Search Results (132)

Mucormycosis, triggered by fungi of the order Mucorales, represents a potentially fatal invasive mycosis, with death rates over 50% despite intensive therapy. The COVID-19 pandemic brought a sharp increase in cases, especially in individuals with diabetes mellitus and those undergoing immunosuppressive treatment, emphasizing significant gaps in our comprehension of disease pathogenesis. Emerging molecular studies have highlighted key virulence factors, such as the CotH family of invasins that facilitate endothelial invasion via interaction with glucose-regulated protein 78 (GRP78), complex iron acquisition systems necessary for fungal growth, and the release of mucoricin, a ricin-like toxin that impairs vascular integrity. Host defense depends mainly on innate immunity, with neutrophils and macrophages working as critical effector cells, while adaptive Th1 and Th17 responses aid in the fungal removal. Mucorales use a variety of immune evasion techniques, such as pathogen-associated molecular pattern (PAMP) masking via cell wall transformations, resistance to phagocytic death, and metabolic utilization of host factors including hyperglycemia and increased free iron in diabetic ketoacidosis (DKA). This review summarizes current evidence of the molecular processes underlying mucormycosis pathogenesis, underscoring host–pathogen interactions at the cellular and molecular levels, immune evasion tactics, and translational potential for new diagnostic and therapeutic approaches. Comprehending these molecular processes is crucial for creating efficient therapies against mucormycosis in an era of growing immunocompromised patients and expanding infectious disease synergies. Full article

Dairy cows with ketosis display immune dysfunction and a high incidence of infectious diseases, which may partly be attributed to excessive endoplasmic reticulum stress (ERS) and apoptosis in macrophages. The objective of the present study was to assess the role of ERS in macrophage apoptosis of ketotic dairy cows. Compared with healthy cows, the apoptosis number of macrophages and the protein abundance of glucose regulated protein 78 (GRP78), activating transcription factor 4 (ATF4), and activating transcription factor 6 (ATF6); the ratio of phosphorylated protein kinase RNA-like endoplasmic reticulum kinase (p-PERK)/PERK, phosphorylated inositol-requiring enzyme 1 (p-IRE1)/IRE1 and phosphorylated eukaryotic translation initiation factor 2α (p-eIF2α)/eIF2α; and mean fluorescence intensity of C/EBP homology protein (CHOP) were greater in cows with clinically ketosis (CK). Treatment with FFA increased protein abundance of GRP78, CHOP, ATF6 and p-IRE1/IRE1, and mean fluorescence intensity of CHOP. Furthermore, FFA increased the protein abundance of cysteinyl aspartate-specific proteinase-3 (Caspase-3) and mean fluorescence intensity of Caspase-3 but decreased the Bcl-2/Bax protein abundance ratio, which was accompanied by an increase in the number macrophage apoptosis. Inhibition of ERS via TUDCA attenuated the increased macrophage apoptosis and the activated apoptotic pathways induced by Tn or FFA. Thus, hyperphysiological concentrations of FFA induce apoptosis in macrophages by triggering ERS in ketotic dairy cows. Full article

Alpha-2-macroglobulin (α₂M) is a conserved plasma glycoprotein traditionally known for its broad-spectrum protease inhibitory activity. However, emerging evidence indicates that its activated form, α₂M*, generated via proteolytic cleavage or nucleophilic attack, functions as a versatile signaling ligand. By engaging specific cell-surface receptors, most notably low-density lipoprotein receptor-related protein 1 (LRP1) and glucose-regulated protein 78 (GRP78), α₂M* orchestrates a diverse array of intracellular programs, including the PI3K/Akt/mTOR, MAPK/ERK, and JAK/STAT cascades, as well as mechanosensitive YAP/TAZ signaling. These pathways collectively govern fundamental cellular processes such as proliferation, metabolic reprogramming, cytoskeletal remodeling, and inflammatory adaptation across various cell types, including macrophages, cardiomyocytes, and malignant cells. Altogether, this review synthesizes current knowledge on α₂M activation, structural transitions, receptor interactions, and downstream signaling, highlighting the expanding functional landscape of α₂M* as a potent regulator of intracellular communication with implications for physiology and disease. Full article

