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Crosstalk between glucocorticoid and mineralocorticoid receptors boosts glucocorticoid-induced killing of multiple myeloma cells.

The glucocorticoid receptor (GR) is a crucial drug target in multiple myeloma as its activation with glucocorticoids effectively triggers myeloma cell death. However, as high-dose glucocorticoids are also associated with deleterious side effects, novel approaches are urgently needed to improve GR action in myeloma. Here, we reveal a functional crosstalk between GR and the mineralocorticoid receptor (MR) that plays a role in improved myeloma cell killing. We show that the GR agonist dexamethasone (Dex) downregulates MR levels in a GR-dependent way in myeloma cells. Co-treatment of Dex with the

Epigenetics in myeloproliferative neoplasms.

The myeloproliferative neoplasms (MPNs) are a group of acquired clonal disorders where mutations drive proliferative disease resulting in increased blood counts and in some cases end-stage myelofibrosis. Epigenetic changes are the reversible modifications to DNA- and RNA-associated proteins that impact gene activity without changing the DNA sequence. This review summarizes mechanisms of epigenetic changes and the nucleosome. The drivers and epigenetic regulators in MPNs are outlined. In MPNs, distinct patterns of epigenetic dysregulation have been seen in chronic and in advanced phases. Methyl

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… The CALR protein is present in the endoplasmic reticulum where it ensures proper glycoprotein folding, contributes to calcium homeostasis, and plays an important role in the unfolded protein response (UPR). …

NRF2: A crucial regulator for mitochondrial metabolic shift and prostate cancer progression.

Metabolic alterations are a common survival mechanism for prostate cancer progression and therapy resistance. Oxidative stress in the cellular and tumor microenvironment dictates metabolic switching in the cancer cells to adopt, prosper and escape therapeutic stress. Therefore, regulation of oxidative stress in tumor cells and in the tumor-microenvironment may enhance the action of conventional anticancer therapies. NRF2 is the master regulator for oxidative stress management. However, the overall oxidative stress varies with PCa clinical stage, metabolic state and therapy used for the cancer.

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… Downregulating NRF2 increases ROS, oxidation of nucleic acids and lipids, decreases the activity of antioxidant enzymes, and increases the unfolded protein response and endoplasmic reticulum stress in advanced stage PCa (J. Yu et al., 2021 ). … Decreases the activity of antioxidative enzymes and increases the unfolded protein response and endoplasmic reticulum stress. | Liang et al. (2019) LNCaP, PC3 and DU145 cells but not in normal prostate cells | Downregulation of NRF2 (by a polyphenol-rich fraction of Bergenia ligulate plant) | Upregulates …

Risk factors associated with overall survival in patients with multiple myeloma following carfilzomib treatment: A retrospective study from a large claims database in Japan.

BackgroundCarfilzomib is a selective proteasome inhibitor approved for treating relapsed or refractory multiple myeloma (RRMM). Carfilzomib improves overall survival (OS) and progression-free survival (PFS); however, treatment with carfilzomib results in a higher incidence of cardiovascular and renal toxicity. More than 70% of patients with RRMM in clinical practice do not meet the eligibility criteria for randomized clinical trials (RCT). OS and PFS are negatively influenced by complications, concomitant medications and prior treatments. Therefore, we assessed the risk factors influencing the

Molecular chess? Hallmarks of anti-cancer drug resistance.

BackgroundThe development of resistance is a problem shared by both classical chemotherapy and targeted therapy. Patients may respond well at first, but relapse is inevitable for many cancer patients, despite many improvements in drugs and their use over the last 40 years.ReviewResistance to anti-cancer drugs can be acquired by several mechanisms within neoplastic cells, defined as (1) alteration of drug targets, (2) expression of drug pumps, (3) expression of detoxification mechanisms, (4) reduced susceptibility to apoptosis, (5) increased ability to repair DNA damage, and (6) altered prolife

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… These include mutations in proteasome subunits, unfolded protein response, XBP1 and MARCKS proteins, aggresomes, the role of constitutive and immunoproteasomes, alterations in pro-survival signalling pathways, changes in bone marrow microenvironment and autophagy as well as other multidrug resistance …

Oxidative Stress: Signaling Pathways, Biological Functions, and Disease.

