ER stress and pain

Pseudoachondroplasia (PSACH), a severe dwarfing condition associated with early-onset joint degeneration and lifelong joint pain, is caused by mutations in cartilage oligomeric matrix protein (COMP). The mechanisms underlying the mutant-COMP pathology have been defined using the MT-COMP mouse model of PSACH that has the common D469del mutation. Mutant-COMP protein does not fold properly, and it is retained in the rough endoplasmic reticulum (rER) of chondrocytes rather than being exported to the extracellular matrix (ECM), driving ER stress that stimulates oxidative stress and inflammation, driving a self-perpetuating cycle...

Soluble epoxide hydrolase (sEH) is a drug target with the potential for therapeutic utility in the areas of inflammation, neurodegenerative disease, chronic pain, and diabetes, among others. Proteolysis-targeting chimeras (PROTACs) molecules offer new opportunities for targeting sEH, due to its capacity to induce its degradation. Here, we describe that the new ALT-PG2, a PROTAC that degrades sEH protein in the human hepatic Huh-7 cell line, in isolated mouse primary hepatocytes, and in the liver of mice. Remarkably, sEH degradation caused by ALT-PG2 was accompanied by an increase in the phosphorylated levels of AMP-activated protein kinase (AMPK), while phosphorylated extracellular-signal-regulated kinase 1/2 (ERK1/2) was reduced...

Central post-stroke pain (CPSP) is a chronic neuropathic pain caused by cerebrovascular lesion or disfunction after stroke. The available treatments for CPSP have either troublesome side effects or limited efficacy, therefore, further advancedment in therapeutic options is needed. Convincing evidence suggest that excessive reactive oxygen species (ROS), reactive nitrogen species (RNS), and generated matrix metalloproteinase (MMPs) are largely involved in the development of pain. In our current study, we report an effective strategy for treating pain hypersensitivity using an endoplasmic reticulum (ER)-targeted metal-organic framework (MOF)-confined ruthenium (Ru) nanozyme...

Temporomandibular joint osteoarthritis (TMJOA) is a degenerative disease with the cessation of matrix anabolism and aggravation of inflammation, which results in severe pain and impaired joint function. However, the mechanisms are not well understood. Circular RNAs (circRNAs) are reported to have various biological functions and participate in the development, diagnosis, prognosis, and treatment of different diseases. This study aimed to investigate the roles and mechanisms of circ-slain2 in TMJOA. We first established TMJOA mouse models and found circ-slain2 was lowly expressed in the cartilage of TMJOA through sequencing data...

Sarcoidosis is a systemic granulomatous disease of unknown etiology with the potential to involve many organs of the body. Less than 1% of patients with sarcoidosis have GI manifestations. Here, we report a case of GI tract sarcoidosis that presented with severe symptomatic anemia. A 51-year-old female with a history of pulmonary and liver sarcoidosis presented to the emergency room with a one-week history of chest pain and shortness of breath. A physical exam was significant for conjunctival pallor. On admission, her hemoglobin was 6...

Poly (ADP-ribose) polymerase-1 (PARP-1) is the most extensively studied member of the PARP superfamily, with its primary function being the facilitation of DNA damage repair processes. Parthanatos is a type of regulated cell death cascade initiated by PARP-1 hyperactivation, which involves multiple subroutines, including the accumulation of ADP-ribose polymers (PAR), binding of PAR and apoptosis-inducing factor (AIF), release of AIF from the mitochondria, the translocation of the AIF/macrophage migration inhibitory factor (MIF) complex, and massive MIF-mediated DNA fragmentation...

Following the contraindication of codeine use in children, increasing use of tramadol has been observed in pain management protocols. However, tramadol's pharmacokinetics (PK) and pharmacodynamics are influenced by cytochrome P450 (CYP)2D6 activity, similarly to codeine. Previous studies in adults have demonstrated a correlation between pupillary response and tramadol PK. Our objective was to evaluate pupillometry as a phenotyping method to assess CYP2D6 activity in children treated with tramadol. We included 41 children (mean age 11 years) receiving a first dose of tramadol (2 mg/kg) in the emergency room (ER) as part of their routine care...

Traumatic brain injury (TBI) in children often leads to poor developmental outcomes attributable to progressive cell loss caused by secondary injuries, including endoplasmic reticulum (ER) stress. Buprenorphine (BPN) is commonly used in children for pain management; however, the effects of BPN on ER stress in the pediatric population are still inconclusive. This study investigated the sex-specific effects of BPN on ER stress, abnormal protein accumulation, and cell loss in a mouse impact acceleration model of pediatric TBI...

Myocardial stress can lead to a myriad of cardiovascular complications, and stress-induced cardiomyopathy is the predominant manifestation. Exogenous or endogenous hormonal excess, sepsis, tachycardia, and physical or emotional trauma can lead to neurohormonal and catecholaminergic surges. Stress-induced cardiomyopathy often presents with chest pain, ischemic-like ECG changes, troponin elevation, and wall motion abnormalities in echocardiography. It is a diagnosis of exclusion, and coronary artery disease needs to be ruled out by a normal angiogram as per guidelines...

