The current scientific literature has extensively explored the potential role of proteasome inhibitors (PIs) in the NF-κB pathway of leukemia and lymphoma. The ubiquitin-proteasome system (UPS) is a critical component in regulating protein degradation in eukaryotic cells. PIs, such as BTZ, are used to target the 26S proteasome in hematologic malignancies, resulting in the prevention of the degradation of tumor suppressor proteins, the activation of intrinsic mitochondrial-dependent cell death, and the inhibition of the NF-κB signaling pathway. NF-κB is a transcription factor that plays a critical role in the regulation of apoptosis, cell proliferation, differentiation, inflammation, angiogenesis, and tumor migration. Despite the successful use of PIs in various hematologic malignancies, there are limitations such as resistant to these inhibitors. Some reports suggest that PIs can induce NF-κB activation, which increases the survival of malignant cells. This article discusses the various aspects of PIs\' effects on the NF-κB pathway and their limitations. Video Abstract.

Ubiquitin and similar proteins, such as SUMO, are utilized by plants to modify target proteins to rapidly change their stability and activity in cells. This review will provide an overview of these crucial protein interactions with a focus on ubiquitylation and sumoylation in plants and how they contribute to stress tolerance. The work will also explore possibilities to use these highly conserved pathways for novel approaches to generate more robust crop plants better fit to cope with abiotic and biotic stress situations.

Cytidine 5\'-diphosphocholine has been widely studied in systemic neurodegenerative diseases, like Alzheimer\'s disease, Parkinson\'s disease, and brain ischemia. The rationale for the use of citicoline in ophthalmological neurodegenerative diseases, including glaucoma, anterior ischemic optic neuropathy, and diabetic retinopathy, is founded on its multifactorial mechanism of action and the involvement in several metabolic pathways, including phospholipid homeostasis, mitochondrial dynamics, as well as cholinergic and dopaminergic transmission, all being involved in the complexity of the visual transmission. This narrative review is aimed at reporting both pre-clinical data regarding the involvement of citicoline in such metabolic pathways (including new insights about its role in the intracellular proteostasis through an interaction with the proteasome) and its effects on clinical psychophysical, electrophysiological, and morphological outcomes following its use in ophthalmological neurodegenerative diseases (including the results of the most recent prospective randomized clinical trials).

Leishmaniasis, a complex disease caused by at least 20 species of unicellular parasites of the genus Leishmania, disproportionately affects impoverished regions of about 90 tropical and sub-tropical countries. Currently available antileishmanial therapies, particularly for visceral leishmaniasis, are severely limited, with treatment outcome depending on many factors, including the immune status of the patient, comorbidities, malnutrition, and socio-economic conditions in the patient\'s geographic location. There is an urgent need for new therapeutics, particularly new effective oral drugs, for visceral leishmaniasis. Despite the availability of the Leishmania genome sequence information and significant research into the biology of the parasites, antileishmanial drug development is hampered by the lack of knowledge about druggable targets in the parasite and difficulties in identifying the molecular targets of compounds that show activity. In this context, we analyzed recent progress in antileishmanial drug development programs, which take advantage of different powerful approaches, such as high-throughput screening of compound libraries, recent developments in genetic methods for assessing essentiality of parasite genes, and chemical, genetic, and proteomics-based target discovery and target validation methods.

The initiation and progression of cancer is dependent on the acquisition of mutations in oncogenes or tumor suppressor genes that ultimately leads to the dysregulation of key regulatory pathways. Though these mutations often occur in direct regulators of such pathways, some may confer tumorigenic potential by indirectly targeting several pathways congruently thereby exerting pleiotropic effects. In recent years, the tumor suppressor gene Speckle Type POZ Protein (SPOP) has gained a lot of attention as it has been found to be altered in a variety of different cancers. SPOP appears to exert pleiotropic tumorigenic effects as multiple different regulatory pathways become dysregulated upon SPOP alterations. SPOP has been identified as an E3 ubiquitin ligase substrate binding subunit of the proteasome complex. Since protein degradation is critical in regulating proper cellular function it is not surprising that the proteasome pathway is often found to be disrupted in cancer. Many studies have now indicated that mutations or changes in the expression of SPOP are one of several underlying reasons of proteasome pathway disruption in different cancers. Ultimately, either SPOP downregulation or mutation promotes stabilization of direct SPOP targets which subsequently promotes cancer through the dysregulation of key regulatory pathways. In this review, we will discuss the current literature on cancer-specific SPOP alterations as well the SPOP targets that are stabilized, and the pathways that are dysregulated, as a result.

Protease inhibitors (PIs) inhibit HIV‑1 and HIV‑2 proteases, impeding virus replication and liberation of viral elements from infected cells. In human immunodeficiency virus (HIV) subjects receiving PI‑based treatment, an impressive decrease in the amount of HIV‑associated cancers, unconnected to viral burden or CD4 amount was observed. Research has reported that PIs have influence on cancer proliferation, spread, and survival as an effect on endoplasmic reticulum stress, proteasome, NF‑κB and Akt signalling. Nelfinavir (NFV) is a nonpeptidic PI that functions by connecting to the catalytic site of the HIV protease, thus stopping the cleavage of viral polyprotein into complete, operative proteins that are fundamental for viral survival. NFV, currently not frequently employed for antiretroviral treatment, has demonstrated noteworthy off target effects in tumor patients with or without HIV disease. NFV appears to cause cell death in tumor cells by different mechanisms, which include necrosis, apoptosis and autophagy. In this review, data from preclinical research and clinical trials are reported and the mechanisms of action of NFV and their results in the treatment of hematologic malignancies, such as acute myeloid leukemia, chronic lymphoid leukemia, and diffuse large B cell lymphoma, and especially in patients with multiple myeloma are examined. In the future, experimental studies may help identify the role of NFV in cancer treatment and may promote the application of this drug into daily clinical practice.