The dysregulated accumulation of reactive oxygen species (ROS) and reactive nitrogen species disrupts redox homeostasis, triggering oxidative stress (OS) and driving pathophysiological changes across multiple organ systems. OS modulates critical signaling pathways, induces inflammation, impairs mitochondrial function, alters metabolic homeostasis, and dysregulates autophagy, contributing to disease progression. While prior research has largely focused on OS within single-organ diseases (e.g., neurodegenerative, cardiovascular, and oncological disorders), the systemic role of OS in pan-organ di

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… However, excess ROS disrupt ER redox homeostasis, leading to misfolded proteins and triggering the unfolded protein response (UPR), which can further increase ROS levels. In protein degradation, ROS enhance the removal of misfolded proteins through the ubiquitin–proteasome system and autophagy. … Accumulation of ROS can disrupt the redox homeostasis of the ER, leading to the accumulation of misfolded proteins and ER stress, which ultimately activates the unfolded protein response (UPR) [ 141 , 142 ]. …

Meibomian Gland Dysfunction Is Associated with Low Levels of Immunoglobulin Chains and Cystatin-SN.

Meibomian gland dysfunction (MGD) is a highly prevalent condition and the most common cause of evaporative dry eye disease. Studying the proteome of MGD can result in important advances in the management of the condition. Here, we collected tear film samples from treatment naïve patients with MGD (n = 10) and age-matched controls (n = 11) with Schirmer filtration paper. The samples were analyzed with label-free quantification nano liquid chromatography-tandem mass spectrometry. The proteins were considered differentially expressed if p < 0.05. A total of 88 proteins were significantly regulate

Genome Instability in Multiple Myeloma: Facts and Factors.

Multiple myeloma (MM) is a malignant neoplasm of terminally differentiated immunoglobulin-producing B lymphocytes called plasma cells. MM is the second most common hematologic malignancy, and it poses a heavy economic and social burden because it remains incurable and confers a profound disability to patients. Despite current progress in MM treatment, the disease invariably recurs, even after the transplantation of autologous hematopoietic stem cells (ASCT). Biological processes leading to a pathological myeloma clone and the mechanisms of further evolution of the disease are far from complete

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… Inhibition of proteasome leads to accumulation of misfolded and unfolded proteins in the endoplasmic reticulum, activates the unfolded protein response, and induces apoptosis; remarkably, the unfolded protein response plays an essential role in antibody-secreting cells [ 216 , 220 , 221 , 222 , 223 , …

Euchromatic Histone Lysine Methyltransferase 2 Inhibition Enhances Carfilzomib Sensitivity and Overcomes Drug Resistance in Multiple Myeloma Cell Lines.

Proteasome inhibitors (PIs) are extensively used for the therapy of multiple myeloma. However, patients continuously relapse or are intrinsically resistant to this class of drugs. In addition, adverse toxic effects such as peripheral neuropathy and cardiotoxicity could arise. Here, to identify compounds that can increase the efficacy of PIs, we performed a functional screening using a library of small-molecule inhibitors covering key signaling pathways. Among the best synthetic lethal interactions, the euchromatic histone-lysine N-methyltransferase 2 (EHMT2) inhibitor UNC0642 displayed a coope

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… Proteasome inhibition disrupts the balance between protein production and disposal of misfolded or non-functional proteins, leading to proteotoxic stress, excess activation of the unfolded protein response, and, ultimately, apoptosis. …

5-Hydroxymethylcytosine Profiles of cfDNA in Urine as Diagnostic, Differential Diagnosis and Prognostic Markers for Multiple Myeloma.

