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Proteasome Inhibitors as a Possible Therapy for SARS-CoV-2.

The COVID-19 global pandemic is caused by SARS-CoV-2, and represents an urgent medical and social issue. Unfortunately, there is still not a single proven effective drug available, and therefore, current therapeutic guidelines recommend supportive care including oxygen administration and treatment with antibiotics. Recently, patients have been also treated with off-label therapies which comprise antiretrovirals, anti-inflammatory compounds, antiparasitic agents and plasma from convalescent patients, all with controversial results. The ubiquitin-proteasome system (UPS) is important for the main

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… Interestingly, these authors observed that by using a calpain inhibitor (MDL28170), virus replication was inhibited, suggesting that MG132 does not inhibit SARS-CoV replication by ER stress induction, unexplained protein response or autophagy [ 47 ]. … Severe Acute Respiratory Syndrome Coronavirus Replication Is Severely Impaired by MG132 due to Proteasome-Independent Inhibition of M-Calpain J. Virol. 2012 10.1128/JVI.01001-12 PMC3446591 22787216 48. Barretto N. Jukneliene D. Ratia K. Chen Z. Mesecar A.D. Baker S.C. …

Ethanol-induced apoptosis in hepatoma cells proceeds via intracellular Ca(2+) elevation, activation of TLCK-sensitive proteases, and cytochrome c release.

Ethanol is known to induce apoptosis in hepatocytes. However, intracellular signaling events of ethanol-induced death are still only partially understood. We studied such processes in ethanol-induced apoptosis in HepG2 cells as a model system for human liver cells. We determined the incidence of apoptosis by DNA fragmentation and tested the effects of various known inhibitors. Ethanol induces apoptosis in HepG2 cells in a dose- and time-dependent manner as well as in rat primary hepatocytes. This effect was not mediated through the death receptor CD95 and the tumor necrosis factor receptors. I

Targeting Metal Ion Homeostasis for Regulated Cell Death-Amplified Tumor Nanomedicine.

Amidst escalating global health challenges, neoplastic diseases remain a predominant cause of morbidity and mortality, exerting complex and far-reaching effects on human health and societal well-being. The advent of precision medicine has ushered in an era of tailored therapeutic strategies, leveraging individual genetic profiles, tumor microenvironmental features, and exogenous factors to redefine oncology care. Central to these advances is the understanding of cell death, a fundamental biological process encompassing both programmed and non-programmed forms. Programmed cell death is orchestr

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… This activates the intrinsic apoptotic pathway. 140 , 141 Ca 2+ -dependent proteases,including calpain,and nucleases are activated, resulting in cytoskeletal protein breakdown and destruction of DNA. … Furthermore, Mn 2+ indirectly activates calpain by boosting intracellular calcium ion levels, which leads to breakdown of cytoskeletal proteins. …

Deep Learning Techniques to Characterize the RPS28P7 Pseudogene and the Metazoa-SRP Gene as Drug Potential Targets in Pancreatic Cancer Patients.

The molecular explanation about why some pancreatic cancer (PaCa) patients die early and others die later is poorly understood. This study aimed to discover potential novel markers and drug targets that could be useful to stratify and extend expected survival in prospective early-death patients. We deployed a deep learning algorithm and analyzed the gene copy number, gene expression, and protein expression data of death versus alive PaCa patients from the GDC cohort. The genes with higher relative amplification (copy number >4 times in the dead compared with the alive group) were EWSR1, FLT3,

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… Calpains are heterodimeric calcium-dependent cysteine proteinases classified as calpains I and II. Both types of calpains share a light (∼30 kDa) regulatory subunit, encoded by the CAPNS1 gene. CAPNS1 is one out of five key prognostic autophagy-related genes in hepatocellular carcinoma [ 33 ]. … Calpain restrains the stem cells compartment in breast cancer Cell Cycle 2016 15 106 116 10.1080/15384101.2015.1121325 26771715 PMC4825769 35. Xavier C.P. Castro I. Caires H.R. Ferreira D. Cavadas B. Pereira L. Santos L.L. Oliveira M.J. Vasconcelos M.H. …

α2-3-sialylated Гликосфинголипиды при нейроинфламмации, иммунитете и запрограммированной смерти клеток: механистические доказательства и регулирование в зависимости от контекста: всеобъемлющий обзор.

