Результаты поиска

Targeting endoplasmic reticulum stress-induced lymphatic dysfunction for mitigating bisphosphonate-related osteonecrosis.

BACKGROUND: Bisphosphonates (BPs) are the first-line treatment to stop bone resorption in diseases, including osteoporosis, Paget's disease, multiple myeloma and bone metastases of cancer. However, BPs-related osteonecrosis of the jaw (BRONJ), characterized by local inflammation and jawbone necrosis, is a severe intractable complication. The cumulative inflammatory burden often accompanies impaired lymphatic drainage, but its specific impact on BRONJ and the underlying mechanisms remain unclear. METHODS: The mouse BRONJ model was established to assess the integrity and drainage function of ly

Совпадение в полном тексте источника
… is a cellular response to alleviating stress caused by the abnormal accumulation of misfolded proteins within the endoplasmic reticulum (ER). 19 Simultaneously, it induces autophagy, a process that selectively targets and degrades unfolded or misfolded proteins in the ER by sequestering them within autophagosomes … The inhibition of mTOR triggers ULK1 to initiate the formation of autophagosomes, with ATG5 playing a pivotal role in this process. 49 Using ATG5 conditional knockout models, we demonstrated that autophagy inhibition exacerbated BRONJ by further impairing lymphatic function. …

Protein Quality Control in Glioblastoma: A Review of the Current Literature with New Perspectives on Therapeutic Targets.

Protein quality control allows eukaryotes to maintain proteostasis under the stress of constantly changing conditions. In this review, we discuss the current literature on PQC, highlighting flaws that must exist for malignancy to occur. At the nidus of PQC, the expression of BAG1-6 reflects the cell environment; each isoform directs proteins toward different, parallel branches of the quality control cascade. The sum of these branches creates a net shift toward either homeostasis or apoptosis. With an established role in ALP, Bag3 is necessary for cell survival in stress conditions including th

Rhabdomyosarcoma: Current Therapy, Challenges, and Future Approaches to Treatment Strategies.

Rhabdomyosarcoma is a rare cancer arising in skeletal muscle that typically impacts children and young adults. It is a worldwide challenge in child health as treatment outcomes for metastatic and recurrent disease still pose a major concern for both basic and clinical scientists. The treatment strategies for rhabdomyosarcoma include multi-agent chemotherapies after surgical resection with or without ionization radiotherapy. In this comprehensive review, we first provide a detailed clinical understanding of rhabdomyosarcoma including its classification and subtypes, diagnosis, and treatment str

Совпадение в полном тексте источника
… This investigation showed that simvastatin inhibited the TMZ-induced autophagic flux by blocking the fusion of autophagosomes and lysosomes [ 141 ]. … In agreement with these observations, disruption of autophagosome formation via a shRNA sequence against ATG7 (shATG7) or by inhibition of both V-ATPase-dependent acidification and autophagosome–lysosome fusion using bafilomycin A1 can mitigate antitumor drug-induced autophagy and abolish the growth …

Targeting Protein Degradation Pathways in Tumors: Focusing on their Role in Hematological Malignancies.

Cells must maintain their proteome homeostasis by balancing protein synthesis and degradation. This is facilitated by evolutionarily-conserved processes, including the unfolded protein response and the proteasome-based system of protein clearance, autophagy, and chaperone-mediated autophagy. In some hematological malignancies, including acute myeloid leukemia, misfolding or aggregation of the wild-type p53 tumor-suppressor renders cells unable to undergo apoptosis, even with an intact p53 DNA sequence. Moreover, blocking the proteasome pathway triggers lymphoma cell apoptosis. Extensive studie

Полимеризация тубулинов, пропагандирующая протеины: функциональное разнообразие с последствиями в неврологических расстройствах.

Полимеризация тубулинов, пропагандирующая протеины (ПППН), в значительной степени сохраняется в различных видах, но по-прежнему недостаточно изучена. В организме человека есть три гена ТППЦ, и только один гомологический ген ТППЦ у беспозвоночных, таких как Дрософила и К. Элеган. TPPP человека (TPPP1/p25/p25α) обогащается в мозгу и имеет сходство с беспозвоночными TPPP. TPPP/p25 ассоциируется с микротубулями и играет ключевую роль в динамике микротубуля, слиянии и полимеризации, тем самым стабилизируя микротубулярную сеть. Это крайне важно для организации цитоскелета и надлежащего функционирова

Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies.

