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Carfilzomib with immunomodulatory drugs for the treatment of newly diagnosed multiple myeloma.

Carfilzomib, a selective proteasome inhibitor (PI), is approved for the treatment of patients with relapsed or refractory multiple myeloma (MM). Combination regimens incorporating a PI and immunomodulatory drug (IMiD) have been associated with deep responses and extended survival in patients with newly diagnosed MM (NDMM). Carfilzomib-based combinations with immunomodulators are being extensively studied in the frontline setting. The objective of this review was to describe efficacy and safety data for carfilzomib-based, PI/immunomodulatory combinations in NDMM. Information sources were articl

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… ER endoplasmic reticulum, HLA human leukocyte antigen, MM multiple myeloma, NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells, NK natural killer, UPR unfolded protein response In MM clinical trials, carfilzomib-based regimens demonstrated robust efficacy and carfilzomib showed single-agent … Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood. 2006;107:4907–16. doi: 10.1182/blood-2005-08-3531. 11. Hideshima T, Chauhan D, Richardson P, Mitsiades C, Mitsiades N, Hayashi T, et al. NF-kappa B as a therapeutic target in multiple myeloma. …

Shutting off the fuel supply to target metabolic vulnerabilities in multiple myeloma.

Pathways that govern cellular bioenergetics are deregulated in tumor cells and represent a hallmark of cancer. Tumor cells have the capacity to reprogram pathways that control nutrient acquisition, anabolism and catabolism to enhance their growth and survival. Tumorigenesis requires the autonomous reprogramming of key metabolic pathways that obtain, generate and produce metabolites from a nutrient-deprived tumor microenvironment to meet the increased bioenergetic demands of cancer cells. Intra- and extracellular factors also have a profound effect on gene expression to drive metabolic pathway

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… Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells . Blood ( 2006 ) 107 ( 12 ): 4907–16 . doi: 10.1182/blood-2005-08-3531 PMC1895817 16507771 36 Schwestermann J Besse A Driessen C Besse L . …

Learn from antibody-drug conjugates: consideration in the future construction of peptide-drug conjugates for cancer therapy.

Cancer is one of the leading causes of death worldwide due to high heterogeneity. Although chemotherapy remains the mainstay of cancer therapy, non-selective toxicity and drug resistance of mono-chemotherapy incur broad criticisms. Subsequently, various combination strategies have been developed to improve clinical efficacy, also known as cocktail therapy. However, conventional "cocktail administration" is just passable, due to the potential toxicities to normal tissues and unsatisfactory synergistic effects, especially for the combined drugs with different pharmacokinetic properties. The drug

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… Furthermore, we revealed a distinctive mechanism whereby DTX-P7 induced unfolded protein response and eventually promoted apoptosis, leading to cell death. … For rapidly proliferating cells, DTX-P7 accelerates the degradation of Hsp90 through lysosome- and proteasome-dependent pathways, which induces unfolded protein response and subsequently promotes apoptosis. …

NLRX1 limits inflammatory neurodegeneration in the anterior visual pathway.

Chronic innate immune activation in the central nervous system (CNS) significantly contributes to neurodegeneration in progressive multiple sclerosis (MS). Using multiple experimental autoimmune encephalomyelitis (EAE) models, we discovered that NLRX1 protects neurons in the anterior visual pathway from inflammatory neurodegeneration. We quantified retinal ganglion cell (RGC) density and optic nerve axonal degeneration, gliosis, and T-cell infiltration in Nlrx1-/- and wild-type (WT) EAE mice and found increased RGC loss and axonal injury in Nlrx1-/- mice compared to WT mice in both active immu

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… Each column’s genotype is indicated below the heatmap. for each gene and each biological replicate When we tested different gene sets, we found that certain pathways, like TNFα signaling via NF-κB (Fig.  5 C,D) and the Unfolded Protein Response, were more strongly activated in Nlrx1 −/− astrocytes … Our RNA sequencing data also identified that Nlrx1 −/− astrocytes compared to WT astrocytes have enhanced induction of unfolded protein response genes and a greater reduction in cell-cycle related targets of E2F transcription factors in response to LPS/IFNγ stimulation. …

Natural products targeting ferroptosis in cancer: molecular mechanisms and applications.

