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The Role of the Ubiquitin System in Eye Diseases.

The ubiquitin-proteasome system (UPS) is a fundamental process that regulates various biological functions, including immune response, cell cycle, oxidative stress, migration, and cellular proliferation. This system is responsible for the degradation of proteins, while proteasomes play a significant role in mechanisms involved in health and human diseases. The participation of the UPS in immune response is particularly relevant, leading to the involvement of immunoproteasomes. This specialized proteasome is involved in the processing and presentation of antigenic peptides, making it crucial fo

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… Altered unfolded protein response and proteasome impairment in pseudoexfoliation pathogenesis. Exp. Eye Res. 2019;181:197–207. doi: 10.1016/j.exer.2019.02.004. 129. Baudouin C., Kolko M., Melik-Parsadaniantz S., Messmer E.M. …

The role of proteasomes in tumorigenesis.

Protein homeostasis is the basis of normal life activities, and the proteasome family plays an extremely important function in this process. The proteasome 20S is a concentric circle structure with two α rings and two β rings overlapped. The proteasome 20S can perform both ATP-dependent and non-ATP-dependent ubiquitination proteasome degradation by binding to various subunits (such as 19S, 11S, and 200 PA), which is performed by its active subunit β1, β2, and β5. The proteasome can degrade misfolded, excess proteins to maintain homeostasis. At the same time, it can be utilized by tumors to deg

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… Next-generation proteasome inhibitor oprozomib synergizes with modulators of the unfolded protein response to suppress hepatocellular carcinoma Oncotarget 7 23 2016 34988 35000 27167000 10.18632/oncotarget.9222 PMC5085204 205 Muchamuel T. Basler M. Aujay M.A. …

CHAC1: a master regulator of oxidative stress and ferroptosis in human diseases and cancers.

CHAC1, an essential regulator of oxidative stress and ferroptosis, is increasingly recognized for its significant roles in these cellular processes and its impact on various human diseases and cancers. This review aims to provide a comprehensive overview of CHAC1's molecular functions, regulatory mechanisms, and effects in different pathological contexts. Specifically, the study objectives are to elucidate the biochemical pathways involving CHAC1, explore its regulatory network, and discuss its implications in disease progression and potential therapeutic strategies. As a γ-glutamyl cyclotrans

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… ChaC1 has been implicated in the unfolded protein response (UPR) in oxidative stress, acting downstream of the ATF4-ATF3-CHOP cascade ( Crawford et al., 2015 ). … This intricate relationship highlights CHAC1 as a pivotal player in the cellular response to oxidative stress, linking metabolic and stress response pathways in a manner that can critically influence cell fate under stress conditions ( Cui et al., 2021 ). 4.2 Unfolded protein response CHAC1 plays a …

Targeting translation initiation in breast cancer.

Over the past 20 years, a better understanding of cancer biology, screening for early detection, improved adjuvant treatment, and targeted therapies have decreased the rate of breast cancer deaths. However, resistance to treatment is common, and new approaches are needed. Deregulation of translation initiation is associated with the commencement and progression of cancer. Often, translation initiation factors are overexpressed and the related signaling pathways activated in human tumors. Recently, a significant number of inhibitors that target translation factors and pathways have become avail

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… protein response Endoplasmic reticulum stress induces selective translation in cancer cells. … Unfolded protein response heals the damage from this stress and restores endoplasmic reticulum homeostasis. …

Genomic profiling enables personalized strategies to overcome drug resistance in multiple myeloma.

