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Calcium (Ca 2+ ) overload therapy gained significant attention in oncology. However, its therapeutic efficacy remained limited due to insufficient Ca 2+ accumulation at the tumor site and suboptimal intracellular Ca 2+ influx. In this study, gambogic acid (GA), a natural phenolic compound known to promote Ca 2+ influx, was encapsulated within an enzyme-triggered, pH-responsive hydrogel (GM@Lip@CHP-Gel) containing Ca 2+ hydrogen phosphate nanowires (CHP) to achieve a synergistic approach for bone tumor therapy. GM@Lip@CHP-Gel selectively responded to the slightly acidic tumor microenvironment, triggering degradation of its 3D network structure and sustaining the release of GA and Ca 2+ into tumor cells. GA subsequently stimulated Ca 2+ influx in tumor cells, effectively disrupting Ca 2+ homeostasis. CHP nanowires served as a continuous Ca 2+ source, enhancing GA-mediated Ca 2+ overload and promoting mitochondrial apoptosis in tumor cells. The combined strategy resulted in an in vivo tumor suppression rate of 79 % and a lung metastasis inhibition rate of 89.4 %, with a protective effect on bone tissue. The naturally derived, Ca 2+ -mediated treatment demonstrated physiochemical stability in physiological environments and minimized side effects on healthy organs, positioning it as a promising approach for clinical bone cancer therapy., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The concept of immunogenic cell death (ICD) induced by chemotherapy as a potential synergistic modality for cancer immunotherapy has been widely discussed. Unfortunately, most chemotherapeutic agents failed to dictate effective ICD responses due to their defects in inducing potent ICD signaling. Here, we report a dual-enzyme-instructed peptide self-assembly platform of CPMC (CPT-GFFpY-PLGVRK-Caps) that cooperatively utilizes camptothecin (CPT) and capsaicin (Caps) to promote ICD and engage systemic adaptive immunity for tumor rejection. Although CPT and Caps respectively prevent tumor progression by inhibiting type-I DNA topoisomerase and activating transient receptor potential cation channel subfamily V member 1 (TRPV1) for intracellular calcium overload, neither alone effectively stimulates sufficient ICD signaling to meet immunotherapeutic needs. CPMC , sequentially allowing an active Caps derivative of VRK-Caps and CPT to release extracellularly and intracellularly, can synergize two distinct apoptosis pathways stimulated by Caps and CPT to increase tumor immunogenicity and elicit systemic T-cell-based immunity. Consequently, CPMC facilitates the generation of improved tumor-specific cytotoxic T-cell responses and sustained immunological memory, successfully suppressing both primary and distant tumors. Moreover, CPMC can render tumors susceptible to PD-L1 blockade and synergize with an antiprogrammed cell death-ligand 1 (aPDL1) antibody for tumor inhibition. Combining two cancer chemotherapeutic drugs with low ICD-stimulating capacity using a peptide self-assembly strategy was demonstrated to boost ICD responses and potentiate cancer immunotherapy.

Acute pancreatitis (AP) is an inflammatory disease of the pancreas and a complex process involving multiple factors, with mitochondrial damage playing a crucial role. Mitochondrial dysfunction is now considered a key driver in the development of AP. This dysfunction often presents as increased oxidative stress, altered membrane potential and permeability, and mitochondrial DNA damage and mutations. Under stress conditions, mitochondrial dynamics and mitochondrial ROS production increase, leading to decreased mitochondrial membrane potential, imbalanced calcium homeostasis, and activation of the mitochondrial permeability transition pore. The release of mitochondrial DNA (mtDNA), recognized as damage-associated molecular patterns, can activate the cGAS-STING1 and NF-κB pathway and induce pro-inflammatory factor expression. Additionally, mtDNA can activate inflammasomes, leading to interleukin release and subsequent tissue damage and inflammation. This review summarizes the relationship between mitochondria and AP and explores mitochondrial protective strategies in the diagnosis and treatment of this disease. Future research on the treatment of acute pancreatitis can benefit from exploring promising avenues such as antioxidants, mitochondrial inhibitors, and new therapies that target mitochondrial dysfunction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Xu, Han, Ding, Ren, Wang, Ma and Cao.)