COVID-19 pneumonia remains a major driver of morbidity and mortality worldwide, with outcomes influenced by demographic, clinical, and systemic factors. Glucose-regulated protein 78 (GRP78) has emerged as a potential biomarker of disease severity, but its clinical significance across different populations remains underexplored. We conducted a retrospective cohort study including 83 hospitalized COVID-19 patients from General Hospital “Sv. Georgi”, Plovdiv, Bulgaria, and 97 from Denizli, Türkiye. Pneumonia diagnosis was based on clinical, laboratory, and radiological criteria. Patient demographics and biomarkers (CRP, D-dimer, oxygen saturation, lymphocyte count, and serum GRP78) were compared between cohorts. Statistical analyses included Mann–Whitney U, t-tests, and logistic regression. Pneumonia prevalence was 48.8% in patients from General Hospital “Sv. Georgi”, Plovdiv and 58.8% in Denizli. Patients in Plovdiv were older and exhibited higher CRP, D-dimer, and GRP78 levels, alongside lower oxygen saturation and lymphocyte counts. Logistic regression demonstrated that GRP78 significantly predicted pneumonia in both cohorts, with robust discriminative performance on ROC analysis. This study highlights significant regional differences in COVID-19 pneumonia presentation between Bulgaria and Türkiye. Elevated GRP78 levels were strongly associated with pneumonia and other severity markers, underscoring its potential as a clinically valuable biomarker for early risk stratification. These findings emphasize the importance of both localized epidemiological analyses and biomarker-based approaches to optimize COVID-19 management. Full article

Follicular development is recognized as a highly complex biological process regulated by multiple factors. Thyroid hormone (TH) is considered one of the key regulators of female reproduction, and its dysregulation can significantly impair follicular development. Epigallocatechin gallate (EGCG), the main active component of green tea, possesses strong antioxidant properties. Numerous studies have demonstrated that EGCG positively influences reproductive function in both humans and animals. However, whether EGCG directly affects follicular development under conditions of TH dysregulation remains poorly understood. The primary objective of this study was to investigate the impact of hyperthyroidism on ovarian development, examine whether EGCG could mitigate the adverse effects of TH dysregulation, and elucidate the underlying molecular mechanisms. In the T₄-induced hyperthyroidism rat model, ovarian tissues were serially sectioned for Hematoxylin-Eosin (HE) and Masson’s trichrome staining to assess morphological changes, and follicle numbers were quantified at each developmental stage. Granulosa cell (GC) viability, proliferation, and apoptosis induced by T₃ were evaluated using CCK8, EdU, and TUNEL assays, respectively. Antioxidant enzyme activity was measured, and the expression levels of related proteins were analyzed via Western blotting. Results showed that hyperthyroidism altered ovarian structure, significantly increasing the number of atretic follicles. Levels of antioxidant enzymes, including Superoxide Dismutase (SOD), Glutathione Peroxidase (GSH-PX), and Catalase (CAT), were markedly decreased, whereas the lipid peroxidation product malondialdehyde (MDA) was significantly elevated. Furthermore, all ERS-related proteins, phosphorylated Eukaryotic Initiation Factor 2 Alpha (p-eIF2α), Activating Transcription Factor 4 (ATF4), C/EBP homologous protein (CHOP), and Caspase-3, were upregulated, accompanied by decreased glucose-regulated protein 78 (GRP78) expression. Treatment with EGCG alleviated these detrimental effects of hyperthyroidism. At the cellular level, high concentrations of T₃ reduced GC viability and proliferation while increasing apoptosis. Reactive oxygen species levels were elevated, and GRP78 expression was decreased. Notably, all T₃-induced effects were reversed by EGCG treatment. In summary, this study demonstrates that hyperthyroidism induces oxidative stress in GCs, which triggers endoplasmic reticulum stress via the eIF2α/ATF4 pathway and leads to apoptosis. EGCG mitigates apoptosis by enhancing antioxidant capacity, thereby preserving ovarian function. These findings establish EGCG as a protective agent for maintaining ovarian health and fertility. Full article

