Search Results (175)

Parasitoids exhibit remarkable abilities to manipulate host physiology, ensuring offspring survival and development. This study investigated the molecular mechanisms underlying how the parasitoid Cotesia chilonis modulates cold tolerance in its host, the rice stem borer Chilo suppressalis, using transcriptome sequencing. We found that the host larvae’s supercooling point was lowest at 3 days post-parasitism but increased significantly by day 4. Transcriptome analysis identified 507 differentially expressed genes (DEGs), including 235 up-regulated by parasitism. Functional enrichment revealed that these DEGs were primarily associated with ribosome biogenesis, protein processing in the endoplasmic reticulum (ER), and oxidative phosphorylation under parasitism stress. Notably, 24 DEGs linked to temperature tolerance were predominantly heat shock proteins (HSPs) and calcium signaling-related genes. The reliability of transcriptome data was confirmed via RT-qPCR for eight randomly selected DEGs. Functional assays demonstrated that parasitism stress significantly inhibited ER activity. However, HSP expression did not significantly affect ER activity or cytosolic Ca²⁺ concentration in the hemolymph cells of C. suppressalis larvae. This research provides insights into the complex physiological and molecular mechanisms through which C. suppressalis responds to parasitism stress, particularly concerning cold tolerance modulation. Full article

Schizophrenia, depression, and bipolar disorder may represent neurodegenerative conditions involving both degeneration and aberrant regeneration of monoaminergic axons. Negative and cognitive symptoms could arise from monoaminergic axon degeneration, whereas positive symptoms and manic states might result from excessive axonal regeneration and sprouting. The molecular mechanisms driving these opposing processes remain largely unclear. This review considers the possible role of calcium-independent phospholipase A₂ (iPLA2) in regulating monoamine axon degeneration and hyper-regeneration in schizophrenia. Emerging evidence suggests that pro-inflammatory signaling mediated by cytosolic PLA₂ (cPLA2) may promote monoamine axon degeneration, while anti-inflammatory iPLA2 activity could facilitate regeneration and sprouting. Overactivation of iPLA2 might lead to aberrant axonal sprouting, potentially contributing to positive symptoms through hyperdopaminergic states in the medial prefrontal cortex (mPFC). Conversely, axon degeneration in the same region may underlie negative and cognitive symptoms. The review also discusses a potential interplay between dopamine and N-methyl-D-aspartate (NMDA) receptor signaling in distinct neuronal populations of the mPFC and suggests that targeting iPLA2 and its pathways could represent a promising therapeutic strategy. Viewing schizophrenia and related disorders through the lens of monoamine axon pathology may eventually improve diagnostic precision and inform the development of treatments aimed at restoring the balance between degeneration and regeneration. Full article

The cytosolic pH (pH_i) of mammalian cells is tightly maintained at values ~7.2. Cytoplasmic acidosis (pH_i < 6.8) occurs when the intracellular proton concentration ([H⁺]_i) exceeds the buffering capacity of the cytosol and transport processes to extrude protons are exhausted. During intracellular acidosis, the contractility of cardiac and skeletal muscle cells is strongly reduced, often at sufficient Ca²⁺ levels. A contraction of striated muscle is achieved when the intracellular calcium (Ca²⁺) concentration rises above resting levels. The amplitude and kinetics of Ca²⁺ signals are controlled by Ca²⁺ handling proteins and force is generated if Ca²⁺ ions interact with contractile filaments of the sarcomere. Some aspects of this phenomenon, such as the biochemical origin of excessive protons in working muscle cells and molecular interactions of protons with Ca²⁺ handling proteins or contractile filaments, are not yet fully understood. This review summarizes our current understanding of how striated muscle cells handle Ca²⁺ and H⁺ and how a rise in [H⁺]_i may interfere with Ca²⁺ signaling in the working skeletal muscle (fatigue) or during ischemic events in cardiac muscle. Finally, we briefly address experimental strategies to measure Ca²⁺ signaling at different pH values with fluorescent probes and highlight their limitations. Full article

