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Molecular Pharmaceutics Nov 2020Many autoimmune therapies focus on immune suppression to reduce symptom severity and halt disease progression; however, currently approved treatments lack specificity...
Many autoimmune therapies focus on immune suppression to reduce symptom severity and halt disease progression; however, currently approved treatments lack specificity for the autoantigen and rely on more global immune suppression. Multivalent antigen arrays can disarm pathogenic autoimmune B cell populations that specifically recognize the antigen of interest via their B cell receptor (BCR). Disarmament may be achieved by BCR engagement, cross-linking, and sustained receptor occupancy as a result of multivalent, high avidity BCR binding. To engage and explore this mechanism, a tetramer display of the encephalogenic proteolipid peptide (PLP), referred to as 4-arm PLP, was synthesized by copper-catalyzed azide-alkyne cycloaddition chemistry. Subcutaneous administration of 4-arm PLP completely ameliorated symptoms of paralysis in a mouse model of multiple sclerosis known as experimental autoimmune encephalomyelitis. Competitive binding of 4-arm PLP to PLP-specific IgG in the mouse serum demonstrated the enhanced avidity associated with the multivalent array compared to the free peptide. Furthermore, key PLP-reactive B cells were depleted following 4-arm PLP treatment, resulting in significant reduction of proinflammatory cytokines. Together, these data demonstrate the potential of 4-arm PLP to silence autoreactive B cell populations and limit the downstream activation of effector cells.
Topics: Administration, Topical; Animals; Autoantigens; B-Lymphocytes; Encephalomyelitis, Autoimmune, Experimental; Female; Immune Tolerance; Immunoglobulin G; Immunotherapy; Mice; Multiple Sclerosis; Myelin Proteolipid Protein; Paralysis; Peptide Fragments; Receptors, Antigen, B-Cell; Treatment Outcome
PubMed: 32903002
DOI: 10.1021/acs.molpharmaceut.0c00665 -
Microbiology Spectrum Sep 2021Candida albicans is a prevalent opportunistic human fungal pathogen for which treatment is limited to only four main classes of antifungal drugs, with the azole and...
Candida albicans is a prevalent opportunistic human fungal pathogen for which treatment is limited to only four main classes of antifungal drugs, with the azole and echinocandin classes being used most frequently. Drug tolerance, the ability of some cells to grow slowly in supra-MIC drug concentrations, decreases the number of available treatment options. Here, we investigated factors affecting tolerance and resistance to ketoconazole in C. albicans. We found both temperature and the composition of growth medium significantly affected tolerance with little effect on resistance. In deletion analysis of known efflux pump genes, was partially required for azole tolerance, while and were dispensable. Tolerance also required Hsp90 and calcineurin components; , which encodes a transcription factor downstream of calcineurin, was required only partially. Deletion of , which encodes a vacuolar ATPase subunit, and concanamycin A, a V-ATPase inhibitor, abolished tolerance, indicating the importance of vacuolar energy transactions in tolerance. Thus, tolerance to ketoconazole is regulated by multiple factors, including physiological and genetic mechanisms. Due to the ever-expanding range of invasive medical procedures and treatments, invasive fungal infections now pose a serious global threat to many people living in an immunocompromised status. Like humans, fungi are eukaryotic, which significantly limits the number of unique antifungal targets; the current arsenal of antifungal agents is limited to just three frontline drug classes. Additional treatment complexities result from the development of drug tolerance and resistance, which further narrows therapeutic options; however, the difference between tolerance and resistance remains largely unknown. This study demonstrates that tolerance and resistance are regulated by multiple genetic and physiological factors. It is prudent to note that some factors affect tolerance only, while other factors affect both tolerance and resistance. The complex underlying mechanisms of these drug responses are highlighted by the fact that there are both shared and distinct mechanisms that regulate tolerance and resistance.