Cuproptosis is an emerging form of programmed cell death and shows enormous prospect in cancer treatment. Excessive generation of reactive oxygen species (ROS), metal ion accumulation, and the tricarboxylic acid (TCA) cycle collapse are pivotal elements in the triggering of cell death via mitochondrial pathways. Herein, a cascade nanoreactor CaCuZC has been constructed by incorporating nanosonosensitizer IR780 carbon dots (IR780 CD) and calcium peroxide (CaO 2 ) into metal-organic frameworks (MOF) for synergistic cuproptosis-ferroptosis and Ca 2+ overload mediated immunotherapy. Within tumor cells, CaCuZC dissociates into CaO 2 , Cu 2+ and sonosensitizer IR780 CD. The decomposition of CaO 2 could generate H 2 O 2 to strengthen the Cu 2+ -based chemodynamic therapy and Ca 2+ overload induces amplified intracellular oxidative stress, thus leading to mitochondrial dysfunction. As a result, the combination of Cu 2+ and Ca 2+ overload together induce cascade mitochondrial damage. Moreover, the sonosensitizer IR780 CD generates ROS under ultrasound irradiation to amplify intracellular oxidative stress. In addition, the overloaded Cu 2+ released from CaCuZC leads to the aggregation of lipoylated protein dihydrolipoamide S-acetyltransferase, thus resulting in cuproptosis. Furthermore, ferroptosis could been concomitantly induced by CaCuZC with intracellular glutathione (GSH) consumption and lipid peroxidation (LPO) accumulation. The cuproptosis-ferroptosis and Ca 2+ overload-enhanced synergistic therapy also activates robust immunogenic cell death. CaCuZC enhances the infiltration and activation of tumor-specific cytotoxic T cells to transform a "cold" tumor into a "hot" tumor, activating the anti-tumor immune response. This study provides a cascade of mitochondrial damage strategy for triggering cuproptosis-ferroptosis and Ca 2+ overload-enhanced immunotherapy and achieving improved therapeutic effects. STATEMENT OF SIGNIFICANCE: To improve the efficacy of tumor immunotherapy, a cascade nanoreactor CaCuZC was successfully constructed based on a self-assembly strategy for cuproptosis-ferroptosis and Ca 2+ overload mediated immunotherapy. Upon decomposition within the acidic and GSH-overexpressing tumor microenvironment, CaCuZC released CaO 2 and Cu 2+ and sonosensitizer IR780 CD. The CaO 2 further produced H 2 O 2 /O 2 and Ca 2+ in a weakly acidic environment to strengthen the Cu 2+ -based CDT and IR780 CD-mediated SDT, respectively. The overload copper ions not only led to cuproptosis, but also efficiently induced ferroptosis. The cuproptosis-ferroptosis and Ca 2+ overload-enhanced synergistic therapy also activates robust immunogenic cell death. This study presents a cascade of mitochondrial damage strategy for cuproptosis-ferroptosis and Ca 2+ overload-enhanced immunotherapy., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Various second messengers exert some vital actions in biological systems, including cancer therapy, but the therapeutic efficacy is often need to be improved. A semiconducting polymer nanomessenger (TCa/SPN/a) consisting of two second messengers, calcium ion (Ca 2+ ) and cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) for metastatic breast cancer therapy, is reported here. Such a TCa/SPN/a is constructed to exhibit X-ray response for the activatable delivery of mitochondria-targeting Ca compound and cGAMP as stimulator of interferon genes (STING) agonist. With X-ray irradiation, TCa/SPN/a could generate singlet oxygen ( 1 O 2 ) via radiodynamic effect for ablating solid tumors and improving the tumor immunogenicity by inducing immunogenic cell death (ICD). Furthermore, the released mitochondria-targeting Ca compounds show a high binging effect on mitochondria and cause reactive oxygen species (ROS) generation and mitochondria damage via calcium overload, while cGAMP boosts immunological effect through activating STING pathway. In this way, TCa/SPN/a enables a radiodynamic-activated calcium overload and immunotherapy to obviously inhibit the growths of bilateral tumors and also abolish tumor metastasis in metastatic breast cancer mouse models. This article should demonstrate the first smart dual-functional nanotherapeutic containing two second messengers for precise and specific cancer therapy., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Lung ischemia-reperfusion (I/R) injury is the main risk factor for primary graft dysfunction and patient death after lung transplantation (LTx). It is widely accepted that the main pathological mechanism of lung I/R injury are calcium overload, oxygen free radical explosion and neutrophil-mediated damage, which leading to the lack of effective treatment options. The aim of this study was to further explore the mechanisms of lung I/R injury after LTx and to provide potential therapeutic strategies. Our bioinformatics analysis revealed that the neutrophil extracellular traps (NETs) formation was closely involved in lung I/R injury after LTx, which was accompanied by up-regulation of peptidylprolyl isomerase F (PPIF) and peptidyl arginine deiminase 4 (PADI4). We further established an orthotopic LTx mouse model to simulate lung I/R injury in vivo, and found that PPIF and PADI4 inhibitors effectively reduced neutrophil infiltration, NETs formation, inflammatory response, and lung I/R injury. In the neutrophil model induced by HL-60 cell line in vitro, we found that PPIF inhibitor cyclosporin A (Cys A) better alleviated calcium overload induced inflammatory response, reactive oxygen species content and NETs formation. Further study demonstrated that interfering with neutrophil PPIF protected mitochondrial function by alleviating store-operated calcium entry (SOCE) during calcium overload and played the above positive role. On this basis, we found that the reduction of calcium content in neutrophils was accompanied by the inhibition of calcineurin (CN) and nuclear factor of activated T cells (NFAT). In conclusion, our findings suggested that neutrophil PPIF could serve as a novel biomarker and potential therapeutic target of lung I/R injury after LTx, which provided new clues for its treatment by inhibiting calcium overload-induced NETs formation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Fluoride, a naturally occurring element found in water, soil, food, and atmospheric precipitation, can lead to fluorosis and various health issues when consumed excessively. However, the mechanism of fluorosis is still under investigation. This study utilizes Caenorhabditis elegans as a model organism to investigate the effects of fluoride exposure on biological systems and to explore the mechanisms by which curcumin mitigates fluoride-induced toxicity. Three groups were established: a blank control, a sodium fluoride (NaF) exposure group (concentration 5 mmol/L), and a curcumin intervention group (concentration 25 μmol/L). Physiological parameters, lipofuscin levels, intracellular reactive oxygen species (ROS) levels, mitochondrial membrane potential, and mitochondrial copy numbers were measured to assess the effects of fluoride toxicity and curcumin protection. RNA-seq and qRT-PCR were utilized to investigate the molecular mechanisms underlying fluoride-induced damage and curcumin's mitigating effects. Results indicated that fluoride-exposed nematodes displayed physiological abnormalities, increased ROS production, higher lipofuscin levels, altered mitochondrial membrane potential and mitochondrial copy number, and activated MAPK signaling pathway genes. Curcumin exhibited protective effects on these parameters, suggesting its potential in preventing fluoride-induced harm by modulating oxidative stress and preserving mitochondrial function. This research enhances our understanding of the mechanisms of fluoride toxicity and highlights the potential benefits of curcumin., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Transient receptor potential vanilloid 1 (TRPV1) pathway can result in the disruption of intracellular calcium ion (Ca 2+ ) homeostasis, but how to effectively control the process of Ca 2+ overload needs to be addressed for tumor treatment. Herein, we developed a mild photothermal activation of TRPV1 pathway strategy for enhanced Ca 2+ overload therapy of hepatocellular carcinoma, in which the multifunctional nanoparticle (CNQ) loading with CaCO 3 , a novel polycyclic conjugated small molecule (2Br-NDIA) and quercetin (Qu) as the core for the efficient mild photothermal therapy (PTT). The photothermal property of CNQ can specifically activate the TRPV1 channel, which leads to mitochondrial Ca 2+ overloading and the disruption of intracellular Ca 2+ homeostasis. This CNQ-mediated activation of the TRPV1 channel by mild PTT provides an emerging paradigm for enhancing mitochondrial Ca 2+ overload therapy and dismantling tumor self-defense, safely expanding cancer therapies for highly refractory tumors., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Targeted breast cancer therapies hold the potential to improve the efficiency of drug delivery to the pathology site without impacting the viability and function of healthy cells. Herein, we developed multifunctional nanocarriers that target simultaneously several downstream signaling processes in triple negative breast cancer cells. The system comprises pH sensitive CaCO 3 nanoparticles (NPs) as carriers of the anticancer drug doxorubicin (DOX). The NPs were coated in a layer-by-layer (LbL) fashion using poly-l-lysine and hyaluronic acid to target receptors overexpressed in breast cancer (e.g. CD44, RHAMM). Spheroids of the triple-negative Hs578T cell line were used as a 3D model to assess the therapeutic potential of this system. Our results showed that the NPs act via a synergistic mechanism that combines Ca 2+ overload causing cell calcification and DNA damage by DOX. The LbL coating was crucial for the protection of the healthy cells, i.e. it provides NPs with targeting capacity. The overall data suggests that the LbL-coated NPs loaded with DOX hold great potential for the treatment of breast cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Acute pancreatitis is a potentially life-threatening inflammatory disorder of the exocrine pancreas characterized by early activation of pancreatic enzymes followed by macrophage-driven inflammation, and pancreatic acinar cell death. The most common causes are gallstones and excessive alcohol consumption. Inflammation and oxidative stress play critical roles in its pathogenesis. Despite increasing incidence, currently, no specific drug therapy is available to treat or prevent acute pancreatitis, in particular severe acute pancreatitis. New therapeutic agents are very much needed. Plant polyphenols have attracted extensive attention in the field of acute pancreatitis due to their diverse pharmacological properties. In this review, we discuss the potential of plant polyphenols in inhibiting the occurrence and development of acute pancreatitis via modulation of inflammation, oxidative stress, calcium overload, autophagy, and apoptosis, based on the currently available in vitro, in vivo animal and very few clinical human studies. We also outline the opportunities and challenges in the clinical translation of plant polyphenols for the treatment of the disease. We concluded that plant polyphenols have a potential therapeutic effect in the management and treatment of acute pancreatitis. Knowledge gained from this review will hopefully inspire new research ideas and directions for the development and application of plant polyphenols for treating this disease., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Cadmium (Cd) is a neurotoxicant that gradually accumulates in the human body with age. High Cd burden is correlated with adult hippocampal neurogenesis (AHN) and memory deficits in mammals. However, little knowledge is known about the mechanism by which Cd exposure impairs neurogenesis and cognition. Here, we investigated the roles of store-operated calcium entry (SOCE)-mediated calcium dyshomeostasis in Cd-induced AHN and memory deficits as well as therapeutic potential for the prevention of Cd-induced neurotoxicity. To achieve this goal, 8 weeks-old C57BL/6 J mice were subjected to different concentrations of cadmium chloride (0, 5, 10, 20 ppm) in drinking water for 8 weeks, we then examined the AHN, calcium homeostasis, SOCE channel and memory in Cd-exposed mice by using immunohistochemistry, calcium imaging, Y-maze and fear conditioning test. Our results indicated that chronic Cd exposure markedly increased Cd levels in serum and cerebrospinal fluid by almost 10-fold, and inhibited the proliferation and differentiation of hippocampal adult neural stem cells in a dose-dependent manner. Additionally, Cd exposure impaired the maturation of hippocampal neural stem cells without inducing gliosis. Transcriptome analysis revealed that Cd exposure inhibited the proliferation of neuroblastoma via alteration of calcium signaling pathway, and attenuated SOCE channels played a pivotal role in mediating Cd-induced cytoplasmic calcium overload and depletion of endoplasmic reticulum calcium stores. Activation of SOCE by hyperforin, a natural derivative from medicinal plant, restored intracellular calcium homeostasis and improved AHN and memory in Cd-exposed mice. Together, this study provided novel insights into the mechanism that Cd exposure impaired AHN and memory by prompting neuronal SOCE-mediated calcium dyshomeostasis, and offered a new therapeutic approach for prevention of Cd-induced neurotoxicity., Competing Interests: Declaration of Competing Interest The authors declared no competing interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The purposes of this study were to (i) verify the role of CXCR2 in tacrolimus-induced nephrotoxicity, (ii) explore the specific mechanism of CXCR2-mediated tacrolimus nephrotoxicity, and (iii) target the antagonism of CXCR2 and provide a potential target for the treatment of tacrolimus-induced nephrotoxicity in children., Methods: CXCR2 knockout (CXCR2-KO) mice were used to evaluate the role of CXCR2 in tacrolimus-induced nephrotoxicity. Wistar rats were used to explore the underlying mechanism., Results: In the knockout mice, compared with N-WT group, the renal function index was deteriorative (P < 0.01), the degree of renal fibrosis was aggravated (P < 0.01), the pathological expression of E-cadherin (P < 0.01) and α-SMA (P < 0.01) were occurred in T-WT group. Inversely, compared with T-WT group, the above indicators were improved in T-KO group (P < 0.01). In wistar rats, compared with N group, the renal function index was deteriorative (P < 0.05 or P < 0.01), fibrosis and calcium overload occurred (P < 0.01), CXCL2-CXCR2 was activated (P < 0.05), and meanwhile PI3K/AKT/mTOR pathway was activated (P < 0.05 or P < 0.01) in T group. Inversely, compared with T group, the above indicators were reversed in C group (P < 0.05 or P < 0.01)., Conclusion: The present study was firstly to report that CXCL2-CXCR2 activated PI3K/AKT/mTOR pathway and calcium overload in tacrolimus-induced nephrotoxicity, and targeting CXCR2 could inhibit the progression of tacrolimus-induced nephrotoxicity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Metalloimmunotherapy has achieved great preclinical success against malignant tumors. Nonetheless, the limited immune cell infiltration and impaired immunogenicity within the tumor microenvironment (TME) significantly hinder its translation to clinical applications. In this study, a zinc coordination lipid nanoparticle is developed loaded with calcium peroxide hydrate (CaO 2 ) nanoparticles and the STING agonist diABZI-2, which is termed A-CaO 2 -Zn-LNP. The release of Zn 2+ from the A-CaO 2 -Zn-LNP and the calcium overload synergistically induced immunogenic cell death (ICD). In addition, CaO 2 nanoparticles can consume H + and release oxygen (O 2 ) under acidic conditions. This treatment increased the pH and alleviated the hypoxia of the TME. Along with cGAS-STING activation by diABZI-2, A-CaO 2 -Zn-LNP ultimately results in enhanced anti-tumor systemic immunity and long-term immune memory via alleviating the immunosuppressive microenvironment. Taken together, A-CaO 2 -Zn-LNP offers a new nanoplatform that expands its application for cancer treatment by metalloimmunotheray., (© 2024 Wiley‐VCH GmbH.)