Multiple myeloma (MM) is a hematologic malignancy characterized by the clonal proliferation of malignant plasma cells within the bone marrow. It is a complex and heterogeneous disease that primarily affects older adults and is associated with significant morbidity and mortality. Despite advances in treatment, including proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies, MM remains largely incurable, with most patients experiencing relapse and disease progression. The disease’s biological complexity is driven by a multitude of genetic and molecular alterations, which contr

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… Enhanced DNA repair mechanisms and the activation of autophagy or unfolded protein response (UPR) pathways can also contribute to cellular resilience and survival under drug-induced stress [ 17 ]. … Compromising the unfolded protein response induces autophagy-mediated cell death in multiple myeloma cells. PLoS ONE. 2011;6(10):e25820. 88. Xiang Y, et al. Monitoring a nuclear factor-κB signature of drug resistance in multiple myeloma. Mol Cell Proteom. 2011;10(11):M110. 89. Niewerth D, et al. …

HIV-1 matrix protein p17 misfolding forms toxic amyloidogenic assemblies that induce neurocognitive disorders.

Human immunodeficiency virus type-1 (HIV-1)-associated neurocognitive disorder (HAND) remains an important neurological manifestation that adversely affects a patient's quality of life. HIV-1 matrix protein p17 (p17) has been detected in autoptic brain tissue of HAND individuals who presented early with severe AIDS encephalopathy. We hypothesised that the ability of p17 to misfold may result in the generation of toxic assemblies in the brain and may be relevant for HAND pathogenesis. A multidisciplinary integrated approach has been applied to determine the ability of p17 to form soluble amyloi

Novel Investigations of Flavonoids as Chemopreventive Agents for Hepatocellular Carcinoma.

We would like to highlight the application of natural products to hepatocellular carcinoma (HCC). We will focus on the natural products known as flavonoids, which target this disease at different stages of hepatocarcinogenesis. In spite of the use of chemotherapy and radiotherapy in treating HCC, patients with HCC still face poor prognosis because of the nature of multidrug resistance and toxicity derived from chemotherapy and radiotherapy. Flavonoids can be found in many vegetables, fruits, and herbal medicines that exert their different anticancer effects via different intracellular signalin

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… To prevent cells from the harmful effects of ER stress, a sophisticated signal pathway called the unfolded protein response (UPR) is triggered to attenuate protein translation, degrade misfolded protein, and induce molecular chaperone expression. … Activation of the unfolded protein response contributed to the selective cytotoxicity of oroxylin A in human hepatocellular carcinoma HepG2 cells Toxicology Letters 2012 212 2 113 125 10.1016/j.toxlet.2012.05.008 22609744 24 Zou M. Lu N. Hu C. …

Targeting Cancer Through Thymoquinone: From Molecular Mechanisms to Clinical Prospects.

Thymoquinone (TQ), the active compound in Nigella sativa (black seed), has shown promising effects against cancer in many laboratory studies. In this review, we explore how TQ works on different aspects of cancer, from stopping cancer cell growth and spread, to triggering cancer cell death, reducing inflammation, and helping the immune system fight back. We also highlight how TQ may overcome one of the biggest problems in cancer treatment-chemoresistance. When used together with common treatments like chemotherapy, radiation, or immunotherapy, TQ has been shown to improve their effects and red

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… Additionally, it impacts the tumor microenvironment, influences epigenetic modifications, and activates endoplasmic reticulum (ER) stress and unfolded protein response (UPR) pathways. … The Role of ER Stress and the Unfolded Protein Response in Cancer. Cancer Genom. Proteom. 2025;22:363–381. doi: 10.21873/cgp.20507. 12. Liang D., Khoonkari M., Avril T., Chevet E., Kruyt F.A.E. …

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

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… The Unfolded Protein Response as a Guardian of the Secretory Pathway Cells 2021 10 2965 10.3390/cells10112965 34831188 PMC8616143 86. Wu Z. Li M. Zheng W. Hu Q. Cheng Z. Guo F. …

Proteasome inhibitors - molecular basis and current perspectives in multiple myeloma.