Ferroptosis is a novel class of programmed cell death that is mainly dependent on intracellular iron accumulation and lipid peroxidation. Ferroptosis is closely related to a variety of human diseases, especially different kinds of cancer. Several small molecule inducers have been developed to induce ferroptosis in tumor cells, some of which have been used in clinical studies. However, these chemical small molecules have toxic effects that limit its wide application. Natural products, however, have a natural advantage in cancer therapy due to their low toxicity and side effects. Some natural pr

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… Dihydroartemisinin-induced unfolded protein response feedback attenuates ferroptosis via PERK/ATF4/HSPA5 pathway in glioma cells . J Exp Clin Cancer Res . ( 2019 ) 38 : 402 . doi: 10.1186/s13046-019-1413-7 , PMID: 31519193 PMC6743121 61 Yi R Wang H Deng C Wang X Yao L Niu W . … Dihydroartemisinin triggers ferroptosis in primary liver cancer cells by promoting and unfolded protein response−induced upregulation of CHAC1 expression . Oncol Rep . ( 2021 ) 46 ( 5 ): 240 . doi: 10.3892/or.2021.8191 , PMID: 34558645 PMC8485000 64 Yuan B Liao F Shi ZZ Ren Y Deng XL Yang TT . …

Myelin Displacement and Revention in the Central Nervous System: Молекулярные механизмы, болезни и перспективные терапевтические цели.

Майлин пластичность имеет основополагающее значение для формирования нейронных сетей и оптимизации нейронных функций, формирования схем, регулирующих эмоции, сознание, сенсацию и управление двигателем. Подкомбинированный олигодендроцитами, миелин подвергается пожизненной реконструкции, которая требует высокой метаболической активности; это делает миелин-олигодендроцитную единицу весьма восприимчивой к метаболическому стрессу, старению и патологическим оскорблениям. Хотя обезвоживание является основной характеристикой различных хронических неврологических расстройств, в настоящем обзоре особо п

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… Studies using induced pluripotent stem cell‐derived oligodendrocytes from patients with PMD demonstrate that mutant PLP1 protein misfolding triggers activation of the unfolded protein response and ER stress‐mediated apoptosis [ 192 ]. … Cx47 is essential for oligodendrocyte–astrocyte gap junction coupling, and its dysfunction results in ER protein retention, unfolded protein response activation, and oligodendrocyte apoptosis [ 193 , 194 ]. …

Gaucher disease, state of the art and perspectives.

Knowledge about Gaucher disease (GD), considered a model for rare diseases, has considerably increased since its discovery. The pathophysiology of this lysosomal disorder is better known, and specific therapies that can control many aspects of the disease have been developed, particularly for the most common form, Type 1 GD. Yet, in part because of the rarity of GD, but also because of a lack of awareness by physicians, diagnostic delay too often leads to a belated management of patients having accumulated comorbidities. Gaucher cells, the most visible consequence of glucocerebrosidase deficie

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… First, activation of a repair pathway, UPR (unfolded protein response), which could also be altered in GD, favoring GCase/LIMP‐2 binding, increasing cellular stress. … The GBA1 gene mutation indeed leads to an accumulation of altered GCase molecules in the ER, generating a chronic stress triggering the unfolded protein response pathway that manages this protein accumulation [ 40 ] (Fig. 2e ). …

VEXAS Syndrome-Review.

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a newly defined refractory adult-onset autoinflammatory syndrome caused by somatic mutations in the ubiquitin-like modifier-activating enzyme 1 (UBA1) gene in hematopoietic stem and progenitor cells, resulting in a shift in UBA1 isoform expression. Thus, patients develop a spectrum of systemic inflammatory manifestations and hematologic symptoms. To date, patients respond poorly to immune suppressive drugs, except high-dose glucocorticoids, and no treatment guidelines have been established. Given the high mortality ra

Revisiting Proteasome Inhibitors: Molecular Underpinnings of Their Development, Mechanisms of Resistance and Strategies to Overcome Anti-Cancer Drug Resistance.

Proteasome inhibitors have shown relevant clinical activity in several hematological malignancies, namely in multiple myeloma and mantle cell lymphoma, improving patient outcomes such as survival and quality of life, when compared with other therapies. However, initial response to the therapy is a challenge as most patients show an innate resistance to proteasome inhibitors, and those that respond to the therapy usually develop late relapses suggesting the development of acquired resistance. The mechanisms of resistance to proteasome inhibition are still controversial and scarce in the literat

The Ubiquitin-Proteasome System (UPS) as a Cancer Drug Target: Emerging Mechanisms and Therapeutics

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Mechanisms of ferroptotic and non-ferroptotic organ toxicity of chemotherapy: protective and therapeutic effects of ginger, 6-gingerol and zingerone in preclinical studies.