Metastatic dissemination of solid tumors, a leading cause of cancer-related mortality, underscores the urgent need for enhanced insights into the molecular and cellular mechanisms underlying metastasis, chemoresistance, and the mechanistic backgrounds of individuals whose cancers are prone to migration. The most prevalent signaling cascade governed by multi-kinase inhibitors is the mitogen-activated protein kinase (MAPK) pathway, encompassing the RAS-RAF-MAPK kinase (MEK)-extracellular signal-related kinase (ERK) pathway. RAF kinase is a primary mediator of the MAPK pathway, responsible for th

Overcoming temozolomide resistance in glioma: recent advances and mechanistic insights.

Temozolomide (TMZ) remains the cornerstone chemotherapy for glioma, yet intrinsic and acquired resistance mechanisms significantly limit its clinical effectiveness. This review summarizes the multifaceted molecular pathways contributing to TMZ resistance, including enhanced DNA repair mechanisms such as O6-methylguanine-DNA methyltransferase (MGMT), mismatch repair (MMR), and base excision repair (BER). Additional resistance factors include genetic mutations that affect the drug response, dysregulated non-coding RNAs (miRNAs, lncRNAs, and circRNAs), glioma stem cells (GSCs), cytoprotective aut

Совпадение в полном тексте источника
… Mature autophagosomes subsequently fuse with lysosomes to form autolysosomes, where autophagic substrates are degraded. … Another promising approach involves NEO214, a conjugate of rolipram and perillyl alcohol, which blocks autophagosome-lysosome fusion. When combined with CQ and TMZ, NEO214 significantly overcomes TMZ resistance [ 377 ]. …

Endothelial TFEB signaling-mediated autophagic disturbance initiates microglial activation and cognitive dysfunction.

Cognitive impairment caused by systemic chemotherapy is a critical question that perplexes the effective implementation of clinical treatment, but related molecular events are poorly understood. Herein, we show that bortezomib exposure leads to microglia activation and cognitive impairment, this occurs along with decreased nuclear translocation of TFEB (transcription factor EB), which is linked to macroautophagy/autophagy disorder, STAT3 (signal transducer and activator of transcription 3) phosphorylation and IL23A (interleukin 23 subunit alpha) expression. Pharmacological enhancement of TFEB

Совпадение в полном тексте источника
… (D and E) Quantification of the number of yellow puncta (autophagosome) (D) and red puncta (autolysosome) (E) in HBMECs from control or BTZ treatment in the presence or absence of BafA1 in ( C ) (mean ± SEM; n = 40 cells from 3 independent experiments; ** P < 0.01, *** P < 0.001; one-way ANOVA with Tukey … In the lysosomes, the acidic condition (pH<5) induces EGFP fluorescence quenching and mRFP no change, the yellow puncta in green and red-merged images are shown in autophagosomes, and the red puncta are shown in autolysosomes [ 53 ]. …

Metformin Increases Survival in Hypopharyngeal Cancer Patients with Diabetes Mellitus: Retrospective Cohort Study and Cell-Based Analysis.

Hypopharyngeal squamous cell carcinoma (HSCC) is usually diagnosed at an advanced stage, leading to a poor prognosis. Even after improvement of surgical techniques, chemotherapy, and radiation technology, the survival rate of HSCC remains poor. Metformin, which is commonly used for type 2 diabetes mellitus (DM), has been suggested to reduce the risk of various cancer types. However, only a few clinical studies mentioned the relationship between metformin use and HSCC. Hence, the aim of this study was to elucidate the specific effect and mechanism of action of metformin in hypopharyngeal cancer

Совпадение в полном тексте источника
… In particular, at 10 mM of metformin, the treatment caused the accumulation of LC3B abundantly in the cytoplasm of FaDu cells, indicating autophagosomes were generated at multiple sites throughout the cytoplasm ( Figure 5 A). … This is evidenced by increased Beclin-1 and LC3B protein levels, which are two essential proteins for autophagy initiation and autophagosomes formation. …

Advancing Brain Health Naturally: β-Caryophyllene and Xanthohumol as Neuroprotective Agents.