Inhibition of proteasome, a proteolytic complex responsible for the degradation of ubiquitinated proteins, has emerged as a powerful strategy for treatment of multiple myeloma (MM), a plasma cell malignancy. First-in-class agent, bortezomib, has demonstrated great positive therapeutic efficacy in MM, both in pre-clinical and in clinical studies. However, despite its high efficiency, a large proportion of patients do not achieve sufficient clinical response. Therefore, the development of a second-generation of proteasome inhibitors (PIs) with improved pharmacological properties was needed. Rece

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… A stress signalling pathway called the unfolded protein response (UPR) ensures that the PCs can handle the proper folding of proteins and prevent the aggregation of accumulating misfolded proteins. These proteins are then transported out of the ER and degraded by proteasome [ 23 , 24 ]. … protein response in multiple myeloma cells Blood 2006 107 4907 16 16507771 10.1182/blood-2005-08-3531 PMC1895817 26 Lee AH Iwakoshi NN Anderson KC Proteasome inhibitors disrupt the unfolded protein response in myeloma cells Proc Natl Acad Sci USA 2003 100 9946 51 12902539 10.1073/pnas.1334037100 PMC187896 …

Болезни Увечье с возрастом в экспериментальной модели множественного склероза: роль иммунозенсии.

Начавшийся множественный склероз (MS) у пожилых людей соотносится с более высоким риском развития первичных прогрессивных MS, ускорения перехода к вторичным прогрессивным MS и увеличения накопления инвалидности. Это явление может быть связано с возрастными изменениями в иммунной системе: с возрастом иммунная система проходит процесс, называемый иммунной сенсацией, который характеризуется снижением функции как врожденной, так и адаптивной иммунной реакции. Такое снижение может привести к снижению способности контролировать воспаление и восстанавливать поврежденные ткани. Кроме того, пожилые люд

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… The unfolded protein response (UPR) is activated to restore ER homeostasis and, ultimately, trigger apoptosis if the cell is suffering excessive ER stress. UPR markers have been reported to be elevated in different cell types in MS and EAE, including T cells (Mhaille et al.  2008 ). …

Different Strategies to Overcome Resistance to Proteasome Inhibitors-A Summary 20 Years after Their Introduction.

Proteasome inhibitors (PIs), bortezomib, carfilzomib, and ixazomib, are the first-line treatment for multiple myeloma (MM). They inhibit cytosolic protein degradation in cells, which leads to the accumulation of misfolded and malfunctioned proteins in the cytosol and endoplasmic reticulum, resulting in cell death. Despite being a breakthrough in MM therapy, malignant cells develop resistance to PIs via different mechanisms. Understanding these mechanisms drives research toward new anticancer agents to overcome PI resistance. In this review, we summarize the mechanism of action of PIs and how M

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… The ER stress activates the unfolded protein response (UPR) pathway. UPR provides cells with a way to survive the ER stress, but when it is overloaded with misfolded proteins, it leads to cell death via apoptosis [ 32 ]. … Mechanisms, regulation and functions of the unfolded protein response Nat. Rev. Mol. Cell Biol. 2020 21 421 438 10.1038/s41580-020-0250-z 32457508 PMC8867924 33. Perez-Galan P. Roue G. Villamor N. Montserrat E. Campo E. Colomer D. …

Pharmaceutical Chaperones and Proteostasis Regulators in the Therapy of Lysosomal Storage Disorders: Current Perspective and Future Promises.

Different approaches have been utilized or proposed for the treatment of lysosomal storage disorders (LSDs) including enzyme replacement and hematopoietic stem cell transplant therapies, both aiming to compensate for the enzymatic loss of the underlying mutated lysosomal enzymes. However, these approaches have their own limitations and therefore the vast majority of LSDs are either still untreatable or their treatments are inadequate. Missense mutations affecting enzyme stability, folding and cellular trafficking are common in LSDs resulting often in low protein half-life, premature degradatio

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… The unfolded protein response, degradation from the endoplasmic reticulum, and cancer. Genes Cancer 1 764 – 778 . 10.1177/1947601910383011 21331300 PMC3039444 Tsaytler P. Harding H. P. Ron D. Bertolotti A. ( 2011 ). … The unfolded protein response: from stress pathway to homeostatic regulation. Science 334 1081 – 1086 . 10.1126/science.1209038 22116877 Wang F. Chou A. Segatori L. ( 2011a ). …

Noncanonical SQSTM1/p62-Nrf2 pathway activation mediates proteasome inhibitor resistance in multiple myeloma cells via redox, metabolic and translational reprogramming.