Topics: ATP Binding Cassette Transporter, Subfamily B; Antifungal Agents; Candida albicans; Candidiasis; Drug Resistance, Fungal; Drug Tolerance; Fungal Proteins; HSP90 Heat-Shock Proteins; Humans; Ketoconazole; Membrane Transport Proteins; Microbial Sensitivity Tests; Nerve Tissue Proteins; Proteolipids; Proton-Translocating ATPases; Temperature
PubMed: 34160280
DOI: 10.1128/Spectrum.00321-21 -
JCI Insight Apr 2024Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease associated with cardiomyopathy. DMD cardiomyopathy is characterized by abnormal intracellular...
Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease associated with cardiomyopathy. DMD cardiomyopathy is characterized by abnormal intracellular Ca2+ homeostasis and mitochondrial dysfunction. We used dystrophin and utrophin double-knockout (mdx:utrn-/-) mice in a sarcolipin (SLN) heterozygous-knockout (sln+/-) background to examine the effect of SLN reduction on mitochondrial function in the dystrophic myocardium. Germline reduction of SLN expression in mdx:utrn-/- mice improved cardiac sarco/endoplasmic reticulum (SR) Ca2+ cycling, reduced cardiac fibrosis, and improved cardiac function. At the cellular level, reducing SLN expression prevented mitochondrial Ca2+ overload, reduced mitochondrial membrane potential loss, and improved mitochondrial function. Transmission electron microscopy of myocardial tissues and proteomic analysis of mitochondria-associated membranes showed that reducing SLN expression improved mitochondrial structure and SR-mitochondria interactions in dystrophic cardiomyocytes. These findings indicate that SLN upregulation plays a substantial role in the pathogenesis of cardiomyopathy and that reducing SLN expression has clinical implications in the treatment of DMD cardiomyopathy.
Topics: Animals; Male; Mice; Calcium; Cardiomyopathies; Disease Models, Animal; Dystrophin; Mice, Inbred mdx; Mice, Knockout; Mitochondria, Heart; Muscle Proteins; Muscular Dystrophy, Duchenne; Myocardium; Myocytes, Cardiac; Proteolipids; Utrophin
PubMed: 38564291
DOI: 10.1172/jci.insight.170185 -
Journal of Molecular and Cellular... Feb 2016In muscle, the Sarco(Endo)plasmic Reticulum Calcium ATPase (SERCA) activity is regulated by two distinct proteins, PLB and SLN, which are highly conserved throughout... (Review)
Review
In muscle, the Sarco(Endo)plasmic Reticulum Calcium ATPase (SERCA) activity is regulated by two distinct proteins, PLB and SLN, which are highly conserved throughout vertebrate evolution. PLB is predominantly expressed in the cardiac muscle, while SLN is abundant in skeletal muscle. SLN is also found in the cardiac atria and to a lesser extent in the ventricle. PLB regulation of SERCA is central to cardiac function, both at rest and during extreme physiological demand. Compared to PLB, the physiological relevance of SLN remained a mystery until recently and some even thought it was redundant in function. Studies on SLN suggest that it is an uncoupler of the SERCA pump activity and can increase ATP hydrolysis resulting in heat production. Using genetically engineered mouse models for SLN and PLB, we showed that SLN, not PLB, is required for muscle-based thermogenesis. However, the mechanism of how SLN binding to SERCA results in uncoupling SERCA Ca(2+) transport from its ATPase activity remains unclear. In this review, we discuss recent advances in understanding how PLB and SLN differ in their interaction with SERCA. We will also explore whether structural differences in the cytosolic domain of PLB and SLN are the basis for their unique function and physiological roles in cardiac and skeletal muscle.
Topics: Adenosine Triphosphate; Animals; Calcium; Calcium-Binding Proteins; Gene Expression; Humans; Ion Transport; Mice; Muscle Proteins; Muscle, Skeletal; Myocardium; Protein Structure, Secondary; Protein Structure, Tertiary; Proteolipids; Sarcoplasmic Reticulum; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Thermogenesis
PubMed: 26743715
DOI: 10.1016/j.yjmcc.2015.12.030 -
BMC Medical Genomics Dec 2022Among the most lethal cancers, pancreatic adenocarcinoma (PAAD) is an essential component of digestive system malignancies that still lacks effective diagnosis and...