α2-3-sialylated glycosphingolids (α2)3-GSLs) являются основными составляющими нейронных мембран и липидных плотов, где они формируют сепарацию рецепторов, комплекс сигналов и связь с клетками. Однако их биологическое воздействие варьируется в зависимости от молекулярного подтипа, типа клеток, стадии заболевания, концентрации и местной микроокружающей среды. В настоящем обзоре обобщены данные о перепончатых изменениях в α2-3-GSL профили и их связи с нейроинфламмацией, иммунной реакцией, протеостазом и запрограммированной клеточной смертностью через болезнь Паркинсона, болезнь Альцгеймера, болез

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… (B) model studies suggest that MAC-associated Ca 2+ influx, calpain activation, and mitochondrial apoptotic signaling may contribute to axonal injury. This framework does not apply to all GBS subtypes and, in particular, cannot be directly generalized to AIDP. … Elevated Ca 2+ can activate calpain ( 157 – 159 ), leading to degradation of axonal cytoskeletal proteins such as neurofilaments ( 154 ). …

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 hypothesis that instead of I-κB stabilization, bortezomib induces I-κB degradation was confirmed by a later study in which I-κB degradation by bortezomib occurred early before induction of apoptosis and could be prevented by calpain inhibitors. … Therefore, in the presence of calpain inhibitors, the apoptosis-inducing activity of bortezomib was dramatically enhanced [ 50 ]. …

Ferroptosis: Frenemy of Radiotherapy.

Recently, it was established that ferroptosis, a type of iron-dependent regulated cell death, plays a prominent role in radiotherapy-triggered cell death. Accordingly, ferroptosis inducers attracted a lot of interest as potential radio-synergizing drugs, ultimately enhancing radioresponses and patient outcomes. Nevertheless, the tumor microenvironment seems to have a major impact on ferroptosis induction. The influence of hypoxic conditions is an area of interest, as it remains the principal hurdle in the field of radiotherapy. In this review, we focus on the implications of hypoxic conditions

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… Another study identified a novel axis activated after RT and involved in ferroptosis induction, namely the PIEZO1/Ca 2+ /calpain/VE-cadherin signaling pathway. Single high dose RT (15 Gy) induced upregulation of PIEZO1, a calcium influx modulator, on lung endothelial cells. … Upregulated levels were linked with increased calcium levels, leading to increased activation of the calcium-dependent calpain, which in turn degraded VE-cadherin, leading to pulmonary endothelial cell ferroptosis. …

Sorcin: a novel potential target in therapies of cancers.

Soluble resistance-related calcium-binding protein (sorcin) is a member of the penta-EF-hand protein family. Sorcin is widely distributed in normal human tissues, such as the brain, heart, lymphocytes, kidneys, breast and skin. Findings suggest that sorcin is associated with the regulation of calcium homeostasis, cell cycle and vesicle trafficking. It has been reported that many types of non-neoplastic diseases such as diabetes, viral infection, infertility, and nervous system diseases were affected by the expression of sorcin. One of the main issues is the role of sorcin in neoplastic disease

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… Due to the existence of the large subunit of calpains, though the N-terminal domain is usually short and flexible, the domain can also be significantly complicated. Human sorcin comprises 198 amino acids and it was reported to be highly similar to hamster sorcin. … A 22-kd protein (sorcin/V19) encoded by an amplified gene in multidrug-resistant cells, is homologous to the calcium-binding light chain of calpain. Embo J . 1986;5(12):3201–3208. doi: 10.1002/embj.1986.5.issue-12 19. Colotti G, Cao Z-H, Wang B, et al. …

Molecular and cellular mechanisms of skeletal muscle atrophy: an update.

Skeletal muscle atrophy is defined as a decrease in muscle mass and it occurs when protein degradation exceeds protein synthesis. Potential triggers of muscle wasting are long-term immobilization, malnutrition, severe burns, aging as well as various serious and often chronic diseases, such as chronic heart failure, obstructive lung disease, renal failure, AIDS, sepsis, immune disorders, cancer, and dystrophies. Interestingly, a cooperation between several pathophysiological factors, including inappropriately adapted anabolic (e.g., growth hormone, insulin-like growth factor 1) and catabolic pr

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… Peptide aldehyde inhibitors such as MG132 can repress certain lysosomal cysteine proteases and calpains, which might explain the total rescue of muscle mass in some studies [ 238 ]. Exercise training—an all-in-one approach? … Smith IJ Lecker SH Hasselgren PO Calpain activity and muscle wasting in sepsis Am J Physiol Endocrinol Metab 2008 295 E762 71 18492780 10.1152/ajpendo.90226.2008 PMC2575901 71. …

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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… In pancreatic cancer, it disrupts iron homeostasis and triggers ferroptosis through direct targeting of calpain-2 ( 43 ). In liver cancer, it induces ferroptosis by targeting TBK1 and sensitizes tumors to the chemotherapy drug sorafenib ( 44 ). … Tiliroside disrupted iron homeostasis and induced ferroptosis via directly targeting calpain-2 in pancreatic cancer cells . Phytomed: Int J Phytother Phytopharmacol . ( 2024 ) 127 : 155392 . doi: 10.1016/j.phymed.2024.155392 , PMID: 38412575 44 Yang C Lu T Liu M Yuan X Li D Zhang J . …

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… Distinct roles for calpain and caspases. 276 6 7 11 2000 4270 4275 J Biol Chem 11069922 10.1074/jbc.M008972200 Greco O. Folkes L. K. Wardman P. Tozer G. M. Dachs G. U. …

Свойства антиракера ВИЧ-ингибатора Нелфинавира.

