Proteosome

Neurodegenerative diseases (NDDs) encompass a range of conditions characterized by the specific dysfunction and continual decline of neurons, glial cells, and neural networks within the brain and spinal cord. The majority of NDDs exhibit similar underlying causes, including oxidative stress, neuroinflammation, and malfunctioning of mitochondria. Elevated levels of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), alongside decreased expression of brain-derived neurotrophic factor (BDNF) and glutamate transporter subtype 1 (GLT-1), constitute significant factors contributing to the pathogenesis of NDDs...

Multiple Myeloma is an incurable plasma cell malignancy with a poor survival rate that is usually treated with immunomodulatory drugs (iMiDs) and proteosome inhibitors (PIs). The malignant plasma cells quickly become resistant to these agents causing relapse and uncontrolled growth of resistant clones. From whole genome sequencing (WGS) and RNA sequencing (RNA-seq) studies, different high-risk translocation, copy number, mutational, and transcriptional markers can be identified. One of these markers, PHF19, epigenetically regulates cell cycle and other processes and is already studied using RNA-seq...

Background Human males and females show differences in the incidence of neutrophil-associated diseases such as systemic lupus erythematosus, rheumatoid arthritis, and reactive arthritis, and differences in neutrophil physiological responses such as a faster response to the chemorepellent SLIGKV. Little is known about the basis of sex-based differences in human neutrophils. Methods Starting with human neutrophils from healthy donors, we used RNA-seq to examine total mRNA profiles, mRNAs not associated with ribosomes and thus not being translated, mRNAs in monosomes, and mRNAs in polysomes and thus heavily translated...

Y-box binding protein-1 (YB-1) is a proto-oncogenic protein associated with protein translation regulation. It plays a crucial role in the development and progression of triple-negative breast cancer (TNBC). In this study, we describe a promising approach to inhibit YB-1 using SU056, a small-molecule inhibitor. SU056 physically interacts with YB-1 and reduces its expression, which helps to restrain the progression of TNBC. Proteome profiling analysis indicates that the inhibition of YB-1 by SU056 can alter the proteins that regulate protein translation, an essential process for cancer cell growth...

The unique prolyl isomerase Pin1 binds to and catalyzes cis-trans conformational changes of specific Ser/Thr-Pro motifs after phosphorylation, thereby playing a pivotal role in regulating the structure and function of its protein substrates. In particular, Pin1 activity regulates the affinity of a substrate for E3 ubiquitin ligases, thereby modulating the turnover of a subset of proteins and coordinating their activities after phosphorylation in both physiological and disease states. In this review, we highlight recent advancements in Pin1-regulated ubiquitination in the context of cancer and neurodegenerative disease...

INTRODUCTION: ALS is a fatal neurodegenerative disease for which underlying mechanisms are incompletely understood. The motor neuron is a central player in ALS pathogenesis but different transcriptome signatures have been derived from bulk analysis of post-mortem tissue and iPSC-derived motor neurons (iPSC-MNs). METHODS: This study performed a meta-analysis of six gene expression studies (microarray and RNA-seq) in which laser capture microdissection (LCM) was used to isolate lower motor neurons from post-mortem spinal cords of ALS and control (CTL) subjects...

A systems analysis was conducted to determine the potential molecular mechanisms underlying differential immunogenicity and protective efficacy results of a clinical trial of the radiation-attenuated whole sporozoite PfSPZ Vaccine in African infants. Innate immune activation and myeloid signatures at pre-vaccination baseline correlated with protection from Pf parasitemia in placebo controls. These same signatures were associated with susceptibility to parasitemia among infants who received the highest and most protective PfSPZ Vaccine dose...

Multiple myeloma (MM) is an incurable hematological disease characterized by the uncontrolled growth of plasma cells primarily in the bone marrow. Although its treatment consists of the administration of combined therapy regimens mainly based on immunomodulators and proteosome inhibitors, MM remains incurable, and most patients suffer from relapsed/refractory disease with poor prognosis and survival. The robust results achieved by immunotherapy targeting MM-associated antigens CD38 and CD319 (also known as SLAMF7) have drawn attention to the development of new immune-based strategies and different innovative compounds in the treatment of MM, including new monoclonal antibodies, antibody-drug conjugates, recombinant proteins, synthetic peptides, and adaptive cellular therapies...

DNA methylation is one of the most important epigenetic mark involved in many physiologic cellular processes and pathologies. During mitosis, the transmission of DNA methylation patterns from a mother to the daughter cells is ensured through the action of the Ubiquitin-like, containing PHD and RING domains, 1/DNA methyltransferase 1 (UHRF1/DNMT1) tandem. UHRF1 is involved in the silencing of many tumor suppressor genes (TSGs) via mechanisms that remain largely to be deciphered. The present study investigated the role and the regulation of UHRF1 poly-ubiquitination induced by thymoquinone, a natural anti-cancer drug, known to enhance or re-activate the expression of TSGs...

Developing prognostic tools specifically for patients themselves represents an important step in empowering patients to engage in shared decision-making. Incorporating patient-reported outcomes may improve the accuracy of these prognostic tools. We conducted a retrospective population-based study of transplant-ineligible (TIE) patients with multiple myeloma (MM) diagnosed between January 2007 and December 2018. A multivariable Cox regression model was developed to predict the risk of death within 1-year period from the index date...