BACKGROUND
Among the most lethal cancers, pancreatic adenocarcinoma (PAAD) is an essential component of digestive system malignancies that still lacks effective diagnosis and treatment methods. As exosomes and competing endogenous RNA (ceRNA) regulatory networks in tumors go deeper, we expect to construct a ceRNA regulatory network derived from blood exosomes of PAAD patients by bioinformatics methods and develop a survival prediction model based on it.
METHODS
Blood exosome sequencing data of PAAD patients and normal controls were downloaded from the exoRbase database, and the expression profiles of exosomal mRNA, lncRNA, and circRNA were differentially analyzed by R. The related mRNA, circRNA, lncRNA, and their corresponding miRNA prediction data were imported into Cytoscape software to visualize the ceRNA network. Then, we conducted GO and KEGG enrichment analysis of mRNA in the ceRNA network. Genes that express differently in pancreatic cancer tissues compared with normal tissues and associate with survival (P < 0.05) were determined as Hub genes by GEPIA. We identified optimal prognosis-related differentially expressed mRNAs (DEmRNAs) and generated a risk score model by performing univariate and multivariate Cox regression analyses.
RESULTS
205 DEmRNAs, 118 differentially expressed lncRNAs (DElncRNAs), and 98 differentially expressed circRNAs (DEcircRNAs) were screened out. We constructed the ceRNA network, and a total of 26 mRNA nodes, 7 lncRNA nodes, 6 circRNA nodes, and 16 miRNA nodes were identified. KEGG enrichment analysis showed that the DEmRNAs in the regulatory network were mainly enriched in Human papillomavirus infection, PI3K-Akt signaling pathway, Osteoclast differentiation, and ECM-receptor interaction. Next, six hub genes (S100A14, KRT8, KRT19, MAL2, MYO5B, PSCA) were determined through GEPIA. They all showed significantly increased expression in cancer tissues compared with control groups, and their high expression pointed to adverse survival. Two optimal prognostic-related DEmRNAs, MYO5B (HR = 1.41, P < 0.05) and PSCA (HR = 1.10, P < 0.05) were included to construct the survival prediction model.
CONCLUSION
In this study, we successfully constructed a ceRNA regulatory network in blood exosomes from PAAD patients and developed a two-gene survival prediction model that provided new targets which shall aid in diagnosing and treating PAAD.
Topics: Humans; RNA, Long Noncoding; Adenocarcinoma; Pancreatic Neoplasms; RNA, Circular; Gene Regulatory Networks; Gene Expression Regulation, Neoplastic; Phosphatidylinositol 3-Kinases; MicroRNAs; RNA, Messenger; Myelin and Lymphocyte-Associated Proteolipid Proteins
PubMed: 36522691
DOI: 10.1186/s12920-022-01409-3 -
Cell Death & Disease Jun 2024Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive cancer characterized by a poor prognosis and resistance to chemotherapy. In this study, utilizing scRNA-seq,...
Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive cancer characterized by a poor prognosis and resistance to chemotherapy. In this study, utilizing scRNA-seq, we discovered that the tetra-transmembrane protein mal, T cell differentiation protein 2 (MAL2), exhibited specific enrichment in ICC cancer cells and was strongly associated with a poor prognosis. The inhibition of MAL2 effectively suppressed cell proliferation, invasion, and migration. Transcriptomics and metabolomics analyses suggested that MAL2 promoted lipid accumulation in ICC by stabilizing EGFR membrane localization and activated the PI3K/AKT/SREBP-1 axis. Molecular docking and Co-IP proved that MAL2 interacted directly with EGFR. Based on constructed ICC organoids, the downregulation of MAL2 enhanced apoptosis and sensitized ICC cells to cisplatin. Lastly, we conducted a virtual screen to identify sarizotan, a small molecule inhibitor of MAL2, and successfully validated its ability to inhibit MAL2 function. Our findings highlight the tumorigenic role of MAL2 and its involvement in cisplatin sensitivity, suggesting the potential for novel combination therapeutic strategies in ICC.