Bufalin is a promising active ingredient in traditional Chinese medicine but has shown limited anticancer applications due to its toxicity. Here, we report BCNPs@gel, a bufalin-containing CaCO 3 nanoparticle hydrogel, for enhancing cancer treatment through inducing cellular pyroptosis. Under the tumor microenvironment's low pH conditions, bufalin and Ca 2+ are released from the delivery system. Bufalin serves as a direct anticancer drug and a Na + /K + -ATPase inhibitor by forcing the Na + /Ca 2+ exchanger to reverse its function, which transfers Ca 2+ into cytoplasm and ultimately causes Ca 2+ overload-triggered pyroptosis. Meanwhile, we found that bufalin can upregulate PD-L1 in tumor cells. In combination with the PD-1 antibody, the delivery system showed a greater performance during the cancer treatment. BCNPs@gel enhances antitumor efficiency, reduces systemic side effects, extends antitumor mechanism of bufalin, and provides new strategies for inducing pyroptosis and calcium overload in cancer immunotherapy via Na + /K + -ATPase inhibitor. This work provides an application model for numerous other traditional Chinese medicine ingredients.

Unfavorable phenotypes characterized by low immunogenicity and acidity within the tumor microenvironment (TME) contribute to immunosuppression and therapeutic resistance. Herein, we rationally synthesized a multifunctional nanoregulator by encapsulating DOX and erianin into calcium carbonate (CaCO 3 )-based nanoparticles using a modified double emulsion method. The DOX and erianin-loaded CaCO 3 -based nanoparticles, termed DECaNPs, could effectively induce the calcium overload by triggering calcium influx and absorbing CaCO 3 nanoparticles. Additionally, DECaNPs also neutralize the acidic TME by interacting with extracellular protons and limiting lactic acid production, a result of metabolic remodeling in cancer cells. As a result, DECaNPs elicit cellular oxidative stress damage, which mediates the activation of ferroptosis/apoptosis hybrid pathways, and profound immunogenic cell death. Treatment with DECaNPs could inhibit the growth of tumors by promoting oxidative stress, acid neutralization, metabolic remodeling, and protective antitumor immunity in vivo . In addition, DECaNPs could synergistically amplify the antitumor effects of αPD-L1 in a bilateral tumor model by eliciting systemic immune responses. In all, our work presents the preparation of CaCO 3 -based nanoregulators designed to reverse the unfavorable TME and enhance αPD-L1 immunotherapy through multiple mechanisms.

The biomimetic nanoparticles (NPs) possessing abilities of tumor targeting and multimodal therapy show great potential for efficient combat of colon cancer. Herein, we developed a multifunctional biomimetic nanoplatform (Fe 3 O 4 @PDA@CaCO 3 -ICG@CM) based on CaCO 3 -modified magnetic polydopamine (PDA) loaded with indocyanine green (ICG), which was encapsulated by a mouse lymphoma cell (EL4) membrane (CM) expressing functional proteins (i.e., lymphocyte function-associated antigen 1, LFA-1; transforming growth factor-β receptor, TGF-βR; programmed cell death protein 1, PD-1; and factor related apoptosis ligand, FasL). Under magnetic attraction and LFA-1/PD-1-mediated endocytosis, Fe 3 O 4 @PDA@CaCO 3 -ICG@CM efficiently targeted CT26 colon tumor cells. The released calcium ion (Ca 2+ ) from the NPs triggered by acidic tumor microenvironment, the enhanced photothermal effect contributed by the combination of PDA and ICG, and FasL's direct killing effect together induced tumor cells apoptosis. Moreover, the apoptosis of CT26 cells induced immunogenic cell death (ICD) to promote the maturation of dendritic cells (DCs) to activate CD4 + /CD8 + T cells, thereby fighting against tumor cells, which could further be boosted by programmed death-ligand 1 (PD-L1) blockage and transforming growth factor-β (TGF-β) scavenging by Fe 3 O 4 @PDA@CaCO 3 -ICG@CM. As a result, in vivo satisfactory therapeutic effect was observed for CT26 tumor bearing-mice treated with Fe 3 O 4 @PDA@CaCO 3 -ICG@CM under laser irradiation and magnetic attraction, which could eradicate primary tumors and restrain distant tumors through dual tumor targeting-assisted multimodal therapy and eliciting adaptive antitumor immune response, generating the immune memory for inhibiting tumor metastasis and recurrence. Taken together, the multifunctional biomimetic nanoplatform exhibits superior antitumor effects, providing an insightful strategy for the field of nanomaterial-based treatment of cancer.

Immune checkpoint inhibitors, are the fourth most common therapeutic tool after surgery, chemotherapy, and radiotherapy for colorectal cancer (CRC). However, only a small proportion (≈5%) of CRC patients, those with "hot" (immuno-activated) tumors, benefit from the therapy. Pyroptosis, an innovative form of programmed cell death, is a potentially effective means to mediate a "cold" to "hot" transformation of the tumor microenvironment (TME). Calcium-releasing hydroxyapatite (HAP) nanoparticles (NPs) trigger calcium overload and pyroptosis in tumor cells. However, current limitations of these nanomedicines, such as poor tumor-targeting capabilities and insufficient calcium (Ca) ion release, limit their application. In this study, chondroitin sulfate (CS) is used to target tumors via binding to CD44 receptors and kaempferol (KAE) is used as a Ca homeostasis disruptor to construct CS-HAP@KAE NPs that function as pyroptosis inducers in CRC cells. CS-HAP@KAE NPs bind to the tumor cell membrane, HAP released Ca in response to the acidic environment of the TME, and kaempferol (KAE) enhances the influx of extracellular Ca, resulting in intracellular Ca overload and pyroptosis. This is associated with excessive endoplasmic reticulum stress triggered activation of the stimulator of interferon genes/interferon regulatory factor 3 pathway, ultimately transforming the TME from "cold" to "hot"., (© 2024 The Author(s). Small published by Wiley‐VCH GmbH.)