While calcium (Ca²⁺) is a universal cellular messenger, the ionic properties of magnesium (Mg²⁺) make it less suited for rapid signaling and more for structural integrity. Still, besides being a passive player, Mg²⁺ is the only active Ca²⁺ antagonist, essential for tuning the efficacy of Ca²⁺-dependent cardiac excitation–contraction coupling (ECC) and for ensuring cardiac function robustness and stability. This review aims to provide a comprehensive framework to link the structural and molecular mechanisms of Mg²⁺/Ca²⁺ antagonistic binding across key proteins of the cardiac ECC machinery to their physiopathological relevance. The pervasive “dampening” effect of Mg²⁺ on ECC activity is exerted across various players and mechanisms, and lies in the ions’ physiological competition for multiple, flexible binding protein motifs across multiple compartments. Mg²⁺ profoundly modulates the cardiac action potential waveform by inhibiting the L-type Ca²⁺ channel Cav1.2, i.e., the key trigger of cardiac ryanodine receptor (RyR2) opening. Cytosolic Mg²⁺ favors RyR2 closed or inactive conformations not only through physical binding at specific sites, but also indirectly through modulation of RyR2 phosphorylation by Camk2d and PKA. RyR2 is also potently inhibited by luminal Mg²⁺, a vital mechanism in the cardiac setting for preventing excessive Ca²⁺ release during diastole. This mechanism, able to distinguish between Ca²⁺ and Mg²⁺, is mediated by luminal partners Calsequestrin 2 (CASQ2) and Triadin (TRDN). In addition, Mg²⁺ favors a rearrangement of the RyR2 cluster configuration that is associated with lower Ca²⁺ spark frequencies. Full article

Alzheimer’s disease (AD) is increasingly recognized as a multifactorial disorder driven by a combination of disruptions in proteostasis and organelle communication. The 2020 Lancet commission reported that approximately 10 million people worldwide were affected by AD in the mid-20th century. AD is the most prevalent cause of dementia. By early 2030, the global cost of dementia is projected to rise by USD 2 trillion per year, with up to 85% of that cost attributed to daily patient care. Several factors have been implicated in the progression of neurodegeneration, including increased oxidative stress, the accumulation of misfolded proteins, the formation of amyloid plaques and aggregates, the unfolded protein response (UPR), and mitochondrial–endoplasmic reticulum (ER) calcium homeostasis. However, the exact triggers that initiate these pathological processes remain unclear, in part because clinical symptoms often emerge gradually and subtly, complicating early diagnosis. Among the early hallmarks of neurodegeneration, elevated levels of reactive oxygen species (ROS) and the buildup of misfolded proteins are believed to play pivotal roles in disrupting proteostasis, leading to cognitive deficits and neuronal cell death. The accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles is a characteristic feature of AD. These features contribute to chronic neuroinflammation, which is marked by the release of pro-inflammatory cytokines and chemokines that exacerbate oxidative stress. Given these interconnected mechanisms, targeting stress-related signaling pathways, such as oxidative stress (ROS) generated in the mitochondria and ER, ER stress, UPR, and cytosolic chaperones, represents a promising strategy for therapeutic intervention. This review focuses on the relationship between stress chaperone responses and organelle function, particularly the interaction between mitochondria and the ER, in the development of new therapies for AD and related neurodegenerative disorders. Full article

Reactive oxygen species (ROS) play a dual role as both essential signaling molecules and harmful mediators of damage. Imbalances in the redox state of the liver can overwhelm antioxidant defenses and promote mitochondrial dysfunction, oxidative damage, and inflammation. Complex feedback loops between ROS and immune signaling pathways are a hallmark of pathological liver conditions, such as hepatic ischemia–reperfusion injury (IRI). This is a major cause of liver transplant failure and is of increasing significance due to the increased use of marginally discarded livers for transplantation. This review outlines the major enzymatic and metabolic sources of ROS in hepatic IRI, including mitochondrial reverse electron transport, NADPH oxidases, cytochrome P450 enzymes, and endoplasmic reticulum stress. Hepatocyte injury activates redox feedback loops that initiate immune cascades through DAMP release, toll-like receptor signaling, and cytokine production. Emerging regulatory mechanisms, such as succinate accumulation and cytosolic calcium–CAMKII signaling, further shape oxidative dynamics. Pharmacological therapies and the use of antioxidant and immunomodulatory approaches, including nanoparticles and redox-sensitive therapeutics, are discussed as protective strategies. A deeper understanding of how redox and immune feedback loops interact is an exciting and active area of research that warrants further clinical investigation. Full article

