Search Results (231)

Oral cancer, the most common head and neck malignancy, has a high recurrence rate and poor prognosis largely owing to chemotherapy resistance. The adverse effects of conventional therapies have prompted investigations into safer and more effective alternative therapies. Chloroquine (CQ) and hydroxychloroquine (HCQ) have shown potential owing to their roles in autophagy modulation and immune regulation. This study clarifies the selective efficacy of hydroxychloroquine (HCQ) and chloroquine (CQ) in oral squamous cell carcinoma models, emphasizing distinct responses in gingival (Ca9-22) and tongue (SCC-9) carcinoma cells. Non-oncogenic oral epithelial cells (GMSM-K) and oral carcinoma cell lines from the tongue (SCC-9, Cal-27) and gingiva (Ca9-22) were used. Cell viability, cytotoxicity, and colony formation were assessed via MTT, LDH, and crystal violet assays. Flow cytometry was used to measure apoptosis, autophagy, oxidative stress, mitochondrial membrane potential, and DNA damage. The transcriptomic profiles of apoptosis and autophagy-related genes were assessed by qPCR arrays. Bioinformatics analysis allowed estimation of the main gene interaction networks. Pre-screening showed that GMSM-K and Cal-27 cells were non-responsive or exhibited non-specific toxicity at high doses; therefore, subsequent analyses focused on Ca9-22 (GC) and SCC-9 (TC). HCQ significantly reduced viability and colony formation in Ca9-22 cells while moderately affecting SCC-9 cells. Autophagy inhibition was accompanied by compensatory up-regulation of autophagy-related genes, consistent with feedback activation of TFEB and FOXO3a pathways. Gene expression profiling and flow-cytometry analyses revealed cell-type-specific differences in apoptosis, mitochondrial potential, and DNA damage, suggesting HCQ’s selective anti-tumor potential in gingival carcinoma. These findings highlight HCQ as a repurposed adjuvant therapy that modulates autophagy and apoptosis to enhance chemosensitivity in oral cancer. Full article

Background: Permanent cancer resolution requires a complete immunological response with generation of memory against malignant cells. Immunogenic cell death (ICD) achieves this by coupling cell death with the emission of damage-associated molecular patterns (DAMPs). Current cancer treatments immunosuppress the host; thus, new alternatives are needed. Ganoderma species produce anticancer triterpenoids (GTs); however, their mechanism remains unclear. Objective: This systematic review aims to provide insights into GTs’ pharmacodynamics and assess hypothetical ICD potential. Methods: Web of Science and PubMed databases were consulted following PRISMA guidelines. Studies from inception until 2024, reporting molecular changes associated with GTs’ anticancer effects, were considered. Nonhuman models were excluded. GTs and GTs-ICD converging molecular targets were listed and submitted to Cytoscape’s stringApp to construct protein interaction networks. Topological and enrichment analysis were performed. Results: A total of 204 articles were found, and 69 remained after screening. Overall anticancer effects include loss of mitochondrial membrane potential, DNA and RNA damage, autophagy, cell cycle arrest, and leukocyte activation. 136 molecular targets of GTs were identified; upregulated proteins include CHOP, PERK, p-eIF2α, and HSP70, a key DAMP. GTs and ICD share 24 molecular targets. GO:BP and KEGG enrichment analysis suggest that GTs’ anticancer effects are related to stress response, cell death regulation, and PD-L1/PD-1 checkpoint inhibition. GT-ICD enrichment converges on endoplasmic reticulum stress, unfolded protein response, and organelle membrane perforation. Conclusions: GTs exhibit polypharmacological anticancer effects, including anti-immunosuppression, upregulation of ICD-adjacent machinery, and even an increase in HSP. However, further studies are required to confirm a proper causal link between GTs’ cancer cell treatment and DAMP emission. Full article