Традиционные методы лечения рака могут потерять свою эффективность после появления новых мутации или развития химиотерапии. Несвоевременная диагностика, высокая стоимость лечения и потребность в высокоэффективной инфраструктуре для лечения раковых заболеваний затрудняют доступ к надлежащему лечению в условиях с низким уровнем доходов и ограниченными ресурсами. Переориентация утвержденных лекарственных средств на лечение рака может привести к снижению стоимости и сокращению сроков разработки новых лекарственных средств и к ускорению появления новых и эффективных вариантов лечения для нуждающихс

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… The authors further observed a decrease in the level of calpain activity following nelfinavir treatment in MM cells [ 81 ]. Calpains are Ca 2+ -dependent cysteine proteases involved in the cleavage of cytoskeletal proteins, signal transducers, and membrane receptors [ 82 ]. … Calpain deficiency has been shown to be involved in impaired autophagy and activation of the apoptotic switch [ 82 ], which was suggested to be a reason for the synergistic lethal interaction between bortezomib and nelfinavir in MM cells [ 81 ]. …

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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… In 1997, Michael et al 2 extracted proteasome 20S crystals from yeast, and they found that calpain inhibitors I with acetyl-Leu-Leu-norleucinal sites can covalently bind to Thr-1, the side chains of calpain inhibitors I project to several amino acids at the ends of β1, β2, and β5 to form pocket-like … Calpain inhibitors I can bind to several amino acids at the ends of β1, β2, and β5. Fig. 1 The proteasome 20S is just like a garbage can, which can bind to different subunits to perform different catalytic functions. …

Доклиническая оценка клеток DC-CCK как потенциально эффективной иммунотерапии для лечения глиобластомы.

Несмотря на благоприятное воздействие иммунотерапии на различные виды раковых заболеваний, ее полный успех в борьбе с вредителями CNS по-прежнему сопряжен с трудностями. Недавно в результате успешного клинического испытания клеточной иммунотерапии, вызванной цитокинами, у пациентов с глиобластомой (ГБМ) открылась новая возможность для иммунотерапии с использованием клеточной селекции в малиньях CNS. На основе этих выводов мы изучили вопрос о том, могут ли дендритные клетки (DC) в сочетании с цитокиновыми клетками-убийцами (DC-CCK) также обеспечить альтернативный и более эффективный способ повы

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… Masilamani AP Calpain-mediated cleavage generates a ZBTB18 N-terminal product that regulates HIF1A signaling and glioblastoma metabolism iScience 2022 25 104625 10.1016/j.isci.2022.104625 35800763 PMC9253709 Masilamani, A. P. et al. … Calpain-mediated cleavage generates a ZBTB18 N-terminal product that regulates HIF1A signaling and glioblastoma metabolism. iScience 25 , 104625 (2022). 35800763 10.1016/j.isci.2022.104625 PMC9253709 27. …

A Narrative Review on the Antitumoral Effects of Selected Mediterranean Plant Products from Southern Italy.

Natural products are a valuable source of bioactive compounds with established roles in oncology. Their structural diversity and ability to target multiple cancer-related pathways make them promising candidates for anticancer drug development. Increasing preclinical and clinical data highlight their potential not only to exert direct antitumor effects but also to enhance patient tolerance to conventional therapies by reducing side effects and improving treatment adherence. The Mediterranean region, known for its biodiversity and traditional dietary habits, provides a rich array of natural comp

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… Notably, it (50 µM) activates the E2F4 pathway in small cell lung cancer (NSCLC) [ 153 ], promotes mutant p53 degradation via autophagy (IC 50 of 200 μM) [ 154 ], and triggers apoptosis through the TRPV6-calcium-calpain axis [ 155 ]. … In SCLC, this compound potentiated camptothecin-induced apoptosis through intracellular Ca 2+ elevation and calpain activation [ 177 ]. …

Bortezomib (PS-341) treatment decreases inflammation and partially rescues the expression of the dystrophin-glycoprotein complex in GRMD dogs.