Transient receptor potential melastatin (TRPM) channels have emerged as potential therapeutic targets for cerebral ischemia-reperfusion (I/R) injury. We highlight recent findings on the involvement of TRPM channels in oxidative stress, mitochondrial dysfunction, inflammation, and calcium overload. We also discuss the challenges and future directions in targeting TRPM channels for cerebral I/R injury., Competing Interests: Declaration of interests No interests are declared., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Renal tubular epithelial cell senescence plays a critical role in promoting and accelerating kidney aging and age-related renal fibrosis. Senescent cells not only lose their self-repair ability, but also can transform into senescence-associated secretory phenotype (SASP) to trigger inflammation and fibrogenesis. Recent studies show that mitochondrial dysfunction is critical for renal tubular cell senescence and kidney aging, and calcium overload and abnormal calcium-dependent kinase activities are involved in mitochondrial dysfunction-associated senescence. In this study we investigated the role of mitochondrial calcium overload and mitochondrial calcium uniporter (MCU) in kidney aging. By comparing the kidney of 2- and 24-month-old mice, we found calcium overload in renal tubular cells of aged kidney, accompanied by significantly elevated expression of MCU. In human proximal renal tubular cell line HK-2, pretreatment with MCU agonist spermine (10 μM) significantly increased mitochondrial calcium accumulation, and induced the production of reactive oxygen species (ROS), leading to renal tubular cell senescence and age-related kidney fibrosis. On the contrary, pretreatment with MCU antagonist RU360 (10 μM) or calcium chelator BAPTA-AM (10 μM) diminished D-gal-induced ROS generation, restored mitochondrial homeostasis, retarded cell senescence, and protected against kidney aging in HK-2 cells. In a D-gal-induced accelerated aging mice model, administration of BAPTA (100 μg/kg. i.p.) every other day for 8 weeks significantly alleviated renal tubuarl cell senescence and fibrosis. We conclude that MCU plays a key role in promoting renal tubular cell senescence and kidney aging. Targeting inhibition on MCU provides a new insight into the therapeutic strategy against kidney aging., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Myocardial ischemia-reperfusion injury (MIRI) frequently complicates postoperative cardiovascular disease treatment. Necroptosis, a cell death mechanism similar to apoptosis, is regulated by specific signaling pathways and plays an important role in MIRI. Receptor-interacting protein 3 (RIP3), a key protein regulating necroptosis during MIRI, directly phosphorylates calmodulin-dependent protein kinase II (CaMKII). Leading to mitochondrial permeablity transition pore (mPTP) opening and inducing necroptosis. Transient receptor potential canonical channel 6 (TRPC6) regulats Ca 2+ entry, is linked to CaMKII as an important upstream effector. However, the connection between TRPC6 and MIRI necroptosis remains unclear. The study aimed to investigate the relationship between TRPC6 and MIRI necroptosis, with a specific focus on elucidating the role of TRPC6 in regulating CaMKII phosphorylation during cardiac necroptosis via Ca 2+ modulation. METHODS AND RESULTS: The experiment used wild-type (WT) and TRPC6 knockout (TRPC6 -/- ) mice for I/R model construction, and H9c2 myocardial cell line for H/R model. After ischemia-reperfusion (I/R), TRPC6 protein levels in mice significantly increased, exacerbating myocardial injury, infarct size (IS), and cardiac function in WT mice. In contrast, TRPC6 knockout attenuated myocardial injury, IS, and improved cardiac function. The results showed a significant correlation between changes in CaMKII and TRPC6. TRPC6 knockout led to decreased intracellular calcium levels, CaMKII phosphorylation, reactive oxygen species levels, mPTP opening, and improve mitochondrial structure. CONCLUSION: I/R upregulates TRPC6, which mediates Ca 2+ entry and CaMKII phosphorylation, exacerbates oxidative stress, and induces necroptosis. These findings suggest a potential therapeutic avenue for mitigating MIRI by targeting TRPC6., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Hypoxia and high concentration of glutathione (GSH) in tumor seriously hinder the role of reactive oxygen species (ROS) and oxygen-dependence strategy in tumor treatment. In this work, a self-generating oxygen and self-consuming GSH hyaluronic acid (HA)-coated porphyrin nanoplatform (TAPPP@CaO 2 /Pt(IV)/HA) is established for enhancing photodynamic/ion/chemo targeting synergistic therapy of tumor. During the efforts of ROS production by nanosystems, a GSH consuming strategy is implemented for augmenting ROS-induced oxidative damage for synergetic cancer therapy. CaO 2 in the nanosystems is decomposed into O 2 and H 2 O 2 in an acidic environment, which alleviates hypoxia and enhances the photodynamic therapy (PDT) effect. Calcium overload causes mitochondria dysfunction and induces apoptosis. Pt (IV) reacts with GSH to produce Pt (II) for chemotherapy and reduce the concentration of GSH, protecting ROS from scavenging for augmenting ROS-induced oxidative damage. In vitro and in vivo results demonstrated the self-generating oxygen and self-consuming GSH strategy can enhance ROS-dependent PDT coupled with ion/chemo synergistic therapy. The proposed strategy not only solves the long-term problem that hypoxia limits therapeutic effect of PDT, but also ameliorates the highly reducing environment of tumors. Thus the preparation of TAPPP@CaO 2 /Pt(IV)/HA provided a novel strategy for the effective combined therapy of cancers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Defects in chaperone-mediated autophagy (CMA) are associated with cellular senescence, but the mechanism remains poorly understood. Here, we found that CMA inhibition induced cellular senescence in a calcium-dependent manner and identified its role in TNF-induced senescence of nucleus pulposus cells (NPC) and intervertebral disc degeneration. Based on structural and functional proteomic screens, PLCG1 (phospholipase C gamma 1) was predicted as a potential substrate for CMA deficiency to affect calcium homeostasis. We further confirmed that PLCG1 was a key mediator of CMA in the regulation of intracellular calcium flux. Aberrant accumulation of PLCG1 caused by CMA blockage resulted in calcium overload, thereby inducing NPC senescence. Immunoassays on human specimens showed that reduced LAMP2A, the rate-limiting protein of CMA, or increased PLCG1 was associated with disc senescence, and the TNF-induced disc degeneration in rats was inhibited by overexpression of Lamp2a or knockdown of Plcg1 . Because CMA dysregulation, calcium overload, and cellular senescence are common features of disc degeneration and other age-related degenerative diseases, the discovery of actionable molecular targets that can link these perturbations may have therapeutic value. Abbreviation: ATRA: all-trans-retinoic acid; BrdU: bromodeoxyuridine; CDKN1A/p21: cyclin dependent kinase inhibitor 1A; CDKN2A/p16-INK4A: cyclin dependent kinase inhibitor 2A; CMA: chaperone-mediated autophagy; DHI: disc height index; ER: endoplasmic reticulum; IP: immunoprecipitation; IP3: inositol 1,4,5-trisphosphate; ITPR/IP3R: inositol 1,4,5-trisphosphate receptor; IVD: intervertebral disc; IVDD: intervertebral disc degeneration; KD: knockdown; KO: knockout; Leu: leupeptin; MRI: magnetic resonance imaging; MS: mass spectrometry; N/L: NH 4 Cl and leupeptin; NP: nucleus pulposus; NPC: nucleus pulposus cells; PI: protease inhibitors; PLC: phospholipase C; PLCG1: phospholipase C gamma 1; ROS: reactive oxygen species; RT-qPCR: real-time quantitative reverse transcription PCR; SA-GLB1/β-gal: senescence-associated galactosidase beta 1; SASP: senescence-associated secretory phenotype; STV: starvation; TMT: tandem mass tag; TNF: tumor necrosis factor; TP53: tumor protein p53; UPS: ubiquitin-proteasome system.

Background: Zishenhuoxue decoction (ZSHX), a Chinese herbal medicine, exhibits myocardial and vascular endothelial protective properties. The intricate regulatory mechanisms underlying myocardial ischemic injury and its association with dysfunctional mitochondrial quality surveillance (MQS) remain elusive., Hypothesis/purpose: To study the protective effect of ZSHX on ischemic myocardial injury in mice using a TMBIM6 gene-modified animal model and mitochondrial quality control-related experiments., Study Design: Using model animals and myocardial infarction surgery-induced ischemic myocardial injury TMBIM6 gene-modified mouse models, the pharmacological activity of ZSHX in inhibiting ischemic myocardial injury and mitochondrial homeostasis disorder in vivo was tested., Methods: Our focal point entailed scrutinizing the impact of ZSHX on ischemic myocardial impairment through the prism of TMBIM6. This endeavor was undertaken utilizing mice characterized by heart-specific TMBIM6 knockout (TMBIM6 CKO ) and their counterparts, the TMBIM6 transgenic (TMBIM6 TG ) and VDAC1 transgenic (VDAC1 TG ) mice., Results: ZSHX demonstrated dose-dependent effectiveness in mitigating ischemic myocardial injury and enhancing mitochondrial integrity. TMBIM6 CKO hindered ZSHX's cardio-therapeutic and mitochondrial protective effects, while ZSHX's benefits persisted in TMBIM6 TG mice. TMBIM6 CKO also blocked ZSHX's regulation of mitochondrial function in HR-treated cardiomyocytes. Hypoxia disrupted the MQS in cardiomyocytes, including calcium overload, excessive fission, mitophagy issues, and disrupted biosynthesis. ZSHX counteracted these effects, thereby normalizing MQS and inhibiting calcium overload and cardiomyocyte necroptosis. Our results also showed that hypoxia-induced TMBIM6 blockade resulted in the over-activation of VDAC1, a major mitochondrial calcium uptake pathway, while ZSHX could increase the expression of TMBIM6 and inhibit VDAC1-mediated calcium overload and MQS abnormalities., Conclusions: Our findings suggest that ZSHX regulates mitochondrial calcium homeostasis and MQS abnormalities through a TMBIM6-VDAC1 interaction mechanism, which helps to treat ischemic myocardial injury and provides myocardial protection. This study also offers insights for the clinical translation and application of mitochondrial-targeted drugs in cardiomyocytess., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Calcium ions (Ca 2+ ) participate in the regulation of cellular apoptosis as a second messenger. Calcium overload, which refers to the abnormal elevation of intracellular Ca 2+ concentration, is a factor that can lead to cell death. Here, based on the unique biological effects of Ca 2+ , hollow mesoporous calcium peroxide nanoparticles (HMCPN) were developed by a facile hydrolysis-precipitation method for drug-free tumor calcicoptosis therapy. The average pore size of the optimized HMCPN17 is 6.4 nm, and the surface area is 81.3 m 2 /g, which enables HMCPN17 with high drug loading capability. The Ca 2+ release from HMCPN17 is much faster at pH 6.8 than that at pH 7.4, which can be ascribed to the acid-triggered conversion of HMCPN17 to Ca 2+ and H 2 O 2 , indicating a pH-responsive decomposition behavior of HMCPN17. The high drug loading contents of doxorubicin (DOX) and/or sorafenib (SFN) indicate that HMCPN17 can be employed as a generic drug delivery system (DDS). The in vitro and in vivo results reinforce the high calcicoptosis therapeutic efficacy of tumors by our HMCPN17 without drug loading, which can be attributed to the efficient accumulation in tumors and the ability of H 2 O 2 and Ca 2+ production at acidic TME. Our HMCPN17 has broad application prospect for construction of multi-drug-loaded composite nanomaterials with diversified functions for the treatment of tumors. STATEMENT OF SIGNIFICANCE: The combination of hollow mesoporous nanomaterials and calcium peroxide nanoparticles has a wide range of applications in the synergistic treatment of tumors. In this study, hollow mesoporous calcium peroxide nanoparticles (HMCPN) were developed based on a simple hydrolysis-precipitation method for tumor calcicoptosis therapy without drug loading. The high drug loading contents of DOX and/or SFN indicate that our HMCPN can serve as a generic DDS. The experimental results demonstrated the high calcicoptosis therapeutic efficacy of HMCPN on tumors even without drug loading., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

