoter-driven oncolytic adenovirus with rapamycin could be an effective lung cancer treatment strategy, offering a targeted approach to exploit lung cancer cells’ vulnerabilities, potentially marking a significant advancement in managing this deadly disease. Full article

In non-small cell lung cancer (NSCLC) treatment, radiotherapy responses are not durable and toxicity limits therapy. We find that AM-101, a synthetic benzodiazepine activator of GABA(A) receptor, impairs the viability and clonogenicity of both primary and brain-metastatic NSCLC cells. Employing a human-relevant ex vivo ‘chip’, AM-101 is as efficacious as docetaxel, a chemotherapeutic used with radiotherapy for advanced-stage NSCLC. In vivo, AM-101 potentiates radiation, including conferring a significant survival benefit to mice bearing NSCLC intracranial tumors generated using a patient-derived metastatic line. GABA(A) receptor activation stimulates a selective-autophagic response via the multimerization of GABA(A) receptor-associated protein, GABARAP, the stabilization of mitochondrial receptor Nix, and the utilization of ubiquitin-binding protein p62. A high-affinity peptide disrupting Nix binding to GABARAP inhibits AM-101 cytotoxicity. This supports a model of GABA(A) receptor activation driving a GABARAP–Nix multimerization axis that triggers autophagy. In patients receiving radiotherapy, GABA(A) receptor activation may improve tumor control while allowing radiation dose de-intensification to reduce toxicity. Full article