Hepatitis A virus (HAV) infection sometimes results in the occurrence of acute liver failure and acute-on-chronic liver failure (ACLF), which is often fatal, especially in patients with diabetes mellitus or elderly individuals. ACLF is observed in patients with cirrhosis who occasionally have zinc deficiency. However, effective drugs for hepatitis A are currently unavailable. Glucose-regulated protein 78 (GRP78) is an antiviral agent that has been reported to prevent HAV replication. The effects of zinc acetate on HAV HA11-1299 genotype IIIA replication and changes in GRP78 levels in human hepatocytes with or without HAV infection were examined. Zinc acetate inhibited HAV HA11-1299 genotype IIIA replication in both Huh7 and GL37 cells. Zinc acetate also inhibited HAV replication in both low- and high-glucose media. Zinc acetate increased the expression of GRP78, in response to HAV replication. The combination of zinc acetate with ribavirin led to greater suppression of both HAV HA11-1299 genotype IIIA and HAV HM175/18f genotype IB replication in Huh7 cells than that of ribavirin alone. In conclusion, zinc acetate inhibits HAV replication in accompany with the elevation of GRP78 expression without causing cellular toxicity. Zinc compounds may be useful for the treatment of ACLF caused by HAV infection. Full article

Cancer cells can adapt to their surrounding microenvironment by upregulating glucose-regulated protein 78 kDa (GRP78) and vacuolar-type ATPase (V-ATPase) proteins to increase their proliferation and resilience to anticancer therapy. Therefore, targeting these proteins can obstruct cancer progression. A comprehensive computational study was conducted to investigate the inhibitory potential of four proton pump inhibitors (PPIs), dexlasnoprazole (DEX), esomeprazole (ESO), pantoprazole (PAN), and rabeprazole (RAB), against GRP78 and V-ATPase. Molecular docking revealed high-affinity scores for PPIs against both proteins. Moreover, molecular dynamics showed favorable root mean square deviation values for GRP78 and V-ATPase complexes, whereas root mean square fluctuations were high at the substrate-binding subdomains of GRP78 complexes and the α-helices of V-ATPase. Meanwhile, the radius of gyration and the surface-accessible surface area of the complexes were not significantly affected by ligand binding. Trajectory projections of the first two principal components showed similar motions of GRP78 structures and the fluctuating nature of V-ATPase structures, while the free-energy landscape revealed the thermodynamically favored GRP78-RAB and V-ATPase-DEX conformations. Furthermore, the binding free energy was −16.59 and −18.97 kcal/mol for GRP78-RAB and V-ATPase-DEX, respectively, indicating their stability. According to our findings, RAB and DEX are promising candidates for GRP78 and V-ATPase inhibition experiments, respectively. Full article