BackgroundAn effective urine-based method for the diagnosis, differential diagnosis and prognosis of multiple myeloma (MM) has not yet been developed. Urine cell-free DNA (cfDNA) carrying cancer-specific genetic and epigenetic aberrations may enable a noninvasive "liquid biopsy" for diagnosis and monitoring of cancer.MethodsWe first identified MM-specific hydroxymethylcytosine signatures by comparing 64 MM patients, 23 amyloidosis (AM) patients and 59 healthy cohort. Then, we applied a machine learning algorithm to develop diagnostic and differential diagnosis model. Finally, the prognosis of

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… Beider K., Rosenberg E., Dimenshtein‐Voevoda V., et al., “Blocking of Transient Receptor Potential Vanilloid 1 (TRPV1) Promotes Terminal Mitophagy in Multiple Myeloma, Disturbing Calcium Homeostasis and Targeting Ubiquitin Pathway and Bortezomib‐Induced Unfolded Protein Response,” Journal of Hematology …

Role of exosomes in pancreatic cancer.

Pancreatic cancer is one of the most lethal malignancies. Exosomes, which are released by multiple cell types, such as cancer cells, contain functional biomolecules (including proteins, nucleic acids and lipids) that can be horizontally delivered to recipient cells. Exosomes act as the most prominent mediator of intercellular communication and can regulate, instruct and re-educate their surrounding microenvironment and target specific organs. The present review performed an extensive search of multiple databases from 2005 to April 23 2017, for eligible literature relating to exosomes and their

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… A potential mechanism has been revealed where pancreatic cancer-derived exosomal adrenomedullin, triggers endoplasmic reticulum stress and dysfunction of the unfolded protein response, resulting in β-cell disorder and apoptosis. …

Melflufen in Multiple Myeloma: Clinical Limitations, Biological Rationale, and Future Perspectives.

Despite transformative therapeutic advances, multiple myeloma (MM) remains an incurable malignancy characterized by sequential relapses and progressive treatment resistance. Patients with heavily pretreated relapsed or refractory MM continue to face limited therapeutic options and poor outcomes. Melflufen (melphalan flufenamide) is a peptide-drug conjugate that enhances intracellular delivery of alkylating agents via aminopeptidase-mediated activation. Early clinical studies demonstrated encouraging activity in advanced MM, leading to accelerated approval by the U.S. Food and Drug Administrati

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… The Peptide-Drug Conjugate Melflufen Modulates the Unfolded Protein Response of Multiple Myeloma and Amyloidogenic Plasma Cells and Induces Cell Death Hemasphere 2022 6 e687 10.1097/HS9.0000000000000687 35243210 PMC8884539 37. Giliberto M. Thimiri Govinda Raj D.B. Cremaschi A. Skanland S.S. …

Потенциальное терапевтическое воздействие ибудиластной и ретиновой кислоты на поведенческие и биохимические изменения в мышечном мозге.

Ibudilast (IBD) — новый препарат, выпущенный в качестве лекарства от множественных склерозов (MS). Ретиноиновая кислота (RA), являющаяся метаболитом витамина А, известна своими прорегенеративными и антивоспалительными свойствами, поэтому она была предложена в качестве дополнительного метода лечения для MS. Цель этого исследования заключается в изучении терапевтического воздействия RA и IBD на модели мышей, вызываемые кухонной зоной (CPZ). Seventy-two Швейцарские мыши-альбино (SWR/J) были разделены на two контроль за основными группами (n = 18); нормальная чау и CPZ (n = 54); 0.25% CPZ, смешанн

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… This disturbance causes a decrease in mRNA levels, the accumulation of misfolded proteins, and triggers the unfolded protein response (UPR). This response leads to a massive influx of calcium into the cytosol, ultimately causing stress in oligodendrocytes (OLGs) ( Malhotra and Kaufman, 2007 ). …

Case Report: Abblation как новая х терапия в режиме слабого гематологического расстройства с внематологическими повреждениями.

Гематологические заболевания как категория злокачественных опухолей, происходящих из гематопоиетической системы, давно полагаются на такие виды лечения, как химиотерапия, радиотерапия и трансплантация стволовых клеток. Вместе с тем по-прежнему сохраняются проблемы, связанные с устранением местных прогрессивных повреждений, рецидивов/обезболивающих повреждений и участием специальных анатомических объектов, особенно в недееспособности. Технология абляции, которая представляет собой минимально инвазивный метод лечения на местном уровне, непосредственно уничтожает поврежденные ткани с помощью физи

Prognostic value of circulating markers of neutrophil activation, neutrophil extracellular traps, coagulation and fibrinolysis in patients with terminal cancer.

