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The intravenous administration of skin-derived mesenchymal stem cells ameliorates hearing loss and preserves cochlear hair cells in cisplatin-injected mice: SMSCs ameliorate hearing loss and preserve outer hair cells in mice.

Mesenchymal stem cells (MSCs) can be isolated from different tissue origins, such as the bone marrow, the placenta, the umbilical cord, adip … association, matrix remodeling, oxidative stress, tissue integrity, transcription, and splicing and unfolded protein responses. Additionally, SMSCs treatment could upregulate the expression of cochlear genes affecting the axon and dendrite structures, cytokines, trophic factors, the neuronal skeleton and those involved in carbohydrate metabolism, growth factor signaling, m …

Lipid Modulation in the Formation of β-Sheet Structures. Implications for De Novo Design of Human Islet Amyloid Polypeptide and the Impact on β-Cell Homeostasis.

Human islet amyloid polypeptide (hIAPP) corresponds to a 37-residue hormone present in insulin granules that maintains a high propensity to … erhans islet β-cells, localized in the endoplasmic reticulum, and trigger critical pathways such as unfolded protein response (UPR), affecting insulin secretion. Since this phenomenon was associated with the presence of cytotoxicity on Langerhans islet β-cells, it can be concluded that the anionic lipid environment and degree of solvation are critical conditions for the st …

Nelfinavir targets multiple drug resistance mechanisms to increase the efficacy of doxorubicin in MCF-7/Dox breast cancer cells.

Development of multidrug resistance (MDR) remains a significant problem in cancer chemotherapy and underscores the importance of using chemo … -1)-induced phosphorylated AKT (p-AKT) levels. Multiple exposures to NFV also resulted in increased unfolded protein response (UPR) transducers, e.g. Grp78, p-PERK, p-eIF2α, and ATF-4; and endoplasmic reticulum (ER) stress induced death sensors, e.g. CHOP & TRIB-3. Multiple exposures to NFV also abrogated the mitogenic effects of IGF-1. In mice carrying MCF-7/Dox tumor xen …

Use of Bioinformatics and Machine Learning to Identify Circadian Rhythm Disruption- and Endoplasmic Reticulum Stress-Associated Biomarkers in Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disorder closely linked to circadian rhythm disruption (CRD) and endoplas … that these biomarkers were associated primarily with endoplasmic reticulum protein processing, the unfolded protein response (UPR), and branched-chain amino acid degradation and implicated retinol and thiamine metabolism. CREB3, DERL2, LYPLAL1, and ERN1 emerged as key NAFLD biomarkers linked to CRD and ERS, providing insights into disease pathogenesis.

The ZIP9-centered androgen pathway compensates for the 2605 MHz radiofrequency electromagnetic radiation-mediated reduction in resistance to H2O2 damage in Sertoli cells of adult rats.

The direct biological effects of radiofrequency electromagnetic radiation (RF-EMR) from wireless communication equipment on the testes are s … which was rescued by enhancing the ZIP9-centered androgen pathway in the short term. Increasing the unfolded protein response might be an important downstream mechanism involved. These results promote a better understanding of the time-dependent reproductive toxicity of 2605 MHz RF-EMR.

Increased Endoplasmic Reticulum Stress in Human Glaucomatous Trabecular Meshwork Cells and Tissues.

PURPOSE: Primary open-angle glaucoma (POAG) is the most common form of glaucoma and is accompanied by elevated intraocular pressure (IOP) re … ared to normal TM cells. However, glaucomatous TM cells did not show splicing of XBP-1, a marker of unfolded protein response pathway. CONCLUSIONS: These studies indicate the presence of chronic ER stress in human glaucomatous TM tissues and cells and further suggest that ER stress pathway may provide a novel target for developing disease-modifying glaucoma treatments.

Moloney Murine Leukemia Virus-like Nanoparticles Pseudo-Typed with SARS-CoV-2 RBD for Vaccination Against COVID-19.