This article describes the case of a 40-year-old individual who presented with fulminant myocarditis. Initial ECG displayed sinus tachycardia with a heart rate of 117 bpm, QS complexes in leads V1-V3, ST-segment depression in leads II, III, aVF, V5-V6, and ST-segment elevation >0.2 mV in leads V1 through V3. The initial clinical assessment suggested an acute anteroseptal myocardial infarction. However, subsequent diagnostic evaluation through coronary angiography disclosed that the coronary arteries were normal. Therefore, clinicians should carefully consider the differential diagnosis between these conditions, as their management strategies differ markedly. Two hours after admission, the patient unexpectedly developed syncope. The ECG findings were consistent with the typical characteristics of bidirectional ventricular tachycardia. Our report described the appearance and morphology as well as mechanism of bidirectional ventricular tachycardia in detail. Additionally, we delineate differential diagnoses for disease that can cause bidirectional ventricular tachycardia, such as aconite poisoning, digoxin overdose, immune checkpoint inhibitor (ICI), myocardial ischemia, and hereditary channelopathies, such as catecholaminergic polymorphic ventricular tachycardia (CPVT) and Andersen-Tawil syndrome. Therefore, clinicians should recognize this ECG finding immediately and initiate appropriate treatment promptly as these measures may be vital in saving the patient's life., (© 2024 The Author(s). Annals of Noninvasive Electrocardiology published by Wiley Periodicals LLC.)

Calcium overload can lead to tumor cell death. However, because of the powerful calcium channel excretory system within tumor cells, simplistic calcium overloads do not allow for an effective antitumor therapy. Hence, the nanoparticles are created with polyethylene glycol (PEG) donor-modified calcium phosphate (CaP)-coated, manganese-doped hollow mesopores Prussian blue (MMPB) encapsulating glucose oxidase (GOx), called GOx@MMPB@CaP-PEG (GMCP). GMCP with a three-mode enhancement of intratumor reactive oxygen species (ROS) levels is designed to increase the efficiency of the intracellular calcium overload in tumor cells to enhance its anticancer efficacy. The released exogenous Ca 2+ and the production of cytotoxic ROS resulting from the perfect circulation of the three-mode ROS outbreak generation that Fenton/Fenton-like reaction and consumption of glutathione from Fe 2+ /Fe 3+ and Mn 2+ /Mn 3+ circle, and amelioration of hypoxia from MMPB-guided and GOx-mediated starvation therapy. Photothermal efficacy-induced heat generation owing to MMPB accelerates the above reactions. Furthermore, abundant ROS contribute to damage to mitochondria, and the calcium channels of efflux Ca 2+ are inhibited, resulting in a calcium overload. Calcium overload further increases ROS levels and promotes apoptosis of tumor cells to achieve excellent therapy., (© 2024 Wiley‐VCH GmbH.)

Background and Purpose: Excitotoxicity due to mitochondrial calcium (Ca 2+ ) overloading can trigger neuronal cell death in a variety of pathologies. Inhibiting the mitochondrial calcium uniporter (MCU) has been proposed as a therapeutic avenue to prevent calcium overloading. Ru265 (ClRu(NH 3 ) 4 (μ-N)Ru(NH 3 ) 4 Cl]Cl 3 ) is a cell-permeable inhibitor of the mitochondrial calcium uniporter (MCU) with nanomolar affinity. Ru265 reduces sensorimotor deficits and neuronal death in models of ischemic stroke. However, the therapeutic use of Ru265 is limited by the induction of seizure-like behaviours., Experimental Approach: We examined the effect of Ru265 on synaptic and neuronal function in acute brain slices and hippocampal neuron cultures derived from mice, in control and where MCU expression was genetically abrogated., Key Results: Ru265 decreased evoked responses from calyx terminals and induced spontaneous action potential firing of both the terminal and postsynaptic principal cell. Recordings of presynaptic Ca 2+ currents suggested that Ru265 blocks the P/Q type channel, confirmed by the inhibition of currents in cells exogenously expressing the P/Q type channel. Measurements of presynaptic K + currents further revealed that Ru265 blocked a KCNQ current, leading to increased membrane excitability, underlying spontaneous spiking. Ca 2+ imaging of hippocampal neurons showed that Ru265 increased synchronized, high-amplitude events, recapitulating seizure-like activity seen in vivo. Importantly, MCU ablation did not suppress Ru265-induced increases in neuronal activity and seizures., Conclusions and Implications: Our findings provide a mechanistic explanation for the pro-convulsant effects of Ru265 and suggest counter screening assays based on the measurement of P/Q and KCNQ channel currents to identify safe MCU inhibitors., (© 2024 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Calcium-overload-mediated tumor therapy has received considerable interest in oncology. However, its efficacy has been proven to be inadequate due to insufficient calcium ion concentration at the tumor site coupled with challenges in facilitating efficient calcium uptake by tumors, leading to unsatisfactory therapeutic outcomes. In the present study, calcium carbonate nanoshell mineralized ferric polydopamine nanoparticles (Fe-PDA@CaCO 3 NPs) were prepared for achieving Ca 2+ -overload-mediated tumor therapy. Upon entering the tumor site, the pH-responsive CaCO 3 layer, acting as a "Ca 2+ storage pool", rapidly degraded and released high quantities of free Ca 2+ within the weakly acidic environment. The Fe-PDA core, with its excellent photothermal conversion properties, could significantly increase the temperature upon exposure to near-infrared (NIR) light irradiation, thereby activating the TRPV1 channel and leading to a large influx of released Ca 2+ into the cytoplasm. Furthermore, the exposed Fe-PDA core could react with the tumor-overexpressed hydrogen peroxide (H 2 O 2 ) to efficiently produce hydroxyl radicals (•OH), significantly increasing intracellular reactive oxygen species (ROS) levels and thus inhibiting the activity of the Ca 2+ efflux pump, resulting in a high intracellular Ca 2+ concentration. Ultimately, the increase in calcium/ROS levels could disrupt mitochondrial homeostasis and activate the apoptosis pathway. The current work presents a promising approach for tumor therapy using photothermal-enhanced calcium-overload-mediated ion interference therapy and chemodynamic therapy.

Evodiamine (EVO), the main active alkaloid in Evodia rutaecarpa, was shown to exert various pharmacological activities, especially anti-tumor. Currently, it is considered a potential anti-cancer drug due to its excellent anti-tumor activity, which unfortunately has adverse reactions, such as the risk of liver and kidney injury, when Evodia rutaecarpa containing EVO is used clinically. In the present study, we aim to clarify the potential toxic target organs and toxicity mechanism of EVO, an active monomer in Evodia rutaecarpa, and to develop mitigation strategies for its toxicity mechanism. Transcriptome analysis and related experiments showed that the PI3K/Akt pathway induced by calcium overload was an important step in EVO-induced apoptosis of renal cells. Specifically, intracellular calcium ions were increased, and mitochondrial calcium ions were decreased. In addition, EVO-induced calcium overload was associated with TRPV1 receptor activation. In vivo TRPV1 antagonist and calcium chelator effects were observed to significantly reduce body weight loss and renal damage in mice due to EVO toxicity. The potential nephrotoxicity of EVO was further confirmed by an in vivo test. In conclusion, TRPV1-mediated calcium overload-induced apoptosis is one of the mechanisms contributing to the nephrotoxicity of EVO due to its toxicity, whereas maintaining body calcium homeostasis is an effective measure to reduce toxicity. These studies suggest that the clinical use of EVO-containing herbal medicines should pay due attention to the changes in renal function of patients as well as the off-target effects of the drugs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Calcium overload therapy refers to the condition of intracellular Ca 2+ overload, which causes mitochondrial damage and leads to the uncontrolled release of apoptotic factors into the cytoplasm through the open mitochondrial permeability pore. Based on this, it is playing an increasingly important role in the field of oncology due to its good efficacy and small side effects. However, the regulation of calcium homeostasis by cancer cells themselves, insufficient calcium ions (Ca 2+ ) in tumor sites and low efficiency of calcium entering tumor have limited its efficacy, resulting in unsatisfactory therapeutic effect. Therefore, a novel CAP/BSA@TCP-ZIF-8 nanoparticle drug carrier system was constructed that can provide Ca 2+ from exogenous sources for pH-controlled degradation and drug release at the same time. Both in vivo and in vitro experiments have proved that the nanomaterial can activate TRPV1 channels and provide exogenous Ca 2+ to cause Ca 2+ overload and apoptosis, thus achieving anti-tumor effects., Competing Interests: Declaration of competing interest All authors have declared that no financial or personal relationships competing interest exists., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Heart failure is a life-threatening cardiovascular disease and characterized by cardiac hypertrophy, inflammation and fibrosis. The traditional Chinese medicine formula Qiangxinyin (QXY) is effective for the treatment of heart failure while the underlying mechanism is not clear. This study aims to identify the active ingredients of QXY and explore its mechanisms protecting against cardiac hypertrophy. We found that QXY significantly protected against isoproterenol (ISO)-induced cardiac hypertrophy and dysfunction in zebrafish. Eight compounds, including benzoylmesaconine (BMA), atractylenolide I (ATL I), icariin (ICA), quercitrin (QUE), psoralen (PRN), kaempferol (KMP), ferulic acid (FA) and protocatechuic acid (PCA) were identified from QXY. PRN, KMP and icaritin (ICT), an active pharmaceutical ingredient of ICA, prevented ISO-induced cardiac hypertrophy and dysfunction in zebrafish. In H9c2 cardiomyocyte treated with ISO, QXY significantly blocked the calcium influx, reduced intracellular lipid peroxidative product MDA, stimulated ATP production and increased mitochondrial membrane potential. QXY also inhibited ISO-induced cardiomyocyte hypertrophy and cytoskeleton reorganization. Mechanistically, QXY enhanced the phosphorylation of Smad family member 2 (SMAD2) and myosin phosphatase target subunit-1 (MYPT1), and suppressed the phosphorylation of myosin light chain (MLC). In conclusion, PRN, KMP and ICA are the main active ingredients of QXY that protect against ISO-induced cardiac hypertrophy and dysfunction largely via the blockage of calcium influx and inhibition of mitochondrial dysfunction as well as cytoskeleton reorganization., Competing Interests: Declaration of competing interest The authors have declared no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background: Challenges such as poor drug selectivity, non-target reactivity, and the development of drug resistance continue to pose significant obstacles in the clinical application of cancer therapeutic drugs. To overcome the limitations of drug resistance in chemotherapy, a viable treatment strategy involves designing multifunctional nano-platforms that exploit the unique physicochemical properties of tumor microenvironment (TME)., Methods: Herein, layer-by-layer nanoparticles with polyporous CuS as delivery vehicles, loaded with a sonosensitizer (tetra-(4-aminophenyl) porphyrin, TAPP) and sequentially functionalized with pH-responsive CaCO 3 , targeting group hyaluronic acid (HA) were designed and synthesized for synergistic treatment involving chemodynamic therapy (CDT), sonodynamic therapy (SDT), photothermal therapy (PTT), and calcium overload. Upon cleavage in an acidic environment, CaCO 3 nanoparticles released TAPP and Ca 2+ , with TAPP generating 1 O 2 under ultrasound trigger. Exposed CuS produced highly cytotoxic ·OH in response to H 2 O 2 and also exhibited a strong PTT effect., Results: CuS@TAPP-CaCO 3 /HA (CTCH) delivered an enhanced ability to release more Ca 2+ under acidic conditions with a pH value of 6.5, which in situ causes damage to HeLa mitochondria. In vitro and in vivo experiments both demonstrated that mitochondrial dysfunction greatly amplified the damage caused by reactive oxygen species (ROS) to tumor, which strongly confirms the synergistic effect between calcium overload and reactive oxygen therapy., Conclusion: Collectively, the development of CTCH presents a novel therapeutic strategy for tumor treatment by effectively responding to the acidic TME, thus holding significant clinical implications., Competing Interests: The authors declare no competing interest in this work., (© 2024 Zhang et al.)

