Search Results (252)

Diabetic retinopathy (DR) is a progressive, multifactorial complication of diabetes and one of the major global causes of visual impairment. Its pathogenesis involves chronic hyperglycaemia-induced oxidative stress, inflammation, mitochondrial dysfunction, neurodegeneration, and pathological angiogenesis, as well as emerging systemic contributors such as gut microbiota dysregulation. While current treatments, including anti-vascular endothelial growth factor (anti-VEGF) agents, corticosteroids, and laser photocoagulation, have shown clinical efficacy, they are largely limited to advanced stages of DR, require repeated invasive procedures, and do not adequately address early neurovascular and metabolic abnormalities. Resveratrol (RSV), a naturally occurring polyphenol, has emerged as a promising candidate due to its potent antioxidant, anti-inflammatory, neuroprotective, and anti-angiogenic properties. This review provides a comprehensive analysis of the molecular mechanisms by which RSV exerts protective effects in DR, including modulation of oxidative stress pathways, suppression of inflammatory cytokines, enhancement of mitochondrial function, promotion of autophagy, and inhibition of pathological neovascularisation. Despite its promising pharmacological profile, the clinical application of RSV is limited by poor aqueous solubility, rapid systemic metabolism, and low ocular bioavailability. Various routes of administration, including intravitreal injection, topical instillation, and oral and sublingual delivery, have been investigated to enhance its therapeutic potential. Recent advances in drug delivery systems, including nanoformulations, liposomal carriers, and sustained-release intravitreal implants, offer potential strategies to address these challenges. This review also explores RSV’s role in combination therapies, its potential as a disease-modifying agent in early-stage DR, and the relevance of personalised medicine approaches guided by metabolic and genetic factors. Overall, the review highlights the therapeutic potential and the key translational challenges in positioning RSV as a multi-targeted treatment strategy for DR. Full article

Background/Objectives: Primary liver cancer (PLC), encompassing hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), constitutes a growing global health concern. Metabolic dysfunction-associated Steatotic Liver Disease (MASLD) and Type 2 diabetes mellitus (T2DM) represent a recurrent epidemiological overlap. Individuals with MASLD and T2DM (MASLD-T2DM) are at a higher risk of PLC. This scoping review highlights the epidemiological burden, the classic and novel pathogenetic frontiers, and the potential strategies optimizing the management of PLC in MASLD-T2DM. Methods: A systematic search of the PubMed, Medline, and SCOPUS electronic databases was conducted to identify evidence investigating the pathogenetic mechanisms linking MASLD and T2DM to hepatic carcinogenesis, highlighting the most relevant targets and the relatively emerging therapeutic strategies. The search algorithm included in sequence the filter words: “MASLD”, “liver steatosis”, “obesity”, “metabolic syndrome”, “body composition”, “insulin resistance”, “inflammation”, “oxidative stress”, “metabolic dysfunction”, “microbiota”, “glucose”, “immunometabolism”, “trained immunity”. Results: In the MASD-T2DM setting, insulin resistance (IR) and IR-induced mechanisms (including chronic inflammation, insulin/IGF-1 axis dysregulation, and autophagy), simultaneously with the alterations of gut microbiota composition and functioning, represent crucial pathogenetic factors in hepatocarcinogenesis. Besides, the glucose-related metabolic reprogramming emerged as a crucial pathogenetic moment contributing to cancer progression and immune evasion. In this scenario, lifestyle changes, simultaneously with antidiabetic drugs targeting IR-related effects and gut-liver axis, in parallel with novel approaches modulating immunometabolic pathways, represent promising strategies. Conclusions: Metabolic dysfunction, classically featuring MASLD-T2DM, constitutes a continuously expanding global issue, as well as a critical driver in PLC progression, demanding integrated and personalized interventions to reduce the future burden of disease. Full article