Golden retriever muscular dystrophy (GRMD) is a genetic myopathy corresponding to Duchenne muscular dystrophy (DMD) in humans. Muscle atrophy is known to be associated with degradation of the dystrophin-glycoprotein complex (DGC) via the ubiquitin-proteasome pathway. In the present study, we investigated the effect of bortezomib treatment on the muscle fibers of GRMD dogs. Five GRMD dogs were examined; two were treated (TD- Treated dogs) with the proteasome inhibitor bortezomib, and three were control dogs (CD). Dogs were treated with bortezomib using the same treatment regimen used for multip

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… The recent literature has shown a diversity of expression and activities for the ubiquitin-proteasome and calpain systems in GRMD muscle, leading to unexpected consequences such as heart-related cardiomyocyte lesions in response to pharmacological inhibition [51] . … Wadosky KM, Li L, Rodríguez JE, Min JN, Bogan D, et al. (2011) Regulation of the calpain and ubiquitin-proteasome systems in a canine model of muscular dystrophy.Muscle Nerve. 44: 553–62. 52. …

Effect of the specific proteasome inhibitor bortezomib on cancer-related muscle wasting.

BACKGROUND: Muscle wasting, a prominent feature of cancer cachexia, is mainly caused by sustained protein hypercatabolism. The enhanced muscle protein degradation rates rely on the activity of different proteolytic systems, although the Adenosine triphosphate (ATP)-ubiquitin-proteasome-dependent pathway and autophagy have been shown to play a pivotal role. Bortezomib is a potent reversible and selective proteasome and NF-κB inhibitor approved for the clinical use, which has been shown to be effective in preventing muscle wasting in different catabolic conditions. The aim of the present study h

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… Indeed, enhanced muscle protein breakdown in cancer cachexia has been demonstrated to depend on the activity of different degradative mechanisms besides proteasome, such as the autophagic‐lysosomal pathway and the calcium‐dependent proteases (calpains). 58 , 59 Moreover, inhibition of a degradative … study, treatment with a different proteasome inhibitor, namely MG132, has been reported to attenuate body weight loss and muscle depletion in mice bearing the C26 colon adenocarcinoma. 62 Such a discrepancy could rely on the fact that MG132 does not just inhibit proteasome, but also cathepsins and calpains …

Revitalizing Cancer Treatment: Exploring the Role of Drug Repurposing.

Cancer persists as a global challenge necessitating continual innovation in treatment strategies. Despite significant advancements in comprehending the disease, cancer remains a leading cause of mortality worldwide, exerting substantial economic burdens on healthcare systems and societies. The emergence of drug resistance further complicates therapeutic efficacy, underscoring the urgent need for alternative approaches. Drug repurposing, characterized by the utilization of existing drugs for novel clinical applications, emerges as a promising avenue for addressing these challenges. Repurposed d

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… Kim et al. demonstrated that the complex of Cu and DSF effectively reduced the invasion and migration of MDA-MB-231 cells by decreasing focal adhesions, promoting vimentin degradation, and activating calpain. … Additionally, in a xenograft model, the complex exhibited a reduction in the growth of established tumors and their localization in the lungs through calpain activation [ 47 ]. …

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

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… Preventing the autophagic survival response by inhibition of calpain enhances the cytotoxic activity of bortezomib in vitro and in vivo Cancer Chemother. Pharmacol. 2013 71 1567 1576 10.1007/s00280-013-2156-3 23572175 PMC3669633 28. Vogl D.T. Stadtmauer E.A. Tan K.S. Heitjan D.F. Davis L.E. … Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis Nat. Cell Biol. 2006 8 1124 1132 10.1038/ncb1482 16998475 71. Heuck C.J. Mehta J. Bhagat T. Gundabolu K. Yu Y. Khan S. Chrysofakis G. Schinke C. Tariman J. Vickrey E. …

Pleiotropic Effects of Modified Citrus Pectin.

Modified citrus pectin (MCP) has a low-molecular-weight degree of esterification to allow absorption from the small intestinal epithelium into the circulation. MCP produces pleiotropic effects, including but not limited to its antagonism of galectin-3, which have shown benefit in preclinical and clinical models. Regarding cancer, MCP modulates several rate-limiting steps of the metastatic cascade. MCP can also affect cancer cell resistance to chemotherapy. Regarding fibrotic diseases, MCP modulates many of the steps involved in the pathogenesis of aortic stenosis. MCP also reduces fibrosis to

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… GCS-100 enhanced calpain activation, which reduced the proapoptotic effect of Gal-3 [ 105 ]. Another Gal-3 inhibitor in pharmaceutical development is an inhalable formulation called TD139, a thiodigalactoside derivative. … Calpain activation through galectin-3 inhibition sensitizes prostate cancer cells to cisplatin treatment Cell Death Dis. 2010 1 e101 10.1038/cddis.2010.79 21368866 PMC3032324 106. Volarevic V. Markovic B.S. Bojic S. Stojanovic M. Nilsson U. Leffler H. Besra G.S. Arsenijevic N. Paunovic V. …