Background: Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterized by recurrent sinopulmonary infections due to motile cilia defects. The disease is genetically heterogeneous, with abnormalities in structural ciliary proteins. Zinc finger MYND-type containing 10 (ZMYND10) is essential for the assembly of outer dynein arms (ODA), with chaperones like Glucose-regulated protein 78 (GRP78) facilitating protein folding. This study investigates ZMYND10 and Dynein axonemal heavy chain 5 (DNAH5) mutations in individuals with PCD. Methods: Eight individuals aged 14–22 with clinical PCD symptoms and confirmed DNAH5 mutations were included. We analyzed the correlation between DNAH5 abnormalities and preassembly/chaperone proteins using immunofluorescence labeling. Nasal swabs were double-labeled (DNAH5–β-tubulin, β-tubulin–ZMYND10, β-tubulin–GRP78) and examined via fluorescence microscopy. Serum metabolomics and proteomics were also assessed. Results: The corrected total cell fluorescence (CTCF) levels of DNAH5, ZMYND10, and GRP78 were significantly different between PCD individuals and controls. Metabolomic analysis showed reduced valine, leucine, and isoleucine biosynthesis, with increased malate and triacylglycerol biosynthesis, malate-aspartate and glycerol phosphate shuttles, and arginine/proline metabolism, suggesting mitochondrial and ER stress. Conclusions: The altered expression of DNAH5, ZMYND10, and GRP78, along with metabolic shifts, points to a complex link between ciliary dysfunction and cellular stress in PCD. Further studies are needed to clarify the underlying mechanisms. Full article

Thyroid hormone (TH) plays a vital role in ovarian follicle development, and glucose-regulated protein 78 (GRP78) is involved in these processes, which is regulated by TH. However, the mechanisms are still unclear. To evaluate the possible mechanism of TH on the regulation of GRP78 expression, Cleavage Under Targets and Tagmentation (CUT & Tag) sequencing, luciferase assays, and Electrophoretic Mobility Shift Assays (EMSA) were employed to delineate the binding sites of thyroid hormone receptor β (TRβ) on the GRP78 promoter and to confirm the interactions. Additionally, Co-Immunoprecipitation (Co-IP) and Immunofluorescence (IF) assays were used to investigate the interactions between TRβ and the coactivator peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) after triiodothyronine (T₃) treatment with different concentrations. Our findings identified a thyroid hormone response element (TRE) on the GRP78 promoter and demonstrated that TRβ can activate GRP78 expression by interacting with PGC-1α. In order to simulate the condition of hyperthyroidism, granulosa cells (GCs) extracted from rats were treated by T₃ with high concentrations, which decreased the expression of PGC-1α, resulting in decreased expressions of GRP78 and other ferroptosis-related markers such as glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11, xCT), thereby inducing ferroptosis in GCs. Taken together, the present study demonstrates that T₃ induces cellular ferroptosis by binding TRE of the GRP78 promoter in ovarian GCs via TRβ. As a switcher, PGC-1α is also involved in these processes. Full article

Glioma is the most common primary malignant brain tumor, accounting for the majority of brain cancer-related deaths. Considering the limited efficacy of conventional therapies, novel molecular targeted therapies have been developed to improve outcomes and minimize toxicity. Glucose-regulated protein 78 (GRP78), a molecular chaperone primarily localized in the endoplasmic reticulum (ER), has received increasing attention for its role in glioma progression and resistance to conventional therapies. Overexpressed in gliomas, GRP78 supports tumor growth, survival, and therapeutic resistance by maintaining cellular homeostasis and regulating multiple signaling pathways. Its aberrant expression correlates with higher tumor grades and poorer patient prognosis. Beyond its intracellular functions, GRP78’s presence on the cell surface and its role in the tumor microenvironment underscore its potential as a therapeutic target. Recent studies have explored innovative strategies to target GRP78, including small molecule inhibitors, monoclonal antibodies, and chimeric antigen receptor (CAR) T cell therapy, showing significant potential in glioma treatment. This review explores the biological characteristics of GRP78, its role in glioma pathophysiology, and the potential of GRP78-targeted therapy as a novel strategy to overcome treatment resistance and improve clinical outcomes. GRP78-targeted therapy, either alone or in combination with conventional treatments, could be a novel and attractive strategy for future glioma treatment. Full article