Postoperative cognitive dysfunction (POCD) is a common surgical complication that causes additional pain in patients and affects their quality of life. To address this problem, emerging studies have focused on the POCD. Recent studies have shown that aging and anesthetic exposure are the two major risk factors for developing POCD. However, few reports described the exact molecular mechanisms underlying POCD in elderly patients. In the previous studies, the endoplasmic reticulum (ER) stress and neuroapoptosis in the hippocampus were associated with inducing POCD; however, no further information on the related signaling pathways could be disclosed...

The endoplasmic reticulum (ER) has been considered as the key site of protein biosynthesis and maturation in the eukaryotic cell. In recent years, the sequence at the N-terminal region of translated protein has shown a particular emphasis as a signal responsible for site-specific translocation mediated by post-translational modification. Once the native conformation is not achieved, the degradation pathway is activated, and therefore the restoration of the homeostasis of ER function in UPR pathway is initiated...

BACKGROUND: Papillary muscle rupture (PMR) is a catastrophic complication of acute myocardial infarction. However, the best timing and modality of circulatory support for surgery are unknown. CASE SUMMARY: A 75-year-old man presented to the emergency room in our hospital for worsening shortness of breath accompanied by chest pain. Transthoracic echocardiograph showed severe mitral regurgitation (MR) with a flail posterior mitral valve leaflet, and coronary angiography demonstrated distal right coronary artery occlusion...

Endoplasmic stress response, the unfolded protein response (UPR), is a homeostatic signaling pathway comprising transmembrane sensors that get activated upon alterations in ER luminal environment. Studies suggest a relation between activated UPR pathways and several disease states such as Parkinson, Alzheimer, inflammatory bowel disease, tumor growth, and metabolic syndrome. Diabetic peripheral neuropathy (DPN), a common microvascular complication of diabetes-related chronic hyperglycemia, causes chronic pain, loss of sensation, foot ulcers, amputations, allodynia, hyperalgesia, paresthesia, and spontaneous pain...

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BACKGROUND: Stress ulcers in the upper gastrointestinal tract can arise from pathologies related to erosive or inflammatory insults in critically ill patients. The relationship between stressful bodily events and the ischemia and perforation of stress ulcers is poorly understood. OBJECTIVE: We present a case of perforated stress ulcer following an abortion that was treated by dilatation and curettage (D&C) and complicated by a coronavirus disease 2019 (COVID-19) infection...

Parkinson's disease is a neurodegenerative disease affecting mainly the elderly population. It is characterized by the loss of dopaminergic neurons of the substantia nigra pars compacta region. Parkinson's disease patients exhibit motor symptoms like tremors, rigidity, bradykinesia/hypokinesia, and non-motor symptoms like depression, cognitive decline, delusion, and pain. Major pathophysiological factors which contribute to neuron loss include excess/misfolded alpha-synuclein aggregates, microglial cell-mediated neuroinflammation, excitotoxicity, oxidative stress, and defective mitochondrial function...

Damage to the central or peripheral nervous system causes neuropathic pain. Endoplasmic reticulum (ER) stress plays a role in peripheral neuropathy. Increase in ER stress is seen in diabetic neuropathy. Inducers of ER stress also give rise to peripheral neuropathy. ER stress leads to the formation of autophagosome but as their degradation is also stalled during ER stress accumulation of autophagosomes is seen. Accumulation of autophagosomes has deleterious effects on cells. In the present study, we show that treatment with tunicamycin (TM) (ER stress inducer) in mice leads to peripheral neuropathy as assessed by Von Frey and Hot plate method...

BACKGROUND: NTRK1 gene, encoding TrkA, is essential for the nervous system and drives a variety of biological processes, including pain. Given the unsatisfied analgesic effects of some new drugs targeting NTRK1 in clinic, a deeper understanding for the mechanism of NTRK1 in neurons is crucial. METHODS: We assessed the transcriptional responses in SH-SY5Y cells with NTRK1 overexpression using bioinformatics analysis. GO and KEGG analyses were performed, PPI networks were constructed, and the functional modules and top 10 genes were screened...

Cartilage oligomeric matrix protein (COMP), an extracellular matrix protein, has been shown to enhance proliferation and mechanical integrity in the matrix, supporting functions of the growth plate and articular cartilage. Mutations in COMP cause pseudoachondroplasia (PSACH), a severe dwarfing condition associated with premature joint degeneration and significant lifelong joint pain. The MT (mutant)-COMP mouse mimics PSACH with decreased limb growth, early joint degeneration and pain. Ablation of endoplasmic reticulum stress CHOP signaling eliminated pain and prevented joint degeneration...

ETHNOPHARMACOLOGICAL RELEVANCE: Tiger bone, which had long been used in traditional Chinese medicine, had the action of removing wind and alleviating pain, strengthening the sinews and bones, and often used to treat bone impediment, and atrophic debility of bones in TCM clinical practice. As a substitute of natural bone tiger, artificial tiger bone Jintiange (JTG), has been approved by the State Food and Drug Administration of China for relief the symptom of osteoporosis, such as lumbago and back pain, lassitude in loin and legs, flaccidity and weakness legs, and walk with difficulty based on TCM theory...