Multiple Myeloma (MM) is a B-cell malignancy characterized by the accumulation of clonal plasma cells in the bone marrow, with drug resistance being a major cause of therapeutic failure. We established a carfilzomib-resistant derivative of the LP-1 MM cell line (LP-1/Cfz) and found that the transcription factor NF-E2 p45-related factor 2 (Nrf2; gene symbol NFE2L2) contributes to carfilzomib resistance. The mechanism of Nrf2 activation involved enhanced translation of Nrf2 as well as its positive regulator, the autophagy receptor sequestosome 1 (SQSTM1)/p62. The eukaryotic translation initiatio

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… PERK is activated upon accumulation of misfolded/unfolded proteins in the endoplasmic reticulum which results in the induction of an “unfolded protein response” (UPR) [ 30 ]. … GSEA indicated that genes upregulated during the unfolded protein response were downregulated in MRD cells. Gene set: HALLMARK_UNFOLDED_PROTEIN_RESPONSE (M5922). C. …

Metformin-induced vitamin B12 deficiency: An underdiagnosed cause of diabetic neuropathy.

Metformin-induced vitamin B12 deficiency is a prevalent condition among patients with type 2 diabetes mellitus. In recent years, a growing body of evidence has demonstrated the association between vitamin B12 deficiency and the onset, progression, and worsening of diabetic neuropathy (DNP) as well as its improvement with supplementation in cases of deficiency. Major clinical guidelines for diabetes and DNP remain vague in their recommendations for B12 measurement and supplementation, and some guidelines do not address it at all. Given that vitamin B12 therapy is an economical, safe, and widely

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… This activates the unfolded protein response, a signaling cascade aimed at restoring normal ER function. However, during prolonged or extreme stress, the unfolded protein response may become overwhelmed, triggering apoptotic pathways[ 19 ]. …

Autophagic mechanisms in longevity intervention: role of natural active compounds.

The term 'autophagy' literally translates to 'self-eating' and alterations to autophagy have been identified as one of the several molecular changes that occur with aging in a variety of species. Autophagy and aging, have a complicated and multifaceted relationship that has recently come to light thanks to breakthroughs in our understanding of the various substrates of autophagy on tissue homoeostasis. Several studies have been conducted to reveal the relationship between autophagy and age-related diseases. The present review looks at a few new aspects of autophagy and speculates on how they m

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… Spautin-1 inhibits the unfolded protein response under 2-deoxy-D-glucose and glucose starvation stressed conditions. … protein response under 2-deoxy-D-glucose and glucose starvation stressed conditions. | (Ref. 75 ) Hypopharyngeal squamous cell carcinoma (head and neck cancer) | BALB/c nude mice with a subcutaneous injection of human hypopharyngeal FaDu cells | CQ-inhibited autophagy by increasing the levels of LC3 …

Сопротивление лекарствам в Множественной миеломе: опухоль-интринтические механизмы и микроокружающая среда костного мозга.