Calcium (Ca²⁺) is a macronutrient essential for the growth, development, yield, and quality of vegetables and fruits. It performs structural, enzymatic, and signaling functions in plants. This review examines Ca²⁺ translocation from soil to the fruit via the plant xylem network, emphasizing the importance of Ca²⁺ compartmentalization within fruit cell organelles in the development of calcium deficiency disorders such as blossom-end rot (BER). The underlying causes of BER and potential control measures are also discussed. Soil-available Ca²⁺, transported by water flow, enters the root apoplast through membrane channels and moves toward the xylem via apoplastic or symplastic routes. The transpiration force and the growth of organs determine the movement of Ca²⁺-containing xylem sap to aerial plant parts, including fruits. At the fruit level, the final step of Ca²⁺ regulation is intracellular partitioning among organelles and cellular compartments. This distribution ultimately determines the fruit’s susceptibility to Ca²⁺-deficiency disorders such as BER. Excessive sequestration of Ca²⁺ into organelles such as vacuoles may deplete cytosolic and apoplastic Ca²⁺ pools, compromising membrane integrity and leading to BER, even when overall Ca²⁺ levels are adequate at the blossom end. Effective BER management requires cultural and physiological practices that promote Ca²⁺ uptake, translocation to the fruit, and appropriate intracellular distribution. Additionally, the use of BER-resistant and Ca²⁺-efficient cultivars can help mitigate this disorder. Therefore, a comprehensive understanding of Ca²⁺ dynamics in plants is critical for managing BER, minimizing production loss and environmental impacts, and maximizing overall crop productivity. Full article

In addition to the male genome, the fertilizing spermatozoon delivers to the oocyte several factors whose deficiency can cause embryo dysfunction. Sperm oocyte-activating factor, identified as phoshoplipase C zeta (PLCζ), drives oocyte exit from meiotic arrest through a signaling pathway initiated by periodic rises of free cytosolic Ca²⁺ concentration (calcium oscillations). Sperm centrioles, together with oocyte proteins, form centrosomes that are responsible for aster formation, pronuclear migration, and DNA polarization before nuclear syngamy and subsequent mitotic divisions. Sperm DNA fragmentation can be at the origin of aneuploidies, while epigenetic issues, mainly abnormal methylation of DNA-associated histones, cause asynchronies of zygotic gene activation among embryonic cells. Sperm long and short non-coding RNAs are important epigenetic regulators affecting critical developmental processes. Dysfunction of sperm PLCζ, centrioles, DNA, and RNA mostly converge to aneuploidy, developmental arrest, implantation failure, miscarriage, abortion, or offspring disease. With the exception of DNA fragmentation, the other sperm issues are more difficult to diagnose. Specific tests, including heterologous human intracytoplasmic sperm injection (ICSI) into animal oocytes, genetic testing for mutations in PLCZ1 (the gene coding for PLCζ in humans) and associated genes, and next-generation sequencing of sperm transcriptome, are currently available. Oral antioxidant treatment and in vitro selection of healthy spermatozoa can be used in cases of sperm DNA fragmentation, while ICSI with assisted oocyte activation is useful to overcome oocyte-activation defects. No clinically confirmed therapy is yet available for sperm RNA issues. Full article

Calcium (Ca²⁺) signaling is a fundamental regulatory mechanism controlling essential processes in the endothelium, vascular smooth muscle cells (VSMCs), and the extracellular matrix (ECM), including maintaining the endothelial barrier, modulation of vascular tone, and vascular remodeling. Cytosolic free Ca²⁺ concentration is tightly regulated by a balance between Ca²⁺ mobilization mechanisms, including Ca²⁺ release from the intracellular stores in the sarcoplasmic/endoplasmic reticulum and Ca²⁺ entry via voltage-dependent, transient-receptor potential, and store-operated Ca²⁺ channels, and Ca²⁺ elimination pathways including Ca²⁺ extrusion by the plasma membrane Ca²⁺-ATPase and Na⁺/Ca²⁺ exchanger and Ca²⁺ re-uptake by the sarco(endo)plasmic reticulum Ca²⁺-ATPase and the mitochondria. Some cell membranes/organelles are multifunctional and have both Ca²⁺ mobilization and Ca²⁺ removal pathways. Also, the individual Ca²⁺ handling pathways could be integrated to function in a regenerative, capacitative, cooperative, bidirectional, or reciprocal feed-forward or feed-back manner. Disruption of these pathways causes dysregulation of the Ca²⁺ signaling dynamics and leads to pathological cardiovascular conditions such as hypertension, coronary artery disease, atherosclerosis, and vascular calcification. In the endothelium, dysregulated Ca²⁺ signaling impairs nitric oxide production, reduces vasodilatory capacity, and increases vascular permeability. In VSMCs, Ca²⁺-dependent phosphorylation of the myosin light chain and Ca²⁺ sensitization by protein kinase-C (PKC) and Rho-kinase (ROCK) increase vascular tone and could lead to increased blood pressure and hypertension. Ca²⁺ activation of matrix metalloproteinases causes collagen/elastin imbalance and promotes vascular remodeling. Ca²⁺-dependent immune cell activation, leukocyte infiltration, and cholesterol accumulation by macrophages promote foam cell formation and atherosclerotic plaque progression. Chronic increases in VSMCs Ca²⁺ promote phenotypic switching to mesenchymal cells and osteogenic transformation and thereby accelerate vascular calcification and plaque instability. Emerging therapeutic strategies targeting these Ca²⁺-dependent mechanisms, including Ca²⁺ channel blockers and PKC and ROCK inhibitors, hold promise for restoring Ca²⁺ homeostasis and mitigating vascular disease progression. Full article