Topics: Cholangiocarcinoma; Humans; ErbB Receptors; Lipid Metabolism; Bile Duct Neoplasms; Cell Line, Tumor; Animals; Cisplatin; Signal Transduction; Cell Proliferation; Single-Cell Analysis; Myelin and Lymphocyte-Associated Proteolipid Proteins; Mice; Gene Expression Regulation, Neoplastic; Sequence Analysis, RNA; Apoptosis; Male
PubMed: 38866777
DOI: 10.1038/s41419-024-06775-7 -
Computational and Mathematical Methods... 2022Breast cancer is a big threat to the women across the world with substantial morbidity and mortality. The pressing matter of our study is to establish a prognostic gene...
BACKGROUND
Breast cancer is a big threat to the women across the world with substantial morbidity and mortality. The pressing matter of our study is to establish a prognostic gene model for breast cancer based on mRNAsi for predicting patient's prognostic survival.
METHODS
From The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, we downloaded the expression profiles of genes in breast cancer. On the basis of one-class logistic regression (OCLR) machine learning algorithm, mRNAsi of samples was calculated. Kaplan-Meier (K-M) and Kruskal-Wallis (K-W) tests were utilized for the assessment of the connection between mRNAsi and clinicopathological variables of the samples. As for the analysis on the correlation between mRNAsi and immune infiltration, ESTIMATE combined with Spearman test was employed. The weighted gene coexpression network analysis (WGCNA) network was established by utilizing the differentially expressed genes in breast cancer, and the target module with the most significant correlation with mRNAsi was screened. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to figure out the biological functions of the target module. As for the construction of the prognostic model, univariate, least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analyses were performed on genes in the module. The single sample gene set enrichment analysis (ssGSEA) and tumor mutational burden were employed for the analysis on immune infiltration and gene mutations in the high- and low-risk groups. As for the analysis on whether this model had the prognostic value, the nomogram and calibration curves of risk scores and clinical characteristics were drawn.
RESULTS
Nine mRNAsi-related genes (CFB, MAL2, PSME2, MRPL13, HMGB3, DCTPP1, SHCBP1, SLC35A2, and EVA1B) comprised the prognostic model. According to the results of ssGSEA and gene mutation analysis, differences were shown in immune cell infiltration and gene mutation frequency between the high- and low-risk groups.
CONCLUSION
Nine mRNAsi-related genes screened in our research can be considered as the biomarkers to predict breast cancer patients' prognoses, and this model has a potential relationship with individual somatic gene mutations and immune regulation. This study can offer new insight into the development of diagnostic and clinical treatment strategies for breast cancer.
Topics: Humans; Female; Prognosis; Breast Neoplasms; Gene Expression Regulation, Neoplastic; Gene Expression Profiling; Biomarkers, Tumor; Proteasome Endopeptidase Complex; Myelin and Lymphocyte-Associated Proteolipid Proteins; Shc Signaling Adaptor Proteins
PubMed: 36267313
DOI: 10.1155/2022/6532591 -
Molecular Medicine Reports Apr 2024The myelin and lymphocyte protein (MAL) family is a novel gene family first identified and characterized in 2002. This family is comprised of seven members, including... (Review)
Review
The myelin and lymphocyte protein (MAL) family is a novel gene family first identified and characterized in 2002. This family is comprised of seven members, including MAL, MAL2, plasmolipin, MALL, myeloid differentiation‑associated marker (MYADM), MYADML2 and CMTM8, which are located on different chromosomes. In addition to exhibiting extensive activity during transcytosis, the MAL family plays a vital role in the neurological, digestive, respiratory, genitourinary and other physiological systems. Furthermore, the intimate association between MAL and the pathogenesis, progression and metastasis of malignancies, attributable to several mechanisms such as DNA methylation has also been elucidated. In the present review, an overview of the structural and functional properties of the MAL family and the latest research findings regarding the relationship between several MAL members and various cancers is provided. Furthermore, the potential clinical and scientific significance of MAL is discussed and directions for future research are summarized.