Introduction: Bisphenol A (BPA) is a synthetic compound widely used in plastics and epoxy resins, and human exposure is virtually unavoidable. Numerous studies indicate that even doses below current regulatory limits may elicit neurotoxic effects, impairing learning, memory, and synaptic plasticity. Methodology: This mini-review. Searches were conducted in PubMed, the Virtual Health Library (VHL/BVS), and ScienceDirect, using MeSH descriptors related to “Bisphenol A,” “Neurotoxicity Syndromes,” “Central Nervous System,” and “Prefrontal Cortex,” combined with Boolean operators. We included studies published between 2007 and 2025, available in English, Portuguese, or Spanish, and focused on the neurotoxic effects of BPA. After screening and application of the eligibility criteria, twelve articles were selected. Results: The analyzed studies show that BPA exposure, even at low concentrations, compromises neuronal survival, dendritic density, and synaptic plasticity. In animal models, cognitive deficits were observed in memory and learning tasks, associated with increased oxidative stress and alterations in molecular pathways such as AMPK, HO-1, and nNOS/Keap1/Nrf2. In cell cultures, BPA induced apoptosis, autophagy dysfunction, cytoskeletal reorganization, and loss of synaptic proteins. The effects were dose-dependent and, in some cases, sex-dependent. Conclusions: BPA exhibits significant neurotoxic potential, affecting both the development and function of the central nervous system. These findings underscore the need to revise current safety limits and reinforce the importance of public policies regulating BPA use, as well as encouraging the search for safer alternatives. Full article

Pine wilt disease (PWD), transmitted by Monochamus alternatus (JPS), poses a severe threat to global pine forests. Although the entomopathogenic fungi Beauveria bassiana (Bb) and Metarhizium anisopliae (Ma) represent environmentally friendly biocontrol alternatives, their practical application is limited by inconsistent field performance and an incomplete understanding of host–pathogen interactions. We employed dual RNA-seq at the critical 48 h infection time point to systematically compare the transcriptional responses between JPS and Bb/Ma during infection. Key findings revealed distinct infection strategies: Bb preferentially induced autophagy pathways and modulated host carbohydrate metabolism to facilitate nutrient acquisition, triggering corresponding tissue degradation responses in JPS. In contrast, Ma primarily co-opted host amino acid and sugar metabolic pathways for biosynthetic processes, eliciting a stronger immune defense activation in JPS. Notably, the mTOR signaling pathway was identified as a key regulator of the differential host responses to various entomopathogenic fungi. Further functional validation-specifically, the application of a chemical inhibitor and RNAi targeting mTOR in JPS-confirmed that mTOR inhibition selectively enhanced Bb-induced mortality in JPS without affecting Ma virulence. Our findings reveal the molecular determinants of host–pathogen specificity in PWD biological control and indicate that mTOR regulation could serve as an effective strategy to improve fungal pesticide performance. Full article

Alzheimer’s disease (AD) is the most common cause of dementia worldwide, and there are still no strategies to slow or prevent its clinical progression. Significant financial and research resources have been invested into studying the pathology of AD. However, its pathogenesis is not fully understood. This review provides a comprehensive analysis of current understanding of AD pathogenesis, including classical hypotheses (amyloid cascade, tau pathology, neuroinflammation, oxidative stress), emerging mechanisms (cellular senescence, endoplasmic reticulum stress, ubiquitin-proteasome system dysfunction), and alternative mechanisms (cholinergic dysfunction, glutamate excitotoxicity, disruption of the microbiota–gut–brain axis, and autophagy). Schematic illustrations summarize the relationships between the hypotheses and their role in the pathogenesis of AD. Particular attention is paid to the systematization of promising biological targets and the analysis of modern ligands of various nature, including small molecules, peptides, antibodies and their fragments, natural compounds, as well as innovative hybrid and multifunctional structures. A separate section is devoted to radiopharmaceuticals for PET imaging (Florbetaben, Flortaucipir, etc.) and promising therapeutic agents. Thus, in this review we (1) systematize modern concepts of AD pathogenesis, including classical, emerging mechanisms and alternative hypotheses; (2) conduct a comparative analysis of ligand classes (small molecules, peptides, antibodies, etc.) and their therapeutic potential; and (3) discuss the clinical prospects of radiopharmaceuticals for PET imaging and targeted therapy. The work provides a comprehensive analysis of modern approaches, which can help in the development of more effective drugs against AD. Full article