Virus-like nanoparticles (VNPs) based on Moloney murine leukemia virus represent a well-established platform for the expression of heterologous molecules such as cytokines, cytokine receptors, peptide MHC (pMHC) and major allergens, but their application for inducing protective anti-viral immunity has remained understudied as of yet. Here, we variably fused the wildtype SARS-CoV-2 spike, its receptor-binding domain (RBD) and nucleocapsid (NC) to the minimal CD16b-GPI anchor acceptor sequence for expression on the surface of VNP. Moreover, a CD16b-GPI-anchored single-chain version of IL-12 was

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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… These molecular pathways include the activation of unfolded protein response (UPR) [ 6 , 7 , 8 ], heat protein chaperones [ 9 ], aggresome formation [ 10 ], and the induction of cellular autophagy [ 5 ]. … Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells Blood 2006 107 4907 4916 10.1182/blood-2005-08-3531 16507771 PMC1895817 7. Lee A.H. Iwakoshi N.N. Anderson K.C. Glimcher L.H. …

Serum From Preeclamptic Women Triggers Endoplasmic Reticulum Stress Pathway and Expression of Angiogenic Factors in Trophoblast Cells.

Preeclampsia (PE) is a hypertensive disease of pregnancy-associated with placental cell death and endoplasmic reticulum (ER) stress. It is unknown whether systemic factors aggravate placental dysfunction. We investigated whether serum factors in pregnant women with PE activate ER stress and unfolded protein responses (UPRs) in placental explants and trophoblast cells lineage. We cultured placental explants from third-trimester term placentas from control non-preeclamptic (NPE) pregnant women with serum from women with PE or controls (NPE). In PE-treated explants, there was a significant increa…

Convergent and Distinct Transcriptional Signatures in Suicide, Bipolar Disorder, and Major Depressive Disorder.

Globally, a person dies by suicide every 40 seconds, underscoring a major global public health concern. In the United States, suicide is the … activation (CIR, SERPiNA1, LGALS3), extracellular matrix remodeling (COL4A1, SERPINH1, PLOD2), and unfolded protein response (BAG3, WFS1, MTHFD2). Suicide-associated DEGs were prominently downregulated, and involved metal-ion homeostasis, stress responses, synaptic regulation, and circadian pathways, whereas BD showed downregulation in synaptic and vesicle-related process …

Multi-region brain transcriptomic analysis of amyotrophic lateral sclerosis reveals widespread RNA alterations and substantial cerebellum involvement.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects the motor neurons, causing progressive … pt, associated with TDP-43 loss-of-function, in the cerebellum and a XBP1 transcript, indicative of unfolded protein response activity, in the motor cortex. Extensive variation in RNA splicing was identified in the ALS brain, with 26-41% of alternatively spliced genes unique to a given brain region. This included detection of TDP-43-associated cryptic splicing events such …

Cross-feeding interactions between Fusobacterium nucleatum and the glycan forager Segatella oris.

Fusobacterium nucleatum is a common member of the oral microbiota frequently associated with extra-oral infections and diverse polymicrobial … ted pathways; however, co-colonization with S. oris modulated the expression of genes linked to the unfolded protein response and apoptosis, among others. These findings demonstrate that glycan-mediated cross-feeding and microbial interactions shape the physiology and pathogenic potential of F. nucleatum in mucosal environments. This work underscores the importance of mode …

Gene Expression Clustering and Selected Head and Neck Cancer Gene Signatures Highlight Risk Probability Differences in Oral Premalignant Lesions.

BACKGROUND: Oral premalignant lesions (OPLs) represent the most common oral precancerous conditions. One of the major challenges in this fie … test, p = 0.0052) and they expressed four enriched hallmarks: "TGF beta signaling" "angiogenesis", "unfolded protein response", "apical junction". Overall, 54 cases entered in the immune related clusters, while the remaining 32 cases belonged to the other clusters. No other signatures showed association with OCFS. Our variance partition analysis proved that clinical and mo …

Prostaglandin EP2 receptor signaling protects human trabecular meshwork cells from apoptosis induced by ER stress through down-regulation of p53.