Neurodegenerative diseases (NDDs) represent a class of incurable and progressive disorders characterized by the gradual degeneration of the structure and function of the nervous system, particularly the brain and spinal cord. A range of innovative therapeutic approaches is currently under investigation, such as stem cell-based therapies, gene-editing platforms such as CRISPR, and immunotherapies directed at pathogenic proteins. Moreover, phytochemicals such as β-caryophyllene and xanthohumol have demonstrated significant neuroprotective potential in preclinical models. These natural agents exe

Galectin Targeted Therapy in Oncology: Current Knowledge and Perspectives.

The incidence and mortality of cancer have increased over the past decades. Significant progress has been made in understanding the underpinnings of this disease and developing therapies. Despite this, cancer still remains a major therapeutic challenge. Current therapeutic research has targeted several aspects of the disease such as cancer development, growth, angiogenesis and metastases. Many molecular and cellular mechanisms remain unknown and current therapies have so far failed to meet their intended potential. Recent studies show that glycans, especially oligosaccharide chains, may play a

Совпадение в полном тексте источника
… Internalization of rLGALS9 resulted in autophagosome–lysosome fusion failure, lysosome swelling, accumulation of autophagosomes and ultimately cell death [ 169 ]. … Inhibition of the autophagosome-lysosome fusion was described earlier following the application of the lysosomal inhibitor, chloroquine [ 170 ]. Conversely, rLGALS9 therapy on CRC cells with the BRAF mutation caused no effects [ 169 ]. …

The emerging role of exosomes in innate immunity, diagnosis and therapy.

Exosomes, which are nano-sized transport bio-vehicles, play a pivotal role in maintaining homeostasis by exchanging genetic or metabolic information between different cells. Exosomes can also play a vital role in transferring virulent factors between the host and parasite, thereby regulating host gene expression and the immune interphase. The association of inflammation with disease development and the potential of exosomes to enhance or mitigate inflammatory pathways support the notion that exosomes have the potential to alter the course of a disease. Clinical trials exploring the role of exo

Role of microRNAs in hematological malignancies research: A bibliometric analysis.

ObjectivesMicroRNAs (miRNAs) are pivotal regulators of cancer biology, including hematological malignancies. Their roles include tumor suppression, oncogenic activities, modulation of immune responses, and treatment resistance. This study aimed to provide a quantitative analysis of research trends, thematic evolution, and key contributions to the field of miRNAs and hematological malignancies.MethodsUsing BIBLIO-Checklist and advanced visualization tools (VOSviewer and bibliometrix), data from key databases were analyzed for publication trends, author co-citations, thematic clusters, and emerg

Organelle-oriented nanomedicines in tumor therapy: Targeting, escaping, or collaborating?

Precise tumor therapy is essential for improving treatment specificity, enhancing efficacy, and minimizing side effects. Targeting organelles is a key strategy for achieving this goal and is a frontier research area attracting a considerable amount of attention. The concept of organelle targeting has a significant effect on the structural design of the nanodrugs employed. Most notably, the intricate interactions among different organelles in a tumor cell essentially create a unified system. Unfortunately, this aspect might have been somewhat overlooked when existing organelle-targeting nanodru

Совпадение в полном тексте источника
… Autophagosomes are formed and regulated by GA-related proteins, such as Golgin-245 and Golgi phosphoprotein 3 [ 246 ]. Ghaemi et al. developed Ag@ZnO nanoparticles, which exhibited the ability to generate ROS under ultraviolet light [ 247 ]. … Developing nanomedicines targeting ER, GA, proteasomes, ribosomes, and autophagosomes presents an opportunity to achieve improved therapeutic effects by leveraging precise structural targeting and function regulation of specific organelles. …

Penfluridol inhibits melanoma growth and metastasis through enhancing von Hippel‒Lindau tumor suppressor-mediated cancerous inhibitor of protein phosphatase 2A (CIP2A) degradation.

Melanoma's high metastatic potential, especially to the brain, poses significant challenges to patient survival. The blood‒brain barrier (BBB) is a major obstacle to the effective treatment of melanoma brain metastases. We screened antipsychotic drugs capable of crossing the BBB and identified penfluridol (PF) as the most active candidate. PF reduced melanoma cell viability and induced apoptosis. In animal models, PF effectively inhibited melanoma growth and metastasis to the lung and brain. Using immunoprecipitation combined with high-resolution mass spectrometry, and other techniques such as

TMED2/9/10 Serve as Biomarkers for Poor Prognosis in Head and Neck Squamous Carcinoma.