BECLIN-1 is a multidomain protein that, through dynamic interaction with a variety of partners, controls autophagy and apoptosis, two processes dysregulated in cancer cells, thus playing a crucial role in cell fate. Although mutations in the BECN1 gene are rare in cancer, its frequent monoallelic deletion contributes to spontaneous cancer initiation by impairing autophagy, establishing it as a haploinsufficient tumor suppressor gene. The expression and activity of BECLIN-1 are further modulated by epigenetic mechanisms, alternative splicing, post-translational modifications, and alternative partner interactions. These layers of regulation critically affect the autophagy response, with an impact on cell proliferation, motility, and resistance to multiple stress stimuli. In this review article we outline the structural and functional properties of BECLIN-1 and discuss how its altered expression and protein–protein interactions can be harnessed for diagnostic and therapeutic purposes in cancer. Full article

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, associated with a high tendency for metastasis to the liver. Proton beam therapy (PBT) is the preferred external radiotherapy treatment for primary UM of certain sizes and locations in the eye, due to its efficacy and good local tumour control, as well as its precision to spare surrounding ocular structures. PBT is an effective alternative to surgical enucleation and other non-precision-targeted radiotherapies. Despite this, the radiobiology of UM in response to PBT is still not fully understood. This enhanced knowledge would help to further optimise UM treatment and improve patient outcomes through reducing radiation dosage to ocular structures, treating larger tumours that would otherwise require enucleation, or even offering a treatment strategy for the otherwise fatal liver metastases. In this review, we explore current knowledge of the treatment of UM with PBT, evaluating the biological responses to the therapy. Molecular factors, such as tumour size, oxygen tension levels, DNA damage proficiency, and autophagy, are known to influence the cellular response to radiotherapy, and these will be discussed. Furthermore, we examine innovative strategies to enhance radiotherapy outcomes, such as combination therapies with DNA damage repair and autophagy modulators, as well as advancements in PBT planning and delivery. By integrating current research and emerging technologies, we aim to provide opportunities to improve the therapeutic effectiveness of PBT in UM management. Full article

Autophagy is a conserved catabolic pathway that degrades intracellular cargo through the lysosomal system. Canonically, this process is orchestrated by the autophagy-related (Atg)5-Atg7 conjugation system, which facilitates the formation of microtubule-associated protein 1 light chain 3 (LC3)-decorated double-membrane vesicles known as autophagosomes. However, accumulating evidence has revealed the existence of an Atg5-Atg7-independent, alternative autophagy pathway that still relies on upstream regulators such as the unc-51 like autophagy activating kinase 1 (Ulk1) kinase and the Beclin1 complex. In this review, we provide a comprehensive overview of the role of the Beclin1 complex in canonical autophagy and highlight its emerging importance in alternative autophagy. Notably, the recent identification of transmembrane protein 9 (TMEM9) as a lysosomal protein that interacts with Beclin1 to promote member RAS oncogene family 9 (Rab9)-dependent autophagosome formation has significantly advanced our understanding of alternative autophagy regulation. Furthermore, this Ulk1-Rab9-Beclin1-dependent mitophagy has been shown to mediate to mitochondrial quality control in the heart, thereby contributing to cardioprotection under ischemic and metabolic stress conditions. We further examine how the Beclin1 complex functions as a central scaffold in both canonical and alternative autophagy, with a focus on its modulation by novel factors such as TMEM9 and the potential therapeutic implications of these regulatory mechanisms. Full article

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, limiting the efficacy of conventional targeted therapies. As a result, novel therapeutic strategies are urgently needed. Photodynamic therapy (PDT), which relies on the activation of photosensitizers (PSs) by light to induce cytotoxic effects, has emerged as a promising alternative for TNBC treatment. Furthermore, the conjugation of PSs with targeting peptides has demonstrated enhanced selectivity and therapeutic efficacy, particularly for porphyrin-based photosensitizers. In this study, we report the synthesis of novel porphyrin–peptide conjugates designed to selectively target the epidermal growth factor receptor (EGFR), which is frequently overexpressed in TNBC. The conjugates were prepared via thiol displacement of the meso-nitro group in a 5,15-diarylporphyrin scaffold using EGFR-binding peptides. Photodynamic activity was evaluated in two EGFR-overexpressing TNBC cell lines. Cellular uptake of the conjugates correlated with EGFR expression levels, and PDT treatment resulted in differential induction of necrosis, apoptosis, and autophagy. Notably, the conjugates significantly inhibited EGFR-expressing cell line migration, a critical hallmark of metastatic progression. These findings underscore the potential of EGFR-targeted porphyrin–peptide conjugates as promising PDT agents for the treatment of TNBC. Full article