Preparing acute brain slices produces trauma that mimics severe penetrating brain injury. In neonatal acute brain slices, the spatiotemporal characteristics of trauma-induced calcium dynamics in neurons and its effect on network activity are relatively unknown. Using multiphoton laser scanning microscopy of the somatosensory neocortex in acute neonatal mouse brain slices (P8-12), we simultaneously imaged neuronal Ca 2+ dynamics (GCaMP6s) and cytotoxicity (propidium iodide or PI) to determine the relationship between cytotoxic Ca 2+ loaded neurons (GCaMP-filled) and cell viability at different depths and incubation times. PI + cells and GCaMP-filled neurons were abundant at the surface of the slices, with an exponential decrease with depth. Regions with high PI + cells correlated with elevated neuronal and neuropil Ca 2+ The number of PI + cells and GCaMP-filled neurons increased with prolonged incubation. GCaMP-filled neurons did not participate in stimulus-evoked or seizure-evoked network activity. Significantly, the superficial tissue, with a higher degree of trauma-induced injury, showed attenuated seizure-related neuronal Ca 2+ responses. Calpain inhibition prevented the increase in PI + cells and GCaMP-filled neurons in the deep tissue and during prolonged incubation times. Isoform-specific pharmacological inhibition implicated calpain-2 as a significant contributor to trauma-induced injury in acute slices. Our results show a calpain-mediated spatiotemporal relationship between cell death and aberrant neuronal Ca 2+ load in acute neonatal brain slices. Also, we demonstrate that neurons in acute brain slices exhibit altered physiology depending on the degree of trauma-induced injury. Blocking calpains may be a therapeutic option to prevent acute neuronal death during traumatic brain injury in the young brain., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Suryavanshi et al.)

Objective: To explore the mechanism by which soybean isoflavone (SI) reduces calcium overload induced by cerebral ischemia-reperfusion (I/R)., Methods: Forty-eight SD rats were randomized into 4 groups to receive sham operation, cerebral middle artery occlusion for 2 h followed by 24 h of reperfusion (I/R model group), or injection of adeno-associated virus carrying Frizzled-2 siRNA or empty viral vector into the lateral cerebral ventricle after modeling.Western blotting was used to examine Frizzled-2 knockdown efficiency and changes in protein expressions in the Wnt/Ca 2+ signaling pathway.Calcium levels and pathological changes in the ischemic penumbra (IP) were measured using calcium chromogenic assay and HE staining, respectively.Another 72 SD randomly allocated for sham operation, I/R modeling, or soy isoflavones pretreatment before modeling were examined for regional cerebral blood flow using a Doppler flowmeter, and the cerebral infarct volume was assessed using TTC staining.Pathologies in the IP area were evaluated using HE and Nissl staining, and ROS level, Ca 2+ level, cell apoptosis, and intracellular calcium concentration were analyzed using immunofluorescence assay or flow cytometry; the protein expressions of Wnt5a, Frizzled-2, and P-CaMK Ⅱ in the IP were detected with Western blotting and immunohistochemistry., Results: In rats with cerebral I/R, Frizzled-2 knockdown significantly lowered calcium concentration ( P < 0.001) and the expression levels of Wnt5a, Frizzled-2, and P-CaMK Ⅱ in the IP area.In soy isoflavones-pretreated rats, calcium concentration, ROS and MDA levels, cell apoptosis rate, cerebral infarct volume, and expression levels of Wnt/Ca 2+ signaling pathway-related proteins were all significantly lower while SOD level was higher than those in rats in I/R model group., Conclusion: Soy isoflavones can mitigate calcium overload in rats with cerebral I/R by inhibiting the Wnt/Ca 2+ signaling pathway.

The emergence of nanomotor provides an innovative concept for tumor treatment strategies. Conventional chemotherapeutic agents for tumors exit various therapeutic constraints due to the unique microenvironment of the tumor itself. Calcium overload, the aberrant accumulation of free calcium ions in the cytoplasm, is a well-recognized contributor to damage and even cell death in numerous cell types. Such undesired destructive processes can be a novel means applicable to cancer ion interference therapy. Herein, the chemotherapeutic drug doxorubicin (DOX) and calcium peroxide as the driving force into nanomotors through a facile and understandable experimental scheme are successfully assembled. The modification of nucleic acid aptamer and NIR-II fluorescent molecules on its surface simultaneously strengthens both the active targeting and imaging capability of tumor loci. Therefore, by a comprehensive assessment of nanomotors both in vitro and in vivo experiments, CaO 2 /DOX@HPS-IR-1061-AS1411 demonstrates superior killing effects on tumor cells, and the intracellular reactive oxygen species produced by nanomotors is verified by molecular biology experiments to induce apoptosis of tumor cells and further achieve tumor therapeutic effects., (© 2024 Wiley‐VCH GmbH.)

The introduction of glucose oxidase, exhibiting characteristics of glucose consumption and H 2 O 2 production, represents an emerging antineoplastic therapeutic approach that disrupts nutrient supply and promotes efficient generation of reactive oxygen species (ROS). However, the instability of natural enzymes and their low therapeutic efficacy significantly impede their broader application. In this context, 2D Ca 2 Mn 8 O 16 nanosheets (CMO NSs) designed and engineered to serve as a high-performance nanozyme, enhancing the enzyodynamic effect for a ferroptosis-apoptosis synergistic tumor therapy, are presented. In addition to mimicking activities of glutathione peroxidase, catalase, oxidase, and peroxidase, the engineered CMO NSs exhibit glucose oxidase-mimicking activities. This feature contributes to their antitumor performance through cascade catalytic reactions, involving the disruption of glucose supply, self-supply of H 2 O 2 , and subsequent efficient ROS generation. The exogenous Ca 2+ released from CMO NSs, along with the endogenous Ca 2+ enrichment induced by ROS from the peroxidase- and oxidase-mimicking activities of CMO NSs, collectively mediate Ca 2+ overload, leading to apoptosis. Importantly, the ferroptosis process is triggered synchronously through ROS output and glutathione consumption. The application of exogenous ultrasound stimulation further enhances the efficiency of ferroptosis-apoptosis synergistic tumor treatment. This work underscores the crucial role of enzyodynamic performance in ferroptosis-apoptosis synergistic therapy against tumors., (© 2024 Wiley‐VCH GmbH.)