Calcium is a versatile ion that regulates diverse intracellular processes, including cell death and survival, cytokine and chemokine production, lipid scrambling, and immune cell activation. In regulated necrosis, an early increase in cytosolic calcium is a hallmark of pathways such as pyroptosis, necroptosis, and ferroptosis, and resembles the calcium surge triggered by pore-forming toxins. The complexity of calcium signaling is orchestrated by specialized channels in various cellular compartments and calcium-binding proteins that respond to localized calcium concentrations. However, the coordination of this intricate code during regulated necrosis and its connections to other calcium-driven processes remains poorly understood. This review provides an overview of the molecular mechanisms of calcium signaling in regulated necrosis, analyzing parallels with pore-forming toxin-mediated membrane damage to uncover nodes that are shared by these seemingly independent pathways. We also discuss advanced techniques for studying calcium dynamics, with high precision, that can be applied to study regulated necrosis. Calcium signaling emerges as a central hub where necrotic cell death pathways converge, shaping the unique signatures of dying cells and influencing their communication with the immune system. This integrated perspective highlights the complex and multifaceted role of calcium in cells and its implications for fundamental cellular processes. Full article

Methylglyoxal is a reactive dicarbonyl intermediate in the advanced glycation end-product (AGE) pathway, and alterations in its levels have been detected in the plasma, cerebrospinal fluid, and brain parenchyma in various pathologies, particularly in diabetes. In this study, we investigate the effects of methylglyoxal (MGO) on murine brain microvascular endothelial cells at both physiological and pathological concentrations. We evaluate molecular parameters, including reactive oxygen species (ROS) production, cytosolic calcium signaling, and ATP synthesis, as well as cellular responses such as cytoskeletal remodeling, cell migration, adhesion, and permeability, across a concentration range of 0–1000 μM. At low concentrations (below ~250 μM), MGO does not induce oxidative stress; instead, it leads to an increase in cytosolic calcium levels and ATP production. At higher concentrations, however, MGO induces significant oxidative stress, which is accompanied by a marked decrease in cell viability, particularly at concentrations exceeding 500 μM. The modulation of key functional processes, including purinergic calcium signaling, actin filament synthesis, cell migration, and adhesion, reveals a threshold concentration beyond which cellular function is impaired due to oxidative stress. Below this threshold, the observed effects appear to be mediated primarily by non-oxidative mechanisms, likely involving protein glycation. In conclusion, our results suggest a dual action of methylglyoxal on brain endothelial cells, with distinct molecular mechanisms underlying its effects at physiological versus pathological concentrations. Full article

Mechanogated (MG) ion channels play a crucial role in mechano-transduction and immune cell regulation, yet their impact on blood cancers, particularly acute lymphoblastic leukemia (ALL), remains poorly understood. This study investigates the pharmacological effects of GsMTx4, an MG channel inhibitor, in human ALL cells both in vitro and in vivo. Unexpectedly, we found that GsMTx4 remarkably increased basal calcium (Ca²⁺) levels in ALL cells through constitutive Ca²⁺ entry and enhanced store-operated Ca²⁺ influx upon thapsigargin stimulation. This increase in basal Ca²⁺ signaling promoted ALL cell viability and proliferation in vitro. Notably, chelating intracellular Ca²⁺ with BAPTA-AM reduces GsMTx4-mediated leukemia cell viability and proliferation. However, in vivo, GsMTx4 decreases cytosolic Ca²⁺ levels in Nalm-6 GFP⁺ cells isolated from mouse blood, effectively countering leukemia progression and significantly extending survival in NSG mice transplanted with leukemia cells (median survival: GsMTx4 vs. control, 37.5 days vs. 29 days, p = 0.0414). Our results highlight the different properties of GsMTx4 activity in in vitro and in vivo models. They also emphasize that Ca²⁺ signaling is a key vulnerability in leukemia, where its precise modulation dictates disease progression. Thus, targeting Ca²⁺ channels could offer a novel therapeutic strategy for leukemia by exploiting Ca²⁺ homeostasis. Full article