Predicting survival accurately in patients with advanced cancer is important in guiding interventions and planning future care. Objective tools are therefore needed. Blood biomarkers are appealing due to their rapid measurement and objective nature. Thrombosis is a common complication in cancer. Recent data indicate that tumor-induced neutrophil extracellular traps (NETs) are pro-thrombotic. We therefore performed a comprehensive investigation of circulating markers of neutrophil activation, NET formation, coagulation and fibrinolysis in 106 patients with terminal cancer. We found that neutrop

Recent advances in drug repositioning for the discovery of new anticancer drugs.

Drug repositioning (also referred to as drug repurposing), the process of finding new uses of existing drugs, has been gaining popularity in recent years. The availability of several established clinical drug libraries and rapid advances in disease biology, genomics and bioinformatics has accelerated the pace of both activity-based and in silico drug repositioning. Drug repositioning has attracted particular attention from the communities engaged in anticancer drug discovery due to the combination of great demand for new anticancer drugs and the availability of a wide variety of cell- and targ

Нетипичное участие белков Альцгеймера в болезнях, выходящих за рамки тауопатии.

Тау — микротубульский белок, традиционно связанный с коллективной группой расстройств, называемых «тауопатией», включая болезнь Альцгеймера. Протеин тау самоагрегирует и формирует нейрофибрилляторы в нейронах, которые считаются патоологической отличительной чертой тауопатии. Несмотря на то, что роль невралической тауопатии в тауопатии широко изучена, недавние исследования пролили свет на ее роль в других болезнях без тау-патологии и в других клетках. В настоящем обзоре мы намерены обсудить "типичное" патологическое участие тау в заболеваниях, отличных от тауопатии, включая заболевания головног

Pathogenesis and kidney prognosis of renal amyloidosis.

Light chain (AL), serum amyloid A (AA), transthyretin (ATTR), leukocyte cell derived chemotaxin 2 (ALECT2), and fibrinogen Aa (AFib) amyloidosis are some of the most common types of protein-deposition disorders involving the kidney. Each amyloidogenic protein differs in its origin and little is known about the exact mechanisms that govern renal tropism and tissue injury for each amyloid subtype. While amyloidogenic precursor protein is different in each subtype of amyloidosis, its aggregation into fibrils depositing in target organs and leading to disruption of tissue architecture and progress

Drug repurposing approach to fight COVID-19.

Currently, there are no treatment options available for the deadly contagious disease, coronavirus disease 2019 (COVID-19). Drug repurposing is a process of identifying new uses for approved or investigational drugs and it is considered as a very effective strategy for drug discovery as it involves less time and cost to find a therapeutic agent in comparison to the de novo drug discovery process. The present review will focus on the repurposing efficacy of the currently used drugs against COVID-19 and their mechanisms of action, pharmacokinetics, dosing, safety, and their future perspective. R

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… Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) activation are responsible for the viral replication and pathogenesis in coronavirus infection [ 182 , 183 ] and high levels of UPR activation has been recorded in the cells which have higher expression of SARS-COV spike protein [ …

Cardiac Amyloidosis in Older Adults With a Focus on Frailty: JACC: Advances Expert Consensus.

Amyloidosis, which is caused by misfolded proteins that form amyloid fibrils, is predominantly diagnosed in older adults. Although previously considered a rare disease, increased awareness and noninvasive diagnostic methods have resulted in a rise in diagnoses. As a multisystem disease that affects multiple organ systems (cardiac, gastrointestinal, renal, and neurological), there is significant overlap with both geriatric conditions and common conditions in heart failure. Frailty is recognized as a distinct biological syndrome of declines across multiple physiological systems, which prevents m

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… Proteostasis ensures proper folding and translocation of proteins, stress-responsive pathways (such as the unfolded protein response), and proteolytic pathways (such as the ubiquitin-proteasome and autophagosome-lysosome systems). … protein response capacity that increase cardiac TTR deposition 17 and ultimately cause disease. …