Background: The candidate therapeutic peptide TnP demonstrates broad, system-level regulatory capacity, revealed through integrated network analysis from transcriptomic data in zebrafish. Our study primarily identifies TnP as a multifaceted modulator of drug metabolism, wound healing, proteolytic activity, and pigmentation pathways. Results: Transcriptomic profiling of TnP-treated larvae following tail fin amputation revealed 558 differentially expressed genes (DEGs), categorized into four functional networks: (1) drug-metabolizing enzymes (cyp3a65, cyp1a) and transporters (SLC/ABC families), where TnP alters xenobiotic processing through Phase I/II modulation; (2) cellular trafficking and immune regulation, with upregulated myosin genes (myhb/mylz3) enhancing wound repair and tlr5-cdc42 signaling fine-tuning inflammation; (3) proteolytic cascades (c6ast4, prss1) coupled to autophagy (ulk1a, atg2a) and metabolic rewiring (g6pca.1-tg axis); and (4) melanogenesis-circadian networks (pmela/dct-fbxl3l) linked to ubiquitin-mediated protein turnover. Key findings highlight TnP’s unique coordination of rapid (protease activation) and sustained (metabolic adaptation) responses, enabled by short network path lengths (1.6–2.1 edges). Hub genes, such as nr1i2 (pxr), ppara, and bcl6aa/b, mediate crosstalk between these systems, while potential risks—including muscle hypercontractility (myhb overexpression) or cardiovascular effects (ace2-ppp3ccb)—underscore the need for targeted delivery. The zebrafish model validated TnP-conserved mechanisms with human relevance, particularly in drug metabolism and tissue repair. TnP’s ability to synchronize extracellular matrix remodeling, immune resolution, and metabolic homeostasis supports its development for the treatment of fibrosis, metabolic disorders, and inflammatory conditions. Conclusions: Future work should focus on optimizing tissue-specific delivery and assessing genetic variability to advance clinical translation. This system-level analysis positions TnP as a model example for next-generation multi-pathway therapeutics. Full article

Hepatocellular carcinoma (HCC) remains a therapeutic challenge due to metabolic plasticity and drug resistance. Oncolytic viruses (OVs), such as thymidine kinase-deleted vaccinia virus (oncoVV), selectively lyse tumors while stimulating antitumor immunity, however, their metabolic interplay with cancer cells is poorly understood. Here, we engineered an oncoVV-expressing Aphrocallistes vastus lectin (oncoVV-AVL) and uncovered its unique ability to exploit the ACSS2/TFEB axis, driving metabolic competition in HCC. In vitro, oncoVV-AVL triggered cell autophagy and lipid accumulation (3.4–5.7-fold upregulation of FASN and ACC1) while suppressing glucose uptake (41–63% higher extracellular glucose and 33–34% reduced lactate). Mechanistically, oncoVV-AVL upregulated acetyl-CoA synthetase 2 (ACSS2), promoting its nuclear translocation and interaction with transcription factor EB (TFEB) to concurrently activate lipogenesis and autophagic flux. The pharmacological inhibition of ACSS2 abolished these effects, confirming its central role. In vivo, oncoVV-AVL suppressed tumor growth while inducing lipid deposition (2-fold triglyceride increase), systemic hypoglycemia (42% glucose reduction), and autophagy activation (elevated LC3B-II/I ratios). This study establishes ACSS2 as a metabolic checkpoint in OV therapy, providing a rationale for combining oncolytic virotherapy with metabolic modulators in HCC. Full article

Oral squamous cell carcinoma (OSCC) is a prevalent and aggressive malignancy with poor prognosis, largely due to its high metastatic potential and resistance to conventional therapies. Recent advances in cancer biology have underscored the significance of regulated cell death pathways, including apoptosis, autophagic cell death (ACD), necroptosis, pyroptosis, and ferroptosis, in modulating tumor progression and therapeutic responses. This review provides the current insights into the molecular mechanisms underlying these cell death pathways and explores their therapeutic relevance in OSCC. Restoration of apoptosis using BH3 mimetics, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptor agonists, and p53 reactivators shows promise for sensitizing OSCC cells to treatment. Autophagy plays context-dependent roles in cancer, acting as a tumor suppressor during early carcinogenesis by maintaining cellular homeostasis, and as a tumor promoter in established tumors by supporting cancer cell survival under stress. Targeting necroptosis and pyroptosis has emerged as a novel strategy for inducing cancer cell death, with compounds such as acetylshikonin and okanin demonstrating antitumor effects. Additionally, the induction of ferroptosis via lipid peroxidation and glutathione peroxidase 4 (GPX4) inhibition offers a promising avenue for overcoming drug resistance, with agents such as quercetin and trifluoperazine exhibiting preclinical success. Integration of these therapeutic approaches may enhance the OSCC treatment efficacy, reduce chemoresistance, and provide novel prognostic biomarkers for clinical management. Future studies should focus on optimizing combinatorial strategies that effectively leverage these pathways to improve OSCC patient outcomes. Full article