Bridged PROTAC is a novel protein complex degrader strategy that exploits the target protein's binding partner to degrade undruggable proteins by inducing proximity to an E3 ubiquitin ligase. In this study, we discovered for the first time that cereblon (CRBN) can be employed for the bridged PROTAC approach and report the first-in-class CRBN-recruiting and EED-binding polycomb repressive complex 1 (PRC1) degrader, compound 1 (MS181). We show that 1 induces preferential degradation of PRC1 components, BMI1 and RING1B, in an EED-, CRBN-, and ubiquitin-proteosome system (UPS)-dependent manner...

Chimeric antigen receptor T-cell (CAR-T) therapy for the treatment of multiple myeloma (MM) has fundamentally changed the relapsed and refractory therapeutic landscape, but the disease remains incurable. Two CAR-T products, idecabtagene vicleucel (ide-cel; Abecma) and ciltacabtagene autoleucel (cilta-cel, Carvykti), have been FDA- and EMA-approved for the treatment of relapsed/refractory MM (RRMM); both target B-cell maturation antigen (BCMA), a surface glycoprotein highly expressed on MM cells. Despite deep and durable responses following CAR-T therapy, most patients will need subsequent treatment, and the optimal next-line therapy is presently unclear...

The mammalian SUMO-targeted E3 Ubiquitin Ligase, Rnf4, has been reported to act as a regulator of DNA repair, but the importance of RNF4 as a tumor suppressor has not been tested. Using a conditional-knockout mouse model, we deleted Rnf4 in the B cell lineage to test the importance of RNF4 for growth of somatic cells. Although Rnf4 conditional-knockout B cells exhibited substantial genomic instability, Rnf4 deletion caused no increase in tumor susceptibility. In contrast, Rnf4 deletion extended the healthy lifespan of mice expressing an oncogenic c-myc transgene...

Skeletal muscle wasting results from numerous pathological conditions impacting both the musculoskeletal and nervous systems. A unifying feature of these pathologies is the upregulation of members of the E3 ubiquitin ligase family, resulting in increased proteolytic degradation of target proteins. Despite the critical role E3 ubiquitin ligases in regulating muscle mass, the specific proteins they target for degradation and the mechanisms by which they regulate skeletal muscle homeostasis remain ill-defined...

Nonalcoholic fatty liver disease (NAFLD) prevalence is rising globally with no pharmacotherapies approved. Hepatic steatosis is closely associated with progression and prognosis of NAFLD. Dapagliflozin, kind of sodium-glucose cotransporter 2 (SGLT2) inhibitor, was found to improve NAFLD in clinical trials, while the underlying mechanism remains poorly elucidated. Here, we reported that dapagliflozin effectively mitigated liver injury and relieved lipid metabolism disorders in vivo. Further investigation showed that dapagliflozin markedly suppressed Liver X Receptor α (LXRα)-mediated synthesis of de novo lipids and bile acids (BAs)...

Candesartan is a common angiotensin-II receptor-1 blocker used for patients with cardiovascular and renal diseases. Angiotensin-converting enzyme 2 (ACE2) is a negative regulator of blood pressure (BP), and also a major receptor for coronaviruses. To determine whether and how candesartan upregulates ACE2, we examined BP and ACE2 in multi-organs from male and female C57BL/6J mice treated with candesartan (1 mg/kg, i.p.) for 7 days. Relative to the vehicle, candesartan lowered BP more in males than females; ACE2 protein abundances were increased in kidneys, not lungs, hearts, aorta, liver, spleen, brain, or serum, only from males...

It has been reported that muscle functional unloading is accompanied by an increase in motoneuronal excitability despite the elimination of afferent input. Thus, we hypothesized that pharmacological potentiation of spontaneous contractile soleus muscle activity during hindlimb unloading could activate anabolic signaling pathways and prevent the loss of muscle mass and strength. To investigate these aspects and underlying molecular mechanisms, we used β-myosin allosteric effector Omecamtiv Mekarbil (OM)...

Early embryonic mortality resulting from insufficient interaction between the embryo and the uterus leads to the failure of pregnancy in livestock animals. Thus, it is imperative to comprehend the multifaceted process of implantation at molecular levels, which requires synchronized feto-maternal interaction. The in-vitro models serve as valuable tools to investigate the specific stages of implantation. The present study was undertaken to develop a simple method to isolate and culture the primary buffalo endometrial epithelial cells (pBuEECs), followed by proteome profiling of the proliferating cells...

Androgen receptor (AR) splice variant 7 (AR-V7) is capable to enter nucleus and activate downstream signaling without ligand. AR-V7 assists the tumor growth, cancer metastasis, cancer stemness, and the evolvement of therapy-resistant prostate cancer (PCa). We discovered that caffeic acid phenethyl ester (CAPE) can repress the expression and downstream signaling of AR-V7 in PCa cells. CAPE blocked the gene transcription, nuclear localization, and protein abundance of AR-V7. CAPE inhibited the expression of U2AF65, SF2 and hnRNPF, which were splicing factors for AR-V7 intron...

The clinical features and pathophysiology of neuropsychiatric symptoms (NPSs) in dementia have been extensively studied. However, the genetic architecture and underlying neurobiological mechanisms of NPSs at preclinical stages of cognitive decline and Alzheimer's disease (AD) remain largely unknown. Mild behavioral impairment (MBI) represents an at-risk state for incident cognitive impairment and is defined by the emergence of persistent NPSs among non-demented individuals in later life. These NPSs include affective dysregulation, decreased motivation, impulse dyscontrol, abnormal perception and thought content, and social inappropriateness...