Oxidative stress, endoplasmic reticulum (ER) stress, and alterations in autophagy activity have been described as prominent factors mediating many pathological processes in chronic kidney disease (CKD). The accumulation of misfolded proteins in the ER may stimulate the unfolded protein response (UPR). The interplay between autophagy and UPR in hemodialysis (HD) patients remains unclear. The aim of the present study was to explore the associations between serum oxidative stress markers, autophagy activity, and ER stress markers in the peripheral blood mononuclear cells (PBMCs) of patients on HD. Autophagy and ER stress-related protein expression levels in PBMCs were measured using western blotting. The redox state of human serum albumin was measured via high-performance liquid chromatography. Levels of the microtubule associated protein light chain 3 (LC3)-II, BECLIN1, and p62/SQSTM1 proteins were significantly increased in PBMCs of HD patients compared to healthy subjects. The PBMCs in HD patients also displayed augmented glucose-regulated protein 78 kDa (GRP78), phosphorylated eukaryotic translation initiation factor 2, subunit 1 alpha (p-eIF2α), and activating transcription factor 6 (ATF6) levels (p < 0.05). Additionally, nuclear factor erythroid 2 (NF-E2)-related factor 2 (NRF2) levels were elevated in the PBMCs of HD patients, compared to those of healthy subjects. Correlation analysis showed that the redox status of albumin was significantly correlated with the p62 protein level in PBMCs. Compared to healthy controls, we found elevated autophagosome formation in HD patients. Increased expression of ER stress markers was also observed in HD patients. Furthermore, increased p62 expression was positively correlated with the protein expression of NRF2, as well as a reduced form of serum albumin (human mercaptalbumin; HMA), in HD patients. Full article

Background: Atherosclerotic calcification (AC) is a common feature of atherosclerotic cardiovascular disease. β-Hydroxybutyrate (BHB) has been identified as a molecule that influences cardiovascular disease. However, whether BHB can influence AC is still unknown. Methods and Results: In this study, ApoE^−/− mice, fed a Western diet, were used to examine the effects of BHB on AC. Rat vascular smooth muscle cells (VSMCs) were used to verify the impacts of BHB on AC and to explore the underlying mechanisms. The results show that Western diet-challenged ApoE^−/− mice, supplemented with BHB for 24 weeks, exhibited reduced calcified areas, calcium content, and alkaline phosphatase (ALP) activity in the aortas, as well as ameliorated severity of AC. Furthermore, BHB downregulated the expression of glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP), thereby reducing endoplasmic reticulum stress (ERS) and ERS-mediated apoptosis in the aortas of the mice. Consistently, in vitro studies showed that BHB reduced ALP activity and calcium content in VSMCs, and inhibited VSMC calcification. Additionally, BHB suppressed ERS-mediated apoptosis in VSMCs. Conclusions: In summary, the present results demonstrate that BHB can alleviate atherosclerotic calcification by inhibiting ERS-mediated apoptosis. Therefore, BHB may serve as a viable therapeutic agent for AC. Full article

Polycystic ovarian syndrome (PCOS) is a multifaceted metabolic and hormonal disorder in females of reproductive age, frequently associated with cardiac disturbances. This research aimed to explore the protective potential of adropin and/or tirzepatide (Tirze) on cardiometabolic aberrations in the letrozole-induced PCOS model. Female Wistar non-pregnant rats were allotted into five groups: CON; PCOS; PCOS + adropin; PCOS + Tirze; and PCOS + adropin+ Tirze. The serum sex hormones, glucose, and lipid profiles were securitized. Cardiac phosphorylated levels of AKT(pAKT), glycogen synthase kinase-3 beta (pGSK-3β), NOD-like receptor family pyrin domain containing 3 (NLPR3), IL-1β and IL-18 were assayed. The cardiac redox status and endoplasmic reticulum stress (ER) parameters including relative glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) gene expressions were detected. Finally, the immunoreactivity of cardiac NF-κB, Bcl2, and BAX were assessed. Our results displayed that adropin and/or Tirze intervention successfully alleviated the PCOS-provoked cardiometabolic derangements with better results recorded for the combination treatment. The synergistic effect of adropin and Tirze is mostly mediated via activating the cardiac Akt, which dampens the GSK3β/NF-κB/NLRP3 signaling pathway, with a sequel of alleviating oxidative damage, inflammatory response, ER stress, and related apoptosis, making them alluring desirable therapeutic targets in PCOS-associated cardiac complications. Full article