Множественная миелома (ММ) — злокачественное расстройство плазменных клеток, и, несмотря на значительные улучшения в прогнозе, полученные благодаря химиотерапии, иммунной терапии и автологической трансплантации стволовых клеток, у большинства пациентов в конечном счете возникает рецидив или рефракторное заболевание. Сопротивление лекарствам (DR) все чаще признается как динамическо развивающаяся экосистема, формируемая из опухоли-интенсивной пластичности и непрерывной реконструкцией микроокружающей среды костного мозга (BMME), а не как одно молекулярное повреждение. В настоящем обзоре резюмирую

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… When proteostasis is disrupted, cells activate the unfolded protein response (UPR) as an adaptive mechanism to buffer cellular stress. However, MM cells can frequently rewire these homeostatic cascades and constitutively activate core pro‐survival signaling pathways [ 7 , 8 ]. … Abbreviations: PIs (Proteasome Inhibitors), proteasome 20S subunit β5 (PSMB5), ER (Endoplasmic Reticulum), UPR (Unfolded Protein Response), BMME (Bone Marrow Microenvironment), MM (Multiple Myeloma), PSMB5 (Proteasome 20S Subunit β5), PSMA3 (Proteasome 20S Subunit α3), CAM‐DR (Cell‐Adhesion Mediated …

The proteasome as a druggable target with multiple therapeutic potentialities: Cutting and non-cutting edges.

Ubiquitin Proteasome System (UPS) is an adaptable and finely tuned system that sustains proteostasis network under a large variety of physiopathological conditions. Its dysregulation is often associated with the onset and progression of human diseases; hence, UPS modulation has emerged as a promising new avenue for the development of treatments of several relevant pathologies, such as cancer and neurodegeneration. The clinical interest in proteasome inhibition has considerably increased after the FDA approval in 2003 of bortezomib for relapsed/refractory multiple myeloma, which is now used in

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… In these diseases, a decrease of proteasome levels, consequent to an altered maturation, is envisaged to activate the Unfolded Protein Response (UPR) through the endoplasmic reticulum stress. … Moreover, the lack of some proteins, such as XBP1, which decreases the endoplasmic reticulum burden and affects the unfolded protein response, has also been proposed as a possible cause of bortezomib resistance (Fall et al., 2014). …

Multiple Myeloma Therapy: Emerging Trends and Challenges.

Multiple myeloma (MM) is a complex hematologic malignancy characterized by the uncontrolled proliferation of clonal plasma cells in the bone marrow that secrete large amounts of immunoglobulins and other non-functional proteins. Despite decades of progress and several landmark therapeutic advancements, MM remains incurable in most cases. Standard of care frontline therapies have limited durable efficacy, with the majority of patients eventually relapsing, either early or later. Induced drug resistance via up-modulations of signaling cascades that circumvent the effect of drugs and the emergenc

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… Panobinostat and vorinostat are pan-HDAC inhibitors leading to blockade of disposal of several proapoptotic proteins through the unfolded protein response, disrupting protein homeostasis and resulting in cell death via apoptosis [ 262 ]. … This leads to activation of the unfolded protein response (UPR), with subsequent activation of downstream pathways inducing apoptosis. Abbreviations: PDIA1, protein disulfide isomerase inhibitor A1; ER, endoplasmic reticulum; UPR, unfolded protein response. …

Bortezomib in the management of multiple myeloma.

Multiple myeloma (MM) is a B-cell malignancy characterized by clonal expansion of plasma cells within the bone marrow, the presence of a serum and/or urine monoclonal protein, lytic bone lesions, and anemia. On a cellular level, the disease is characterized by complex interactions between tumor cells and the surrounding bone marrow microenvironment. Understanding of the relationship between malignant plasma cells and the microenvironment has sparked ongoing efforts to develop targeted therapeutic agents for treatment of this disease. The successful development of the first-in-class small-molec

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… Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood. 2006;107(12):4907–4916. doi: 10.1182/blood-2005-08-3531. 20. Dong H, Chen L, Chen X, et al. … Dysregulation of unfolded protein response partially underlies proapoptotic activity of bortezomib in multiple myeloma cells. Leuk Lymphoma. 2009;50(6):974–984. doi: 10.1080/10428190902895780. 21. Hideshima T, Chauhan D, Hayashi T, et al. …