Chemotherapy (CT) is one of the flagship options for the treatment of cancers worldwide. It involves the use of cytotoxic anticancer agents to kill or inhibit the proliferation of cancer cells. However, despite its clinical efficacy, CT triggers side effect toxicities in several organs, which may impact cancer patient's quality of life and treatment outcomes. While the side effect toxicity is consistent with non-ferroptotic mechanisms involving oxidative stress, inflammation, mitochondrial impairment and other aberrant signalling leading to apoptosis and necroptosis, recent studies show that f

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… By interfering with these processes, chemotherapeutic medications can cause ER stress and an accumulation of unfolded or misfolded proteins in the ER lumen that triggers the unfolded protein response (UPR), a signalling network that aims to restore ER homeostasis. …

A Perspective on Withania somnifera Modulating Antitumor Immunity in Targeting Prostate Cancer.

Medicinal plants serve as a lead source of bioactive compounds and have been an integral part of day-to-day life in treating various disease conditions since ancient times. Withaferin A (WFA), a bioactive ingredient of Withania somnifera, has been used for health and medicinal purposes for its adaptogenic, anti-inflammatory, and anticancer properties long before the published literature came into existence. Nearly 25% of pharmaceutical drugs are derived from medicinal plants, classified as dietary supplements. The bioactive compounds in these supplements may serve as chemotherapeutic substance

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… Ghosh et al. reported WFA-induced cell death in breast cancer cells by introducing impaired autophagy and unfolded protein response [ 31 ]. … Withaferin A induced impaired autophagy and unfolded protein response in human breast cancer cell-lines MCF-7 and MDA-MB-231 Toxicology In Vitro 2017 44 330 338 10.1016/j.tiv.2017.07.025 2-s2.0-85026892123 28782635 32 Yang H. Shi G. Dou Q. P. …

Адаптация эукариот-подобных PRS к прокариот-подобным tRNAPro.

Синтеты Проли-ТРНА (ПРОРС) уникальны среди аминоачил-тРНК (ААРС) two различные структурные архитектуры различных организмов: прокариота-подобные (П-тип) и эукариоте/археон-подобные (Е-тип). Интересно, что Бакиллус Тюрингьенси гавань обоих типов, сосуществует P-тип (BtProRS1) и E-тип PRS (BtProRS2). Несмотря на свои различия, оба фермента формально выражаются и функционируют в vivo. По аналогии с BtProRS1, BtPRS2 выборочно заряжает TRNAPro типа P и демонстрирует более высокий допуск к галоугинону, чем каноническая PRS. Однако эти two Изозимы признают основные идентификационные элементы типа P t

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… Measuring ER stress and the unfolded protein response using mammalian tissue culture system. Methods Enzymol. 2011; 490:71–92. 39. Banerjee B., Banerjee R.. Urea unfolding study of E. coli alanyl-tRNA synthetase and its monomeric variants proves the role of C-terminal domain in stability. J. …

Programmed Cell Death in Health and Disease.

Programmed cell death is a conserved evolutionary process of cell suicide that is central to the development and integrity of eukaryotic organisms [...].

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… Their focus is on the mechanisms that lead to HIV-related caspase activation and cell death, including induction of mitochondrial dysfunction, oxidative stress, endoplasmic reticulum (ER) stress and unfolded protein response (UPR). …

Dynamic multimodal survival prediction in multiple myeloma integrating gene expression, longitudinal laboratory measurements, and treatment history.

Prognostic stratification in multiple myeloma (MM) relies on staging systems fixed at diagnosis, discarding temporal information accumulated during treatment. We developed a dynamic multimodal framework that predicts residual overall survival from observation windows of 1-18 months post-diagnosis. The model integrates DeepInsight-transformed gene expression, longitudinal trajectories of 10 laboratory analytes, and treatment history through missingness-aware gated fusion. On the Multiple Myeloma Research Foundation (MMRF) cohort from the Relating Clinical Outcomes in Multiple Myeloma to Persona

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… ORA on both risk-increasing and protective gene sets ( Supplementary Figs S7 and S8 ; Materials and Methods) also identified Unfolded Protein Response and mTORC1 Signaling among risk-enriched terms. … Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood 2006;107:4907–16. 10.1182/blood-2005-08-3531 36. Huang HH, Ferguson ID, Thornton AM et al. …

Окисляющий/нетрозирующий стресс, апоптоз и сигнализация " Redox " : основные игроки в нейродегенеративных заболеваниях.

Нейродегенеративные заболевания представляют собой серьезную проблему для здоровья, которая оказывает глубокое воздействие на качество и продолжительность жизни миллионов людей. Эти заболевания характеризуются патологическими изменениями в различных областях мозга, конкретными генетическими мутациями, связанными с болезнью, залежами аномальных белков и дегенерацией неврологических клеток. Поскольку нейродегенеративные расстройства различаются по своим эпидемиологическим характеристикам и степени уязвимости нейронов, лечение этих заболеваний обычно направлено на замедление развития заболеваний.