Calpains, calcium-dependent cytosolic cysteine proteases, perform controlled proteolysis of their substrates for various cellular and physiological activities. In different cancers, missense mutations accumulate in the genes coding for the calpain cleavage sites in various calpain substrates termed as the calpain cleavage-related mutations (CCRMs). However, the impact of such CCRMs on the calpain–substrate interaction is yet to be explored. This study focuses on the interaction of wild-type and mutant β-integrins with calpain-1 and 2 in uterine corpus endometrial carcinoma (UCEC). A total of 48 calpain substrates with 176 CCRMs were retrieved from different datasets and shortlisted on the basis of their involvement in cancer pathways. Finally, three calpain substrates, ITGB1, ITGB3, and ITGB7, were selected to assess the structural changes due to CCRMs. These CCRMs were observed towards the C-terminal of the cytoplasmic domain within the calpain cleavage site. The wild-type and mutant proteins were docked with calpain-1 and 2, followed by molecular simulation. The interaction between mutant substrates and calpains showcased variations compared to their respective wild-type counterparts. This may be attributed to mutations in the calpain cleavage sites, highlighting the importance of the cytoplasmic domain of β-integrins in the interactions with calpains and subsequent cellular signaling. Highlights: 1. Calpain cleavage-related mutations (CCRMs) can alter cellular signaling. 2. CCRMs impact the structure of C-domains of human integrin-β subunits. 3. Altered structure influences the cleavability of human integrin-β subunits by human calpains. 4. Altered cleavability impacts the cell signaling mediated through calpain–integrin-β axis. 5. Presence of CCRMS may influence the progression of uterine corpus endometrial carcinoma (UCEC). Full article

Calcium ions (Ca²⁺) are an important secondary messenger in plant signal transduction networks. The cytosolic free Ca²⁺ concentration ([Ca²⁺]_i) of plants changes rapidly when they are subjected to different abiotic stresses, which drives calcium signaling. Although this process has been extensively studied in spermatophytes, the details of calcium signaling in bryophytes remains largely unknown. In our study, we reconstituted aequorin in the bryophyte Physcomitrella patens, optimized the percentage of ethanol in the Ca²⁺ discharging solution, and measured the [Ca²⁺]_i changes induced by different stresses. In addition, we observed that the sources of Ca²⁺ accessed following exposure to cold, drought, salt, and oxidative stress were different. Furthermore, we showed that long-term saline environments could suppress the basal [Ca²⁺]_i of P. patens, and the peak value of [Ca²⁺]_i induced by different stresses was lower than that of plants growing in non-stressed environments. This is the first systematic study of calcium signaling in bryophytes, and we provided an efficient and convenient tool to study calcium signaling in response to different abiotic stresses in bryophytes. Full article

Long non-coding RNAs (lncRNAs) are involved in plant biotic and abiotic stress responses, in which Ca²⁺ also plays a significant role. There is diversity in the regulation of different gene expressions by cytosolic Ca²⁺ ([Ca²⁺]_cyt) and nucleosolic Ca²⁺ ([Ca²⁺]_nuc). However, no studies have yet explored the interrelationship between lncRNAs and calcium signaling, nor how calcium signaling regulates the expression of lncRNAs. Here, we use transgenic materials PV-NES and NLS-PV, which simulate [Ca²⁺]_cyt- and [Ca²⁺]_nuc-deficient mutants, respectively, and wild type (WT) materials in response to hyperosmolarity (250 mM sorbitol) or salt stresses (125 mM NaCl) at different time points to obtain RNA-seq data, respectively. Then, we proceed with the screening of lncRNAs, adding 688 new lncRNAs to the known Arabidopsis lncRNA database. Subsequently, through the analysis of differentially expressed lncRNA genes, it was found that cytosolic or nucleosolic calcium signals have distinct regulatory effects on differentially expressed lncRNAs (DElncRNAs) and differentially expressed protein-coding genes (DEPCGs) treated with high-concentration NaCl and sorbitol at different times. Furthermore, through weighted correlation network analysis (WGCNA), it is discovered that under hyperosmolarity and salt stresses, lncRNA-associated PCGs are related to the cell wall structure, the plasma membrane component, and osmotic substances through trans-regulation. In addition, by screening for cis-regulatory target PCGs of Ca²⁺-regulated lncRNAs related to osmotic stress, we obtain a series of lncRNA-PCG pairs related to water transport, cell wall components, and lateral root formation. Therefore, we expand the existing Arabidopsis lncRNA database and obtain a series of lncRNAs and PCGs regulated by [Ca²⁺]_cyt or [Ca²⁺]_nuc in response to salt and hyperosmolarity stress, providing a new perspective for subsequent research on lncRNAs. We also explore the trans- and cis-regulated target PCGs of lncRNAs regulated by calcium signaling, providing new insights for further studying salt stress and osmotic stress. Full article