Autophagy-dependent cell death (ADCD) presents a promising but challenging therapeutic strategy in cancer treatment. Autophagy regulates cellular breakdown and stress responses, serving a dual function—either inhibiting tumorigenesis or facilitating the survival of cancer cells in advanced stages. This paradox presents both opportunities and challenges in the exploration of autophagy as a potential target for cancer treatment. In this review, we explore various pharmacological agents, including autophagy inhibitors (e.g., chloroquine, 3-MA) and activators (e.g., rapamycin, metformin), which have demonstrated effectiveness in modulating autophagy-dependent cell death (ADCD). These agents either enhance cancer cell apoptosis or sensitize tumors to conventional therapies. Combination therapies, such as the use of autophagy modulators alongside chemotherapy, immunotherapy, or radiation therapy, offer enhanced therapeutic potential by overcoming drug resistance and improving overall treatment efficacy. Nonetheless, significant challenges remain, including tumor heterogeneity, treatment resistance, and off-target effects of autophagy-targeting agents. Future progress in biomarker discovery, precision medicine, and targeted medication development will be crucial for enhancing ADCD-based methods. Although autophagy-dependent cell death presents significant potential in cancer treatment, additional studies and clinical validation are necessary to confirm its position as a conventional therapeutic approach. Therefore, this review aims to identify the existing restrictions that will facilitate the development of more effective and personalized cancer therapies, hence enhancing patient survival and outcomes. Full article

According to the WHO, in 2022, there were 2.3 million women diagnosed with breast cancer (BC) and 670,000 deaths globally. BC remains the leading cause of cancer-related mortality, with therapeutic resistance representing a significant barrier to effective treatment, particularly in aggressive subtypes like triple-negative breast cancer (TNBC). This review article discusses emerging strategies to overcome resistance by integrating precision oncology, nanotechnology-based drug delivery, and immune modulation. Resistance mechanisms—such as metabolic reprogramming, tumor heterogeneity, immune evasion, autophagy, and the role of cancer stem cells—are critically examined. We highlight cutting-edge nanoplatforms that co-deliver chemotherapeutics and immune stimulants with spatiotemporal precision, including sonodynamic and photothermal systems, ADCs, and targeted nanoparticles. Moreover, advances in tumor microenvironment (TME) modulation, photoimmunotherapy, and exosomal miRNA targeting offer promising avenues to enhance immunogenicity and therapeutic durability. The integration of molecular profiling with advanced computational approaches, including artificial intelligence and biomimetic models, holds significant promise for the future development of personalized resistance-mitigating interventions, though a detailed exploration is beyond the current scope. Collectively, these strategies reflect a paradigm shift from conventional monotherapies toward multifaceted, precision-guided treatment approaches. This review aims to provide a comprehensive overview of current innovations and propose future directions for overcoming drug resistance in BC. Full article

Nucleobase and nucleoside analogs are critical components of antimetabolite chemotherapy treatments used to disrupt DNA replication and induce apoptosis in rapidly proliferating cancer cells. However, the development of resistance to these agents remains a major clinical challenge. This review explores the epigenetic mechanisms that contribute to acquired chemoresistance, focusing on DNA methylation, histone modifications, and non-coding RNAs (ncRNAs). These epigenetic alterations regulate key processes such as DNA repair, drug metabolism, cell transport, and autophagy, enabling cancer cells to survive and resist therapeutic pressure. We highlight how dysregulation of DNA methyltransferases (DNMTs) and histone acetyltransferases (HATs) modulates expression of transporters (e.g., hENT1, ABCB1), DNA repair enzymes (e.g., Polβ, BRCA1/2), and autophagy-related genes (e.g., CSNK2A1, BNIP3). Furthermore, emerging roles for long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) in regulating nucleoside export and DNA damage response pathways underscore their relevance as therapeutic targets. The interplay of these epigenetic modifications drives resistance to agents such as gemcitabine and 5-fluorouracil across multiple tumor types. We also discuss recent progress in therapeutic interventions, including DNMT and HDAC inhibitors, RNA-based therapeutics, and CRISPR-based epigenome editing. Full article