Nanocatalytic therapy, an emerging approach in cancer treatment, utilizes nanomaterials to initiate enzyme-mimetic catalytic reactions within tumors, inducing tumor-suppressive effects. However, the targeted and selective catalysis within tumor cells is challenging yet critical for minimizing the adverse effects. The distinctive reliance of tumor cells on glycolysis generates abundant lactate, influencing the tumor's pH, which can be manipulated to selectively activate nanozymatic catalysis. Herein, small interfering ribonucleic acid (siRNA) targeting lactate transporter-mediated efflux is encapsulated within the iron-based metal-organic framework (FeMOF) and specifically delivered to tumor cells through cell membrane coating. This approach traps lactate within the cell, swiftly acidifying the tumor cytoplasm and creating an environment for boosting the catalysis of the FeMOF nanozyme. The nanozyme generates hydroxyl radical (·OH) in the reversed acidic environment, using endogenous hydrogen peroxide (H 2 O 2 ) produced by mitochondria as a substrate. The induced cytoplasmic acidification disrupts calcium homeostasis, leading to mitochondrial calcium overload, resulting in mitochondrial dysfunction and subsequent tumor cell death. Additionally, the tumor microenvironment is also remodeled, inhibiting migration and invasion, thus preventing metastasis. This groundbreaking strategy combines metabolic regulation with nanozyme catalysis in a toxic drug-free approach for tumor treatment, holding promise for future clinical applications., (© 2024 The Authors. Small published by Wiley‐VCH GmbH.)

Calcium overload, a notable instigator of acute pancreatitis (AP), induces oxidative stress and an inflammatory cascade, subsequently activating both endogenous and exogenous apoptotic pathways. However, there is currently lack of available pharmaceutical interventions to alleviate AP by addressing calcium overload. In the present study, the potential clinical application of liposome nanoparticles (LNs) loaded with 1,2‑bis(2‑aminophenoxy)ethane‑N,N,N',N'‑tetraacetic acid tetrakis (acetoxymethyl ester) (BAPTA‑AM), a cell‑permeant calcium chelator, was investigated as a therapeutic approach for the management of AP. To establish the experimental models in vitro , AR42J cells were exposed to high glucose/sodium oleate (HGO) to induce necrosis, and in vivo , intra‑ductal taurocholate (TC) infusion was used to induce AP. The findings of the present study indicated that the use of BAPTA‑AM‑loaded LN (BLN) effectively and rapidly eliminated excessive Ca 2+ and reactive oxygen species, suppressed mononuclear macrophage activation and the release of inflammatory cytokines, and mitigated pancreatic acinar cell apoptosis and necrosis induced by HGO. Furthermore, the systemic administration of BLN demonstrated promising therapeutic potential in the rat model of AP. Notably, BLN significantly enhanced the survival rates of rats subjected to the TC challenge, increasing from 37.5 to 75%. This improvement was attributed to the restoration of pancreatic function, as indicated by improved blood biochemistry indices and alleviation of pancreatic lesions. The potential therapeutic efficacy of BLN in rescuing patients with AP is likely attributed to its capacity to inhibit oxidative stress, prevent premature activation of zymogens and downregulate the expression of TNF‑α, IL‑6 and cathepsin B. Thus, BLN demonstrated promising value as a novel therapeutic approach for promptly alleviating the burden of intracellular Ca 2+ overload in patients with AP.

Chemotherapy remains one of the most widely used cancer treatment modalities in clinical practice. However, the characteristic microenvironment of solid tumors severely limits the anticancer efficacy of chemotherapy. In addition, a single treatment modality or one death pathway reduces the antitumor outcome. Herein, tumor-targeting O 2 self-supplied nanomodules (CuS@DOX/CaO 2 -HA) are proposed that not only alleviate tumor microenvironmental hypoxia to promote the accumulation of chemotherapeutic drugs in tumors but also exert photothermal effects to boost drug release, penetration and combination therapy. CuS@DOX/CaO 2 -HA consists of copper sulfide (CuS)-loaded calcium peroxide (CaO 2 ) and doxorubicin (DOX), and its surface is further modified with HA. CuS@DOX/CaO 2 -HA underwent photothermal treatment to release DOX and CaO 2 . Hyperthermia accelerates drug penetration to enhance chemotherapeutic efficacy. The exposed CaO 2 reacts with water to produce Ca 2+ , H 2 O 2 and O 2 , which sensitizes cells to chemotherapy through mitochondrial damage caused by calcium overload and a reduction in drug efflux via the alleviation of hypoxia. Moreover, under near infrared (NIR) irradiation, CuS@DOX/CaO 2 -HA initiates a pyroptosis-like cell death process in addition to apoptosis. In vivo, CuS@DOX/CaO 2 -HA demonstrated high-performance antitumor effects. This study provides a new strategy for synergistic enhancement of chemotherapy in hypoxic tumor therapy via combination therapy and multiple death pathways., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ischemic stroke is currently the most common type of stroke, and the key pathological link is cerebral ischemia-reperfusion injury (CIRI), while the key factor leading to apoptosis and necrosis of ischemic nerve cells is calcium overload. Current studies have confirmed that acupuncture therapy has a good modulating effect on calcium homeostasis and can reduce cerebral ischemia-reperfusion induced damage of neuronal cells by inhibiting calcium overload. After reviewing the relevant literature published in the past 15 years, we find that acupuncture plays a role in regulating the pathological mechanism of calcium overload after CIRI by inhibiting the opening of connexin 43 hemichannels, regulating the intracellular free calcium ion concentration, suppressing the expression of calmodulin, and blocking the function of L-type voltage-gated calcium channels, thereby inhibiting calcium overload, regulating calcium homeostasis and antagonizing neuronal damage resulted from cerebral ischemia-reperfusion, which may provide ideas for future research.

Endocardial endothelium (EE) is a layer of cells covering the cardiac cavities and modulates cardiomyocyte function. This cell type releases several cardioactive factors, including Angiotensin II (Ang II). This octopeptide is known to induce cardiac hypertrophy. However, whether this circulating factor also induces EE hypertrophy is not known. Taurine is known to prevent cardiac hypertrophy. Whether this endogenous antioxidant prevents the effect of Ang II on human EE (hEE) will be verified. Using quantitative fluorescent probe imaging for calcium and reactive oxygen species (ROS), our results show that Ang II induces (10 -7 M, 48 h treatment) an increase in hEE cell (hEEC) volume and its nucleus. Pretreatment with 20 mM of taurine prevents morphological remodeling and increases intracellular calcium and ROS. These results suggest that the reported Ang II induces cardiac hypertrophy is associated with hEEC hypertrophy. This later effect is prevented by taurine by reducing intracellular calcium and ROS overloads. Thus, taurine could be an excellent tool for preventing Ang II-induced remodeling of hEECs.

Regarded as one of the hallmarks of tumorigenesis and tumor progression, the evasion of apoptotic cell death would also account for treatment resistance or failure during cancer therapy. In this study, a Ca 2+ /Cu 2+ dual-ion "nano trap" to effectively avoid cell apoptosis evasion by synchronously inducing paraptosis together with apoptosis was successfully designed and fabricated for breast cancer treatment. In brief, disulfiram (DSF)-loaded amorphous calcium carbonate nanoparticles (NPs) were fabricated via a gas diffusion method. Further on, the Cu 2+ -tannic acid metal phenolic network was embedded onto the NPs surface by self-assembling, followed by mDSPE-PEG/lipid capping to form the DSF-loaded Ca 2+ /Cu 2+ dual-ions "nano trap". The as-prepared nanotrap would undergo acid-triggered biodegradation upon being endocytosed by tumor cells within the lysosome for Ca 2+ , Cu 2+ , and DSF releasing simultaneously. The released Ca 2+ could cause mitochondrial calcium overload and lead to hydrogen peroxide (H 2 O 2 ) overexpression. Meanwhile, Ca 2+ /reactive oxygen species-associated mitochondrial dysfunction would lead to paraptosis cell death. Most importantly, cell paraptosis could be further induced and strengthened by the toxic dithiocarbamate (DTC)-copper complexes formed by the Cu 2+ combined with the DTC, the metabolic products of DSF. Additionally, the released Cu 2+ will be reduced by intracellular glutathione to generate Cu + , which can catalyze the H 2 O 2 to produce a toxic hydroxyl radical by a Cu + -mediated Fenton-like reaction for inducing cell apoptosis. Both in vitro cellular assays and in vivo antitumor evaluations confirmed the cancer therapeutic efficiency by the dual ion nano trap. This study can broaden the cognition scope of dual-ion-mediated paraptosis together with apoptosis via a multifunctional nanoplatform.