Despite significant advances in cancer diagnostics and therapeutics the majority of cancer unfortunately remains incurable, which has led to continued research to better understand its exceptionally diverse biology. As a result of genomic instability, cancer cells typically have elevated proteotoxic stress. Recent appreciation of this functional link between the two secondary hallmarks of cancer: aneuploidy (oxidative stress) and proteotoxic stress, has therefore led to the development of new anticancer therapies targeting this emerging \"Achilles heel\" of malignancy. This review highlights the importance of managing proteotoxic stress for cancer cell survival and provides an overview of the integral role proteostasis pathways play in the maintenance of protein homeostasis. We further review the efforts undertaken to exploit proteotoxic stress in multiple myeloma (as an example of a hematologic malignancy) and triple negative breast cancer (as an example of a solid tumor), and give examples of: (1) FDA-approved therapies in routine clinical use; and (2) promising therapies currently in clinical trials. Finally, we provide new insights gleaned from the use of emerging technologies to disrupt the protein secretory pathway and repurpose E3 ligases to achieve targeted protein degradation.

Maintenance of genome integrity under the stressed condition is paramount for normal functioning of cells in the multicellular organisms. Cells are programmed to protect their genome through specialized adaptive mechanisms which will help decide their fate under stressed conditions. These mechanisms are the outcome of activation of the intricate circuitries that are regulated by the p53 master protein. In this paper, we provided a comprehensive review on p53, p53 homologues and their isoforms, including a description about the ubiquitin-proteasome system emphasizing its role in p53 regulation. p53 induced E3(Ub)-ligases are an integral part of the ubiquitin-proteasome system. This review outlines the roles of important E3(Ub)-ligases and their splice variants in maintaining cellular p53 protein homeostasis. It also covers up-to-date and relevant information on small molecule Mdm2 inhibitors originated from different organizations. The review ends with a discussion on future prospects and investigation directives for the development of next-generation modulators as p53 therapeutics.

The ubiquitin-proteasome system is responsible for maintaining protein homeostasis and regulating a variety of cellular processes. The constitutive proteasome is expressed in all cells while the immunoproteasome (IP) is predominantly found in cells of hematopoietic origin. In other cells, the expression of IP can be induced under the influence of cytokines released by T cells during acute immune and stress responses. Inhibitors of IP are of significant interest, because it is expected that selective inhibition of the IP would cause fewer adverse effects.
There is a considerable interest on patenting IP-specific inhibitors. Relevant patents and patent applications disclosing IP inhibitors are summarized and divided into two parts according to the chemical characteristics of compounds. We also briefly report on the biochemical methods used in the patents to profile the characteristics of IP inhibitors.
Several selective inhibitors of IP with a promising ability to address autoimmune and inflammatory diseases are being developed. Peptidic compounds are prevalent and the most advanced IP-selective compounds to date, ONX-0914 and KZR-616, are tripeptide epoxyketone-based molecules. However, some patents disclose that IP-selective inhibition is possible with compounds possessing non-peptidic scaffolds indicating countless possibilities to address inhibition of IP in the future.

New therapies, including daratumumab plus lenalidomide plus dexamethasone (DRd) and daratumumab plus bortezomib plus dexamethasone (DVd), have recently been approved in the United States for patients with multiple myeloma (MM) who have received at least 1 prior line of therapy. However, few treatments have been compared in head-to-head clinical trials to determine the most efficacious therapy. In an update of the POLLUX (Phase 3 Study Comparing DRd Versus Rd in Subjects with Relapsed or Refractory Multiple Myeloma [RRMM]) trial, median progression-free survival (PFS) for DRd was not reached; the hazard ratio compared with Rd was 0.41. In an update of the CASTOR (Phase 3 Study Comparing DVd Versus Vd in Subjects with RRMM) trial, median PFS for DVd was 16.7 months, compared with 7.1 months for Vd with a PFS hazard ratio of 0.31. A systematic literature review and network meta-analysis (NMA) was performed to estimate the relative efficacy of treatments for previously treated patients with MM.
A systematic search of MEDLINE, EMBASE, BioSciences Information Service, and the Cochrane Library databases was conducted from initiation to September 2016. Abstracts published by international congresses (2014-2016) and bibliographies of pertinent systematic reviews and meta-analyses were also searched. Eligible studies consisted of randomized controlled trials (RCTs) or long-term follow-up studies with >1 treatment arm assessing the efficacy or safety of MM therapies. An NMA was conducted by using Bayesian fixed effect mixed-treatment comparisons. Outcomes considered were hazard ratios for PFS and odds ratios for overall response rate (ORR).
In total, 108 articles reporting 27 RCTs were included in the NMA. Data formed 2 evidence networks: RCTs with DRd and RCTs with DVd. Primary analysis of PFS found that DRd and DVd had a higher probability of being the best treatments (probability, 0.997 and 0.999, respectively) and had the lowest risk of progression or death than other treatments approved by the US Food and Drug Administration for the treatment of MM. Results from sensitivity analyses using time to progression as a proxy for missing PFS data were consistent. DRd and DVd also showed improved ORR compared with other treatments. Subgroup analyses of PFS in patients treated with only 1 prior therapy were like the results of the primary analyses.
This NMA provides comparative efficacy for MM treatments not studied in head-to-head RCTs. The NMA suggests that, compared with other approved MM treatments in the United States, DRd and DVd have a higher probability of providing the longest PFS in patients who have received at least 1 prior therapy and in patients who have received only 1 prior therapy.