Marine-derived compounds represent a rich source of structurally diverse molecules with therapeutic potential for cancer, renal disorders, metabolic-associated fatty liver disease (MAFLD), and atherosclerosis. This review systematically evaluates recent advances, highlighting compounds such as Microcolin H, Benzosceptrin C, S14, HN-001, Equisetin, glycosides (e.g., cucumarioside A₂-2), ilimaquinone, and Aplidin (plitidepsin). Key mechanisms include autophagy modulation, immune checkpoint inhibition, anti-inflammatory effects, and mitochondrial homeostasis. Novel findings reveal glycosides’ dual role in cytotoxicity and immunomodulation, ilimaquinone’s induction of the DNA damage response, and Aplidin’s disruption of protein synthesis via eEF1A2 binding. Pharmacokinetic challenges and structure–activity relationships are critically analyzed, emphasizing nanodelivery systems and synthetic analog development. This review bridges mechanistic insights with translational potential, offering a cohesive framework for future drug development. Full article

Lung cancer remains one of the leading causes of death associated with cancer globally, with non-small cell lung cancer (NSCLC) accounting for 80–85% of all lung cancer cases. Despite its high prevalence, the underlying mechanisms of NSCLC have not been completely clarified, and current therapeutic strategies face significant limitations. Recent research has revealed the important role of long non-coding RNAs (lncRNAs) in NSCLC, particularly in regulating processes such as autophagy and drug resistance. LncRNAs are a class of non-coding RNA molecules, typically with transcript lengths exceeding 200 nucleotides, and have been the subject of extensive investigation in recent years. Their involvement in critical cellular processes has opened up new research avenues for precision medicine in NSCLC. This review aims to offer a comprehensive analysis of the mechanisms by which lncRNAs regulate autophagy and drug resistance in NSCLC, explore their potential clinical applications as diagnostic biomarkers and therapeutic targets, and provide both theoretical foundations and practical guidance to advance precision medicine in this area. By deepening our understanding of the role of lncRNAs in NSCLC, this article also highlights the promising potential of lncRNA-based approaches for the diagnosis and treatment of this disease. Full article

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of upper and lower motor neurons. One of its major genetic causes is C9ORF72, where mutations lead to hexanucleotide repeat expansions in the C9ORF72 gene. These expansions drive disease progression through mechanisms, including the formation of toxic RNAs and the accumulation of damaged proteins such as dipeptide repeats (DPRs). This review highlights these pathogenic mechanisms, focusing on RNA foci formation and the accumulation of toxic DPRs, which contribute to neuronal damage. It also discusses promising targeted therapies, including small molecules and biological drugs, designed to counteract these specific molecular events. Small molecules such as G-quadruplex stabilizers, proteasome and autophagy modulators, and RNase-targeting chimeras show potential in reducing RNA foci and DPR accumulation. Furthermore, targeting enzymes involved in repeat-associated non-AUG (RAN) translation and nucleocytoplasmic transport, which are crucial for disease pathogenesis, opens new therapeutic avenues. Even some anti-viral drugs show encouraging results in preclinical studies. Biological drugs, such as antisense oligonucleotides and gene-editing technologies like CRISPR-Cas, were explored for their potential to specifically target C9ORF72 mutations and modify the disease’s molecular foundations. While preclinical and early clinical data show promise, challenges remain in optimizing delivery methods, ensuring long-term safety, and improving efficacy. This review concludes by emphasizing the importance of continued research and the potential for these therapies to alter the disease trajectory and improve patient outcomes. Full article

Stress granules (SG), dynamic cytoplasmic condensates formed via liquid-liquid phase separation (LLPS), serve as a critical hub for cellular stress adaptation and antiviral defense. By halting non-essential translation and sequestering viral RNA, SG restrict viral replication through multiple mechanisms, including PKR-eIF2α signaling, recruitment of antiviral proteins, and spatial isolation of viral components. However, viruses have evolved sophisticated strategies to subvert SG-mediated defenses, including proteolytic cleavage of SG nucleators, sequestration of core proteins into viral replication complexes, and modulation of stress-responsive pathways. This review highlights the dual roles of SG as both antiviral sentinels and targets of viral manipulation, emphasizing their interplay with innate immunity, autophagy, and apoptosis. Furthermore, viruses exploit SG heterogeneity and crosstalk with RNA granules like processing bodies (P-bodies, PB) to evade host defenses, while viral inclusion bodies (IBs) recruit SG components to create proviral microenvironments. Future research directions include elucidating spatiotemporal SG dynamics in vivo, dissecting compositional heterogeneity, and leveraging advanced technologies to unravel context-specific host-pathogen conflicts. This review about viruses and SG formation helps better understand the virus-host interaction and game process to develop new drug targets. Understanding these mechanisms not only advances virology but also informs innovative strategies to address immune escape mechanisms in viral infections. Full article