Background: Head and neck squamous carcinoma (HNSC) is one of the most common malignant tumors with high incidence and poor prognosis. Transmembrane emp24 structural domain (TMED) proteins are involved in protein transport and vesicle budding processes, which have implicated various malignancies' progression. However, the roles of TMEDs in HNSC, especially in terms of development and prognosis, have not been fully elucidated. Methods: We applied TIMER 2.0, UALCAN, GEPIA 2, Kaplan-Meier plotter, GEO, The Human Protein Atlas (HPA), cBioPortal, Linkedomics, Metascape, GRNdb, STRING, and Cytoscape

Совпадение в полном тексте источника
… In addition, membrane contact between the ER—Golgi intermediate compartment (ERGIC) and the ER-exit site (ERES) mediated by TMED9 constituted the occurrence of autophagosomes ( Li et al., 2021 ). … A New Type of ERGIC-ERES Membrane Contact Mediated by TMED9 and SEC12 Is Required for Autophagosome Biogenesis . Cell Res. 32 , 119 – 138 . 10.1038/s41422-021-00563-0 34561617 PMC8461442 Li T. Fu J. Zeng Z. Cohen D. Li J. Chen Q. ( 2020 ). TIMER2.0 for Analysis of Tumor-Infiltrating Immune Cells . …

Exosomal circRNA as a novel potential therapeutic target for multiple myeloma-related myocardial damage.

INTRODUCTION: Myocardial damage is a mostly incurable complication of multiple myeloma (MM) that seriously affects the treatment outcome and quality of life of patients. Exosomal circular RNAs (exo-circRNAs) play an important role in tumor occurrence and development and are considered key factors in MM pathogenesis. However, the role and mechanism of action of exo-circRNAs in MM-related myocardial damage are still unclear. This study aimed to investigate correlations between exo-circRNAs and MM and to preliminarily explore the role of exo-circRNAs in MM-related myocardial damage. METHODS: Six

Polymorphisms within Autophagy-Related Genes as Susceptibility Biomarkers for Multiple Myeloma: A Meta-Analysis of Three Large Cohorts and Functional Characterization.

Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic dat

Совпадение в полном тексте источника
… Given that p62 serves as a useful marker for the induction of autophagy, clearance of protein aggregates, and the inhibition of autophagy and LC3-II serves to track the binding of p62 and subsequent recruitment of autophagosomes, this result might suggest that this genetic variant could be involved in … Bortezomib induces AMPK-dependent autophagosome formation uncoupled from apoptosis in drug resistant cells Oncotarget 2014 5 12358 12370 10.18632/oncotarget.2590 25481044 PMC4323002 34. Di Lernia G. Leone P. Solimando A.G. Buonavoglia A. Saltarella I. Ria R. Ditonno P. Silvestris N. Crudele L. …

The Potential Role of Sildenafil in Cancer Management through EPR Augmentation.

Enhanced permeation retention (EPR) was a significant milestone discovery by Maeda et al. paving the path for the emerging field of nanomedicine to become a powerful tool in the fight against cancer. Sildenafil is a potent inhibitor of phosphodiesterase 5 (PDE-5) used for the treatment of erectile dysfunction (ED) through the relaxation of smooth muscles and the modulation of vascular endothelial permeability. Overexpression of PDE-5 has been reported in lung, colon, metastatic breast cancers, and bladder squamous carcinoma. Moreover, sildenafil has been reported to increase the sensitivity of

Results of an abbreviated Phase Ib study of the HDAC6 inhibitor ricolinostat and paclitaxel in recurrent ovarian, fallopian tube, or primary peritoneal cancer.

Peripheral neuropathy is a common side effect of chemotherapeutic agents that frequently necessitates dose-reduction, truncation of, or change in therapy. HDAC6 inhibition has demonstrated preclinical efficacy in preventing and/or reversing chemotherapy-induced peripheral neuropathy and furthermore has demonstrated synergistic antitumor activity with various chemotherapies. Here, we report the abbreviated results of a Phase Ib trial of ricolinostat, an HDAC6-specific inhibitor, in combination with paclitaxel, in the treatment of recurrent ovarian, fallopian tube, or primary peritoneal cancer.

Совпадение в полном тексте источника
… HDAC6 facilitates the degradation of damaged or misfolded proteins by trafficking them to aggresomes and promoting fusion of autophagosomes and lysosomes. …