Background: Obesity is a risk factor for developing cardiovascular diseases (CVDs) by impairing normal vascular function. Natural products are gaining momentum in the clinical setting due to their high efficacy and low toxicity. Caralluma fimbriata extract (CFE) has been shown to control appetite and promote weight loss; however, its effect on vascular function remains poorly understood. This study aimed to determine the effect that CFE had on weight loss and vascular function in mice fed a high-fat diet (HFD) to induce obesity, comparing this effect to that of lorcaserin (LOR) (an anti-obesity pharmaceutical) treatment. Methods: C57BL/6J male mice (n = 80) were fed a 16-week HFD to induce obesity prior to being treated with CFE and LOR as standalone treatments or in conjunction. Body composition data, such as weight gain and fat mass content were measured, isometric tension analyses were performed on isolated abdominal aortic rings to determine relaxation responses to acetylcholine, and immunohistochemistry studies were utilized to determine the expression profiles on endothelial nitric oxide synthase (eNOS) and cell stress markers (nitrotyrosine (NT) and 78 kDa glucose-regulated protein (GRP78)) in the endothelial, medial and adventitial layers of aortic rings. Results: The results demonstrated that CFE and CFE + LOR treatments significantly reduced weight gain (17%; 24%) and fat mass deposition (14%; 16%). A HFD markedly reduced acetylcholine-mediated relaxation (p < 0.05, p < 0.0001) and eNOS expression (p < 0.0001, p < 0.01) and significantly increased NT (p < 0.05, p < 0.0001) and GRP78 (p < 0.05, p < 0.01, p < 0.001). Obese mice treated with CFE exhibited significantly improved ACh-induced relaxation responses, increased eNOS (p < 0.05, p < 0.01) and reduced NT (p < 0.01) and GRP78 (p < 0.05, p < 0.01) expression. Conclusions: Thus, CFE alone or in combination with LOR could serve as an alternative strategy for preventing obesity-related cardiovascular diseases. Full article

Background/Objectives: Acute mesenteric ischemia can lead to severe liver damage due to ischemia–reperfusion (I/R) injury. This study investigated the protective effects of trimetazidine (TMZ) and dexmedetomidine (DEX) against liver damage induced by mesenteric artery I/R via endoplasmic reticulum stress (ERS) mechanisms. Methods: Twenty-four rats were divided into four groups: control, I/R, I/R+TMZ, and I/R+DEX. TMZ (20 mg/kg) was administered orally for seven days, and DEX (100 µg/kg) was given intraper-itoneally 30 min before I/R induction. Liver tissues were analyzed for creatinine, alanine ami-notransferase (ALT), aspartate aminotransferase (AST), thiobarbituric acid reactive substances (TBARS), and total thiol (TT) levels. Results: Compared with the control group, the I/R group presented significantly increased AST, ALT, TBARS, and TT levels. TMZ notably reduced creatinine levels. I/R caused significant liver necrosis, inflammation, and congestion. TMZ and DEX treatments reduced this histopathological damage, with DEX resulting in a more significant reduction in infiltrative areas and vascular congestion. The increase in the expression of caspase-3, Bax, 8-OHdG, C/EBP homologous protein (CHOP), and glucose-regulated protein 78 (GRP78) decreased with the TMZ and DEX treatments. In addition, Bcl-2 positivity decreased both in the TMZ and DEX treatments. Conclusions: Both TMZ and DEX have protective effects against liver damage. These effects are likely mediated through the reduction in ERS and apoptosis, with DEX showing slightly superior protective effects compared with TMZ. Full article