E-prostanoid receptor subtype 2 (EP2) agonists are currently under clinical development as hypotensive agents for the treatment of ocular hypertension. However, the effects of EP2 receptor agonists on trabecular meshwork (TM) alterations leading to primary open-angle glaucoma (POAG) are still unknown. Here, we evaluated whether EP2 receptor activation exhibits protective functions on TM cell death induced by endoplasmic reticulum (ER) stress. We show that the EP2 receptor agonist butaprost protects TM cell death mediated by the ER stress inducer tunicamycin through a cyclic AMP (cAMP)-dependen

High N-glycan multiplicity is critical for neuronal adhesion and sensitizes the developing cerebellum to N-glycosylation defect.

Proper brain development relies highly on protein N-glycosylation to sustain neuronal migration, axon guidance and synaptic physiology. Impairing the N-glycosylation pathway at early steps produces broad neurological symptoms identified in congenital disorders of glycosylation. However, little is known about the molecular mechanisms underlying these defects. We generated a cerebellum specific knockout mouse for Srd5a3, a gene involved in the initiation of N-glycosylation. In addition to motor coordination defects and abnormal granule cell development, Srd5a3 deletion causes mild N-glycosylatio

Enzymology of the metazoan tRNA ligase complex: a lifetime in cycles.

This review highlights the emerging biochemistry and biology of the metazoan tRNA-ligase complex (tRNA-LC). We begin with an overview of the cleavage-ligation pathways dependent on the tRNA-LC, epitomised by the essential process of pre-tRNA splicing, but also critical for the unfolded protein response and the struggle against transposons. The catalytic core of the tRNA-LC is the non-conventional RNA ligase RTCB, found in all domains of life. We start from the universal principles of its catalytic cycle, entailing GTP-dependent ligation of RNA molecules with 2’,3’-cyclic phosphate and 5’-hydro…

Cellular stress is triggered by tick-borne encephalitis virus and limits the virus replication in PMJ2-R mouse macrophage cell line.

Viral infection may represent a stress condition to the host cell. Cells react to it by triggering the defence programme to restore homeosta … 62, Gclm and Hmox1, was detected. Next, we evaluated the ER stress upon TBEV infection by analysing unfolded protein responses (UPR). We found that infection induced gene expression of two general sensors BiP and CHOP and activated the IRE1 pathway of UPR. Finally, since the natural transmission route of TBEV from its tick vector to the host is mediated via tick saliva, th …

Overexpression of human mutated G93A SOD1 changes dynamics of the ER mitochondria calcium cycle specifically in mouse embryonic motor neurons.

Motor neurons vulnerable to the rapidly progressive deadly neurodegenerative disease amyotrophic lateral sclerosis (ALS) inherently express low amounts of calcium binding proteins (CaBP), likely to allow physiological motor neuron firing frequency modulation. At the same time motor neurons are susceptible to AMPA receptor mediated excitotoxicity and internal calcium deregulation which is not fully understood. We analysed ER mitochondria calcium cycle (ERMCC) dynamics with subsecond resolution in G93A hSOD1 overexpressing motor neurons as a model of ALS using fluorescent calcium imaging. When c

Proteomics of human duodenum in pre-diabetes and type 2 diabetes reveals potential novel therapeutic targets for aetiology and therapeutics.

BACKGROUND: Remission from pre-diabetes and type 2 diabetes (T2D) is frequently observed immediately after a duodenal/jejunal bypass. This d … g disruption in gene transcription, microtubule stability, mitochondrial function, Ca2+ signalling, unfolded protein response, redox status and multivesicular body formation. Two secreted proteins (APOA4 and RBP4; ROC AUC = 0.79 and 0.80) were also increased in T2D. Modelling using k-fold cross-validation, identified predictive power for 17 of the 23 proteins. At the mRNA …

Severe offtarget effects following intravenous delivery of AAV9-MECP2 in a female mouse model of Rett syndrome.

Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder that is primarily caused by mutations in the methyl CpG binding protein … he Mecp2 HET mice treated with the higher doses of AAV9-MCO. We then studied the involvement of the unfolded protein response (UPR) in triggering apoptosis since it can be activated by AAV vectors. Increased expression of the C/EBP homologous protein (CHOP), one of UPR downstream effectors, was confirmed in Mecp2 HET mice after vector administration. The toxic reaction see …