At the intersection of nanotechnology and cancer biology, gold nanoparticles (AuNPs) have emerged as more than passive carriers—they are active agents capable of reshaping cellular fate. Among their most promising attributes is the potential to modulate apoptosis and autophagy, two intricately linked pathways that determine tumor response to stress, damage, and treatment. Apoptosis serves as the principal mechanism of programmed cell death, while autophagy offers a dualistic role—preserving survival under transient stress or contributing to cell death under sustained insult. Thus, understanding how these mechanisms interact—and how AuNPs influence this crosstalk—may be key to unlocking more effective oncologic therapies. This review explores the molecular interplay between apoptosis and autophagy in cancer and evaluates how AuNPs impact these pathways. By enhancing radiosensitization in radiation therapy and improving drug delivery and chemotherapeutic precision, AuNPs offer a unique strategy to circumvent resistance in aggressive or refractory tumors towards shaping their biological behavior and cellular pathways and, therefore, forming a patient-centered personalized therapeutic potential. Yet, clinical translation remains challenging. The dynamic physicochemical nature of AuNPs makes their biological behavior highly context-dependent. Combined with the complexity of apoptotic and autophagic signaling and tumor heterogeneity, this creates a triad of profound intricacy. However, within this complexity lies therapeutic opportunity. Framing AuNPs, apoptosis, and autophagy as a synergistic axis may enable mechanism-informed, adaptable, and patient-specific cancer therapies. This paradigm shift invites a more strategic integration of nanotechnology with molecular oncology, advancing the frontier of precision medicine. Full article

Anthracyclines play an irreplaceable role in cancer treatment, although their clinical application is limited due to severe side effects such as arrhythmia, cardiomyopathy, and myocardial infarction. The currently available clinical drugs for treating anthracycline-induced cardiotoxicity (AIC) are limited by numerous drawbacks, including the side effects of the therapeutic agents, single treatment mechanisms, and individual patient variations. Therefore, novel drugs with broader applicability and multitarget synergistic protective effects are, therefore, urgently needed. Ginsenosides, the primary bioactive constituents of plants belonging to the genus Panax (family Araliaceae), exhibit a wide range of pharmacological activities, including anti-inflammatory, antioxidative, and antitumor effects, and have demonstrated cardioprotective properties against AIC. This article examines the mechanisms of AIC and the modulatory effects of ginsenosides on these mechanisms. This review highlights the potential molecular targets and signaling pathways through which ginsenosides exert therapeutic effects on AIC, including the regulation of oxidative-stress-related pathways such as Keap1/Nrf2, MAPK, STAT, PI3K/Akt, and AMPK; the restoration of mitochondrial function; the modulation of autophagy; and the inhibition of pyroptosis, ferroptosis, and apoptosis. Therefore, this review serves as a theoretical basis and provides a research direction for future investigation regarding the prevention and treatment of AIC with ginsenosides, as well as clinical translation studies. Full article

Hepatocellular carcinoma (HCC) is still a leading cause of cancer-related mortality worldwide, characterized by poor prognosis and limited therapeutic efficacy of conventional chemotherapeutics such as doxorubicin. Phytochemicals are promising adjuvants in cancer therapy due to their multi-targeted effects. In this in vitro study, we investigated the impact of a methanol–water extract (70:30 v/v, MET70) from Muscari comosum bulbs, rich in polyphenols and flavonoids, on doxorubicin-treated HepG2 human hepatoma cells. Co-treatment with MET70 increased intracellular reactive oxygen species (ROS) associated with downregulation of Nrf2 signaling, suppression of antioxidant enzymes (SOD2, GPX-1) and decreased mitochondrial UCP2 expression. MET70 modulated the inflammatory response induced by doxorubicin by decreasing TNF-α and increasing IL-6 expression. MET70 also promoted protein homeostasis through PDIA2 upregulation without exacerbating endoplasmic reticulum stress and inhibited autophagy by reducing Beclin-1 levels, contributing to increased chemosensitivity. Moreover, MET70 downregulated ABCC1 expression, suggesting a role in overcoming multidrug resistance. All these findings demonstrate that Muscari comosum extract enhances doxorubicin efficacy by targeting redox balance, inflammatory signaling, autophagy, and drug resistance, offering a promising redox-based strategy for improving HCC therapy. However, further studies should be performed in vivo. Full article