Sonodynamic therapy (SDT) is an emerging cancer treatment method in recent years. However, the ultrasound signal utilized for SDT is usually located at a low-frequency spectrum (<2 MHz), and in the field of SDT research, few studies have focused on the exploration and development of ultrasound frequency. Studies have shown that the GHz-level ultrasound can increase cell membrane permeability and have a negligible effect on cell vitality. Herein, we reported the study of a GHz thin film bulk acoustic resonator as an ultrasound source for synergistic treatment with nanoscale calcium peroxide (CaO 2 ). It was discovered that this ultrasound source ultimately achieved an efficient therapeutic outcome on mouse breast cancer cell line 4T1. Such GHz-level ultrasound application in SDT is of high significance to broaden the cognition and application scope of SDT., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Mitochondrial calcium (Ca 2+ ) uptake augments metabolic processes and buffers cytosolic Ca 2+ levels; however, excessive mitochondrial Ca 2+ can cause cell death. Disrupted mitochondrial function and Ca 2+ homeostasis are linked to numerous neurodegenerative diseases (NDs), but the impact of mitochondrial Ca 2+ disruption is not well understood. Here, we show that Drosophila models of multiple NDs (Parkinson's, Huntington's, Alzheimer's, and frontotemporal dementia) reveal a consistent increase in neuronal mitochondrial Ca 2+ levels, as well as reduced mitochondrial Ca 2+ buffering capacity, associated with increased mitochondria-endoplasmic reticulum contact sites (MERCs). Importantly, loss of the mitochondrial Ca 2+ uptake channel MCU or overexpression of the efflux channel NCLX robustly suppresses key pathological phenotypes across these ND models. Thus, mitochondrial Ca 2+ imbalance is a common feature of diverse NDs in vivo and is an important contributor to the disease pathogenesis. The broad beneficial effects from partial loss of MCU across these models presents a common, druggable target for therapeutic intervention., Competing Interests: Declaration of interests T.P.G. is now an employee of Costello Medical Consulting, Ltd., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Tumor therapy presents significant challenges, and conventional treatments exhibit limited therapeutic effectiveness. Imbalance of calcium homeostasis as a key cause of tumor cell death has been extensively studied in tumor therapy. Calcium overload therapy has garnered significant interest as a new cancer treatment strategy. This study involves the synthesis of a transformable nanosonosensitizer with a shell of a calcium ion nanomodulator. The nanosystem is designed to induce mitochondrial dysfunction by combining the calcium ion nanomodulator, nanosonosensitizer, and chemotherapeutic drug. Under ultrasound-activated conditions, CaCO 3 dissolves in the tumor microenvironment, causing the nanosonosensitizer to switch from the "off" to the "on" state of ROS generation, exacerbating mitochondrial calcium overload. A two-dimensional Ti 3 C 2 /TiO 2 heterostructure generates reactive oxygen species (ROS) under ultrasound and exhibits an efficient sonodynamic effect, enhancing calcium overload. Under ultrasound irradiation, Ti 3 C 2 /TiO 2 @CaCO 3 /KAE causes multilevel damage to mitochondria by combining the effects of rapid Ca 2+ release, inhibiting Ca 2+ efflux, enhancing tumor inhibition, and converting a "cold" tumor into a "hot" tumor. Therefore, this study proposes a method to effectively combine mitochondrial Ca 2+ homeostasis and sonodynamic therapy (SDT) by the preparing pH-sensitive, double-activated, and multifunctional Ti 3 C 2 /TiO 2 -based nanosystems for cancer therapy.

Remote Ischemic Preconditioning (RIPC) can reduce myocardial ischemia-reperfusion injury, but its mechanism is not clear. In order to explore the mechanism of RIPC in myocardial protection, we collected myocardial specimens during cardiac surgery in children with tetralogy of Fallot for sequencing. Our study found RIPC reduces the expression of the calcium channel subunit cacna2d3, thereby impacting the function of calcium channels. As a result, calcium overload during ischemia-reperfusion is reduced, and the activation of calpain 1 is inhibited. This ultimately leads to a decrease in calpain 1 cleavage of Bax, consequently inhibiting increased mitochondrial permeability-mediated apoptosis. Notably, in both murine and human models of myocardial ischemia-reperfusion injury, RIPC inhibiting the expression of the calcium channel subunit cacna2d3 and the activation of calpain 1, improving cardiac function and histological outcomes. Overall, our findings put forth a proposed mechanism that elucidates how RIPC reduces myocardial ischemia-reperfusion injury, ultimately providing a solid theoretical foundation for the widespread clinic application of RIPC., Competing Interests: Declaration of competing interest All authors declare no conflict of interest for this contribution., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Low selectivity and tumor drug resistance are the main hinderances to conventional radiotherapy and chemotherapy against tumor. Ion interference therapy is an innovative anti-tumor strategy that has been recently reported to induce metabolic disorders and inhibit proliferation of tumor cells by reordering bioactive ions within the tumor cells. Calcium cation (Ca 2+ ) are indispensable for all physiological activities of cells. In particular, calcium overload, characterized by the abnormal intracellular Ca 2+ accumulation, causes irreversible cell death. Consequently, calcium overload-based ion interference therapy has the potential to overcome resistance to traditional tumor treatment strategies and holds promise for clinical application. In this review, we 1) Summed up the current strategies employed in this therapy; 2) Described the outcome of tumor cell death resulting from this therapy; 3) Discussed its potential application in synergistic therapy with immunotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Fan, Wang, He, Xu and Li.)

Calcium overload is the key trigger in cardiac microvascular ischemia-reperfusion (I/R) injury, and calreticulin (CRT) is a calcium buffering protein located in the endoplasmic reticulum (ER). Additionally, the role of pinacidil, an antihypertensive drug, in protecting cardiac microcirculation against I/R injury has not been investigated. Hence, this study aimed to explore the benefits of pinacidil on cardiac microvascular I/R injury with a focus on endothelial calcium homeostasis and CRT signaling. Cardiac vascular perfusion and no-reflow area were assessed using FITC-lectin perfusion assay and Thioflavin-S staining. Endothelial calcium homeostasis, CRT-IP3Rs-MCU signaling expression, and apoptosis were assessed by real-time calcium signal reporter GCaMP8, western blotting, and fluorescence staining. Drug affinity-responsive target stability (DARTS) assay was adopted to detect proteins that directly bind to pinacidil. The present study found pinacidil treatment improved capillary density and perfusion, reduced no-reflow and infraction areas, and improved cardiac function and hemodynamics after I/R injury. These benefits were attributed to the ability of pinacidil to alleviate calcium overload and mitochondria-dependent apoptosis in cardiac microvascular endothelial cells (CMECs). Moreover, the DARTS assay showed that pinacidil directly binds to HSP90, through which it inhibits chaperone-mediated autophagy (CMA) degradation of CRT. CRT overexpression inhibited IP3Rs and MCU expression, reduced mitochondrial calcium inflow and mitochondrial injury, and suppressed endothelial apoptosis. Importantly, endothelial-specific overexpression of CRT shared similar benefits with pinacidil on cardiovascular protection against I/R injury. In conclusion, our data indicate that pinacidil attenuated microvascular I/R injury potentially through improving CRT degradation and endothelial calcium overload., (© 2024. The Author(s).)

As a transcriptional activator widely expressed in various tissues, nuclear factor of activated T cells (NFAT) is involved in the regulation of the immune system, the development of the heart and brain systems, and classically mediating pathological processes such as cardiac hypertrophy. Oxidative stress is an imbalance of intracellular redox status, characterized by excessive generation of reactive oxygen species, accompanied by mitochondrial dysfunction, calcium overload, and subsequent lipid peroxidation, inflammation, and apoptosis. Oxidative stress occurs during various pathological processes, such as chronic hypoxia, vascular smooth muscle cell phenotype switching, ischemia-reperfusion, and cardiac remodeling. Calcium overload leads to an increase in intracellular calcium concentration, while NFAT can be activated through calcium-calcineurin, which is also the main regulatory mode of NFAT factors. This review focuses on the effects of NFAT transcription factors on reactive oxygen species production, calcium overload, mitochondrial dysfunction, redox reactions, lipid peroxidation, inflammation, and apoptosis in response to oxidative stress. We hope to provide a reference for the functions and characteristics of NFAT involved in various stages of oxidative stress as well as related potential targets., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2023. Published by Elsevier Ltd.)

Circadian mechanisms have been associated with the pathogenesis of a variety of cardiovascular diseases, including myocardial ischemia-reperfusion injury (I-R). Myocardial ischemia resulting from impaired oxygen delivery to cardiac muscle sets into motion a cascade of cellular events that paradoxically triggers greater cardiac dysfunction upon reinstitution of coronary blood supply, a phenomenon known as I-R. I-R injury has been attributed to a number of cellular defects including increased reactive oxygen species (ROS), increased intracellular calcium and impaired mitochondrial bioenergetics that ultimately lead to cardiac cell death, ventricular remodeling and heart failure. Emerging evidence has identified a strong correlation between cellular defects that underlie I-R and the disrupted circadian. In fact, recent studies have shown that circadian dysfunction exacerbates cardiac injury following MI from impaired cellular quality control mechanisms such as autophagy, which are vital in the clearance of damaged cellular proteins and organelles such as mitochondria from the cell. The accumulation of cellular debris is posited as the central underlying cause of excessive cardiac cell death and ventricular dysfunction following MI. The complexities that govern the interplay between circadian biology and I-R injury following MI is at its infancy and understanding how circadian misalignment, such as in shift workers impacts I-R injury is of great scientific and clinical importance toward development of new therapeutic strategies using chronotherapy and circadian regulation to mitigate cardiac injury and improve cardiac outcomes after injury. In this review, we highlight recent advances in circadian biology and adaptive cellular quality control mechanisms that influence cardiac injury in response to MI injury with a specific focus on how circadian biology can be utilized to further cardiovascular medicine and patient care., (Copyright © 2022. Published by Elsevier Inc.)