Topics: Humans; Myelin and Lymphocyte-Associated Proteolipid Proteins; Proteolipids; Myelin Proteins; Proteins; Neoplasms; Cell Transformation, Neoplastic; Carcinogenesis; Lymphocytes; Chemokines; MARVEL Domain-Containing Proteins
PubMed: 38362940
DOI: 10.3892/mmr.2024.13181 -
Science Advances Mar 2023The cytoskeletal proteins tubulin and actin are the obligate substrates of TCP-1 ring complex/Chaperonin containing TCP-1 (TRiC/CCT), and their folding involves...
The cytoskeletal proteins tubulin and actin are the obligate substrates of TCP-1 ring complex/Chaperonin containing TCP-1 (TRiC/CCT), and their folding involves co-chaperone. Through cryo-electron microscopy analysis, we present a more complete picture of TRiC-assisted tubulin/actin folding along TRiC adenosine triphosphatase cycle, under the coordination of co-chaperone plp2. In the open S1/S2 states, plp2 and tubulin/actin engaged within opposite TRiC chambers. Notably, we captured an unprecedented TRiC-plp2-tubulin complex in the closed S3 state, engaged with a folded full-length -tubulin and loaded with a guanosine triphosphate, and a plp2 occupying opposite rings. Another closed S4 state revealed an actin in the intermediate folding state and a plp2. Accompanying TRiC ring closure, plp2 translocation could coordinate substrate translocation on the CCT6 hemisphere, facilitating substrate stabilization and folding. Our findings reveal the folding mechanism of the major cytoskeletal proteins tubulin/actin under the coordination of the biogenesis machinery TRiC and plp2 and extend our understanding of the links between cytoskeletal proteostasis and related human diseases.
Topics: Humans; Actins; Cryoelectron Microscopy; MARVEL Domain-Containing Proteins; Molecular Chaperones; Protein Folding; Proteolipids; Tubulin; Cytoskeletal Proteins
PubMed: 36921056
DOI: 10.1126/sciadv.ade1207 -
Scientific Reports Feb 2022Malignant melanoma is the main cause of death in patients with skin cancer. Overexpression of Proteolipid protein 2 (PLP2) increased tumor metastasis and the knockdown...
Malignant melanoma is the main cause of death in patients with skin cancer. Overexpression of Proteolipid protein 2 (PLP2) increased tumor metastasis and the knockdown of PLP2 inhibited the growth and metastasis of melanoma cells. In the present work, we studied the antitumor activity of peptide Rb4 derived from protein PLP2. In vitro, Rb4 induced F-actin polymerization, prevented F-actin depolymerization and increased the ER-derived cytosolic calcium. Such effects were associated with necrosis of murine melanoma B16F10-Nex2 cells and with inhibition of the viability of human cancer cell lines. Loss of plasma membrane integrity, dilation of mitochondria, cytoplasm vacuolation and absence of chromatin condensation characterized tumor cell necrosis. Cleavage of PARP-1 and inhibition of RIP1 expression were also observed. In vivo, peptide Rb4 reduced the lung metastasis of tumor cells and delayed the subcutaneous melanoma growth in a syngeneic model. Rb4 induced the expression of two DAMPs molecules, HMGB1 and calreticulin, in B16F10-Nex2. Our results suggest that peptide Rb4 acts directly on tumor cells inducing the expression of DAMPs, which trigger the immunoprotective effect in vivo against melanoma cells. We suggest that peptide Rb4 is a promising compound to be developed as an anticancer drug.
Topics: Animals; Antineoplastic Agents; Calreticulin; Cell Death; Cell Line, Tumor; Gene Expression; HMGB1 Protein; Humans; MARVEL Domain-Containing Proteins; Melanoma; Mice; Necrosis; Nuclear Pore Complex Proteins; Peptides; Poly (ADP-Ribose) Polymerase-1; Proteolipids; RNA-Binding Proteins; Skin Neoplasms
PubMed: 35190586
DOI: 10.1038/s41598-022-06429-8