Background: Colorectal cancer (CRC) is a prevalent gastrointestinal malignancy, ranking third in incidence and second in cancer-related mortality. Despite therapeutic advances, challenges such as chemotherapy toxicity and drug resistance persist. Thus, there is an urgent need for novel CRC treatments. However, developing new drugs is time-consuming and resource-intensive. As a more efficient approach, drug repurposing offers a promising alternative for discovering new therapies. Methods: In this study, we screened 1068 small molecular compounds from an FDA-approved drug library in CRC cells. Menadione was selected for further study based on its activity profile. Mechanistic analysis included a cell death pathway PCR array, differential gene expression, enrichment, and network analysis. Gene expressions were validated by RT-qPCR. Results: We identified menadione as a potent anti-tumor drug. Menadione induced three programmed cell death (PCD) signaling pathways: necroptosis, apoptosis, and autophagy. Furthermore, we found that the anti-tumor effect induced by menadione in CRC cells was mediated through a key gene: MAPK8. Conclusions: By employing methods of cell biology, molecular biology, and bioinformatics, we conclude that menadione can induce multiple forms of PCD in CRC cells by activating MAPK8, providing a foundation for repurposing the “new use” of the “old drug” menadione in CRC treatment. Full article

The midgut of Antheraea pernyi plays a critical role in antiviral defense. However, its transcriptional complexity remains poorly understood. Here, a full-length (FL) transcriptome atlas of A. pernyi midgut was developed by integrating PacBio Iso-Seq and RNA-seq techniques. The transcriptome sequences included 1850 novel protein-coding genes, 17,736 novel alternative isoforms, 1664 novel long non-coding RNAs (lncRNAs), and 858 transcription factors (TFs). In addition, 2471 alternative splicing (AS) events and 3070 alternative polyadenylation (APA) sites were identified. Moreover, 3426 and 4796 differentially expressed genes (DEGs) and isoforms were identified after ApNPV infection, respectively, besides the differentially expressed lncRNAs (164), TFs (171), and novel isoforms of ApRelish (1) and ApSOCS2 (4). Enrichment analyses showed that KEGG pathways related to metabolism were suppressed, whereas GO terms related to DNA synthesis and replication were induced. Furthermore, the autophagy and apoptosis pathways were significantly enriched among the upregulated genes. Protein–protein interaction network (PPI) analysis revealed the coordinated downregulation of genes involved in mitochondrial ribosomes, V-type and F-type ATPases, and oxidative phosphorylation, indicating the disruption of host energy metabolism and organelle acidification. Moreover, coordinated upregulation of genes associated with cytoplasmic ribosomes was observed, suggesting that the infection by ApNPV interferes with host translational machinery. These results show that ApNPV infection reprograms energy metabolism, biosynthetic processes, and immune response in A. pernyi midgut. Our study provides a foundation for elucidating the mechanisms of A. pernyi–virus interactions, particularly how the viruses affect host defense strategies. Full article

Parkinson’s disease (PD) is a common neurodegenerative disorder with substantial global impact. Although current therapies can provide symptomatic relief, they are often associated with high costs and adverse effects. Natural compounds with a history of traditional medicinal use have emerged as promising alternatives. In this study, we investigated the therapeutic potential and underlying mechanisms of berberine in both cellular and animal models of PD. In vitro, SH-SY5Y cells exposed to 6-hydroxydopamine (6-OHDA) exhibited decreased viability and increased oxidative stress, both of which were significantly alleviated by berberine treatment based on cell viability assays and DCFH-DA staining. Western blot analysis revealed that berberine modulated the AMPK–PGC-1α–SIRT1 signaling pathway and restored the expression of autophagy-related proteins LC3B and P62, suggesting that berberine could improve mitochondrial function and autophagy balance. In vivo studies using a 6-OHDA-induced PD mouse model further confirmed these effects, showing that berberine could improve motor function and lead to molecular changes consistent with in vitro studies. Additionally, safety evaluations indicated no significant hepatotoxicity based on AST and ALT levels. Body weight also remained stable throughout treatment. Collectively, our findings suggest that berberine can not only alleviate PD-related symptoms but also target key pathological mechanisms, supporting its potential as a therapeutic candidate for PD and other neurodegenerative diseases. Full article