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… Studies examining the pathogenesis of PD have reported that 6‐hydroxydopamine affects p53 and DNA damage repair pathways, activates the unfolded protein response (UPR) and OS pathways, triggers the release of cytochrome‐c from mitochondria, activates modulator caspases, and induces ROS‐induced apoptosis …

Recent Trends in anti-tumor mechanisms and molecular targets of celastrol.

Celastrol, a compound derived from traditional Chinese medicine, has therapeutic effects and has been used to treat inflammation-related diseases, cancer, cardiovascular diseases, and neurodegenerative diseases. However, current reviews lack a comprehensive and systematic summary of the anti-tumor mechanisms and molecular targets of celastrol. For this reason, this paper reviews the anticancer properties of celastrol and the molecular mechanisms underlying its anticancer effects. This paper primarily focuses on the mechanism of action of celastrol in terms of inhibition of cell proliferation a

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… The ER, a major cellular organelle that modifies and secretes proteins, activates ERS under constant and intense stimulation, leading to protein folding errors and excessive accumulation of unfolded proteins, triggering the unfolded protein response and initiating apoptosis. … More importantly, celastrol was found to exert its pro-apoptotic effect through ER stress and the unfolded protein response 141 . …

Heart failure with preserved ejection fraction in cancer patients and survivors. A scientific statement of the Heart Failure Association of the ESC and the ESC Council of Cardio-Oncology.

Heart failure with preserved ejection fraction (HFpEF) is increasingly recognized in cancer patients and survivors, yet it remains underdiagnosed and its epidemiology largely unknown. This statement underscores the imperative need to include HFpEF in the cardiotoxicities identified during or after anticancer treatments. It also highlights the prognostic value of pre-existing HFpEF for periprocedural and cardiotoxicity risk and it discusses the challenges in the diagnosis and treatment of HFpEF in cancer patients. It also explores the aetiologic role of anticancer therapies (chemotherapy, targe

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… Interestingly, T cells involvement in HFpEF was also recently demonstrated in a 2‐hit cardiometabolic HFpEF animal model. 91 In this model, myocardial and splenic T cells were characterized by impaired activation of proteins involved in the unfolded protein response. … The same impaired activation of the unfolded protein response had previously been reported in cardiomyocytes. 92 , 93 The similarity of T‐cell and cardiomyocyte responses in this HFpEF model illustrates the emerging importance of cardioimmunology. 94 CAR‐T cell therapy for acute lymphoblastic leukaemia …

Молекулярная динамическая симуляция диких и мутантных протеиновых субъектов бета-белка типа 8 (PSMB8): Последствия для восстановления воспаления в экспериментальном аутоиммунном энцефаломиэлите патогенез.

Множественный склероз (MS) — аутоиммунное и хроническое заболевание мозга и спинного мозга. В НР наблюдается подстрекательский прогресс, характеризующийся своими отличительными подстрекательскими знаками. Гистологические и клинические характеристики MS разделяются экспериментальным аутоиммунным энцефаломелитом (EAE). Генетические и экологические факторы способствуют развитию НР. В болезни EAE-MS уровень протеазонного компонента бета-типа 8 (PSMB8), закодированного геном PSMB8, увеличивается и регулирует подстрекательскую реакцию в этой болезни. У людей синдром Накахо-Нишимура вызван мутации в

Review on Bortezomib Resistance in Multiple Myeloma and Potential Role of Emerging Technologies.

Multiple myeloma is a hematological cancer type. For its treatment, Bortezomib has been widely used. However, drug resistance to this effective chemotherapeutic has been developed for various reasons. 2D cell cultures and animal models have failed to understand the MM disease and Bortezomib resistance. It is therefore essential to utilize new technologies to reveal a complete molecular profile of the disease. In this review, we in-depth examined the possible molecular mechanisms that cause Bortezomib resistance and specifically addressed MM and Bortezomib resistance. Moreover, we also included

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… Therefore, these cells are under a constant endoplasmic reticulum stress and can easily induce unfolded protein response (UPR) [ 88 ]. The efficacy of the proteasome inhibitor Bortezomib is limited by the resistance development in the disease [ 89 ]. … Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood. 2006;107:4907–4916. doi: 10.1182/blood-2005-08-3531. 89. Egan P., Drain S., Conway C., Bjourson A.J., Alexander H.D. Towards Stratified Medicine in Plasma Cell Myeloma. Int. J. Mol. …