Targeted protein degradation (TPD) has emerged as a revolutionary strategy for modulating protein function, offering a promising alternative to traditional small-molecule inhibitors. The distinctive mechanism of action in TPD has previously allowed researchers to target undruggable proteins, broadening the scope of “druggable” properties and expanding the scope of therapeutic possibilities. As the field of TPD advances, several alternative strategies to proteolysis-targeting chimeras (PROTACs) have emerged, which do not rely on the E3 ubiquitin ligase recruitment mechanism, expending the scope of TPD. Recently, several new technologies have emerged for TPD of extracellular and membrane proteins. While encouraging progress has been made in this field, the application of these technologies remains in its early stages. In this review, we explore the therapeutic potential of current key emerging lysosome-mediated TPD approaches by summarizing key discoveries and address the challenges associated with degrading extracellular and membrane protein targets. We also outline the chemical structure, activity, and pharmaceutical properties of each degrader, as well as the development of chemical probes for perturbing autophagy pathways. Full article

The existence of s-DAPK-1, an alternatively spliced variant of DAPK-1, adds complexity to our understanding of the proteins involved in the regulation of cell survival, apoptosis, and autophagy. DAPK-1 has been implicated in the regulation of these processes; however, it remains unclear whether s-DAPK-1 also plays a similar role or a separate function; thus, determining its involvement in these processes is challenging due to the limited understanding of its regulation, interacting partners, function, and three-dimensional (3D) structure. Hence, this study was aimed at (1) understanding the regulation of s-DAPK-1 by predicting its microRNA targets, (2) predicting the 3D structure of s-DAPK-1, (3) its physicochemical and thermodynamic properties, (4) its interacting partners, and (5) molecular functions using computational methods. To achieve this aim, various bioinformatics tools and in silico webservers, such as ProteinPrompt, ProtParam, ProtScale, ScooP, Hawkdock, Phyre2, I-TASSER, PSIPRED, SAVES, and PROCHECK, along with user-friendly databases, such as NCBI, TarBase, and Protein Data Bank (PDB), were employed. For miRNA prediction, we used TarBase, and identified the specific microRNAs targeting s-DAPK-1. Furthermore, the Phyre2 database demonstrated that s-DAPK-1 possesses 40% alpha helices and 4% beta strands, forming a stable 3D structure. Additionally, s-DAPK-1 demonstrated stability to withstand high temperatures, suggesting that it is a thermostable protein. Moreover, s-DAPK-1 was found to interact with a variety of proteins involved in tumor progression and gene regulation, including a prion protein and histone H2B type 2-E (H2B2E). This suggests that s-DAPK-1 may perform diverse molecular functions such as regulation of metabolic processes, nucleic acid binding, and mRNA splicing by interacting with different proteins. Full article

Colorectal cancer (CRC) is the third most common cancer in the world, with increasing incidence and mortality rates. Standard conventional treatments for CRC are surgery, chemotherapy, and radiotherapy. Recently, immunotherapy has been introduced as a promising alternative to CRC treatment that utilizes patients’ immune system to combat cancer cells. The beneficial effect of immune checkpoint inhibitors, specifically anti-PD-1/ PD-L1, has been ascribed to the abundance of DNA replication errors that result in the formation of neoantigens. Such neoantigens serve as distinct flags that amplify the immune response when checkpoint inhibitors (ICIs) are administered. DNA replication errors in CRC patients are expressed as two statuses: the first is the deficient mismatch repair (MSI-H/dMMR) with a higher overall immune response and survival rate than the second status of patients with proficient mismatch repair (MSS/pMMR). There is a limitation to using anti-PD-1/PD-L1 as it is only confined to MSI-H/dMMR, where there is an abundance of T-cell inhibitory ligands (PD-L1). This calls for investigating new therapeutic interventions to widen the scope of ICIs’ role in the treatment of CRC. Autophagy modulation provides a good example. Autophagy is a cellular process that plays a crucial role in maintaining cellular homeostasis and has been studied for its impact on tumor development, progression, and response to treatment. In this review, we aim to highlight autophagy as a potential determinant in tumor immune response and to study the impact of autophagy on the tumor immune microenvironment. Moreover, we aim to investigate the value of a combination of anti-PD-1/PD-L1 agents with autophagy modulators as an adjuvant therapeutic approach for CRC treatment. Full article