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Chemotherapy is a life‐saving treatment for cancer patients, but also causes long‐term cognitive impairment, or “chemobrain”, in survivors. However, several challenges, including imprecise diagnosis criteria, multiple confounding factors, and unclear and heterogeneous molecular mechanisms, impede effective investigation of preventions and treatments for chemobrain. With the rapid increase in the number of cancer survivors, chemobrain is an urgent but unmet clinical need. Here, we leverage the extensive knowledge in various fields of neuroscience to gain insights into the mechanisms for chemobrain. We start by outlining why the post‐mitotic adult brain is particularly vulnerable to chemotherapy. Next, through drawing comparisons with normal aging, Alzheimer's disease, and traumatic brain injury, we identify universal cellular mechanisms that may underlie the cognitive deficits in chemobrain. We further identify existing neurological drugs targeting these cellular mechanisms that can be repurposed as treatments for chemobrain, some of which were already shown to be effective in animal models. Finally, we briefly describe future steps to further advance our understanding of chemobrain and facilitate the development of effective preventions and treatments. Graphical Abstract Timely and important review on chemobrain, from the existing consensus to new potential mechanisms based on Alzheimer's disease or traumatic brain injury pathologies, suggesting chemobrain as a persistent neurological disorder.

Background After chemotherapy, many cancer survivors suffer from long-lasting cognitive impairment, colloquially known as “chemobrain.” However, the trajectories of cognitive changes and the underlying mechanisms remain unclear. We previously established paclitaxel-induced inositol trisphosphate receptor (InsP3R)-dependent calcium oscillations as a mechanism for peripheral neuropathy, which was prevented by lithium pretreatment. Here, we investigated if a similar mechanism also underlay paclitaxel-induced chemobrain. Method Mice were injected with 4 doses of 20 mg/kg paclitaxel every other day to induced cognitive impairment. Memory acquisition was assessed with the displaced object recognition test. The morphology of neurons in the prefrontal cortex and the hippocampus was analyzed using Golgi-Cox staining, followed by Sholl analyses. Changes in protein expression were measured by Western blot. Results Mice receiving paclitaxel showed impaired short-term spatial memory acquisition both acutely 5 days post injection and chronically 23 days post injection. Dendritic length and complexity were reduced in the hippocampus and the prefrontal cortex after paclitaxel injection. Concurrently, the expression of protein kinase C α (PKCα), an effector in the InsP3R pathway, was increased. Treatment with lithium before or shortly after paclitaxel injection rescued the behavioral, cellular, and molecular deficits observed. Similarly, memory and morphological deficits could be rescued by pretreatment with chelerythrine, a PKC inhibitor. Conclusion We establish the InsP3R calcium pathway and impaired neuronal morphology as mechanisms for paclitaxel-induced cognitive impairment. Our findings suggest lithium and PKC inhibitors as candidate agents for preventing chemotherapy-induced cognitive impairment.

Unidirectional fluid flow plays an essential role in the breaking of left-right (L-R) symmetry in mouse embryos, but it has remained unclear how the flow is sensed by the embryo. We report that the Ca²⁺ channel Polycystin-2 (Pkd2) is required specifically in the perinodal crown cells for sensing the nodal flow. Examination of mutant forms of Pkd2 shows that the ciliary localization of Pkd2 is essential for correct L-R patterning. Whereas Kif3a mutant embryos, which lack all cilia, failed to respond to an artificial flow, restoration of primary cilia in crown cells rescued the response to the flow. Our results thus suggest that nodal flow is sensed in a manner dependent on Pkd2 by the cilia of crown cells located at the edge of the node.

Background/Objectives: Repeat low-level blast exposure has emerged as a significant concern for military populations exposed to explosive events. Blast-Related Traumatic Brain Injury (bTBI) is a unique form of brain trauma with poorly understood molecular mechanisms. Loss of calcium homeostasis has emerged as a mediator of early neuronal dysfunction after blast injury. This review aims to examine the role of calcium signaling in bTBI, focusing on the dual function of calcium channels as mediators and modulators of injury, and to explore therapeutic strategies targeting calcium homeostasis. Methods: We conducted a review of peer-reviewed articles published between 2000 and 2024, using the databases PubMed, Scopus, and EBSCO. Search terms included “blast traumatic brain injury”, “calcium channels”, and “calcium”. Studies investigating intracellular calcium dynamics after bTBI were included. Exclusion criteria included studies lacking evaluation of calcium signaling, biomarker studies, and studies on extracellular calcium. Results: We identified 13 relevant studies, primarily using preclinical models. Dysregulated calcium signaling was consistently linked to cellular dysfunction, including plasma membrane abnormalities, cytoskeletal destabilization, mitochondrial dysfunction, and proteolytic enzyme activation. Studies highlighted spatially compartmentalized vulnerabilities across neurons and astrocytes, suggesting that targeting specific cellular regions, such as the neuronal soma or axons, could enhance the therapeutic outcome. Therapeutic strategies included pharmacological inhibitors, plasma membrane stabilizers, and modulators of secondary injury. Conclusions: Calcium signaling is implicated in the pathophysiology of bTBI. Standardized experimental approaches would reduce variability in findings and improve the understanding of the relationship between calcium channel dynamics and bTBI and help guide the development of neuroprotective interventions that mitigate injury and promote recovery.

Dramatic improvements in cancer survival have occurred in the last decade, but the quality of life for many survivors is compromised due to severe, long-lasting, and often irreversible side effects of chemotherapy. The neurological side effects, chemotherapy induced peripheral neuropathy (CIPN) and cancer related/induced cognitive impairment (CRCI/CICI), are under-recognized and can occur after chemotherapy, immunotherapy, or radiation. The cellular mechanisms underlying these neurological side effects are poorly understood and there are no effective treatments or preventions, other than reduction or termination of cancer therapy. In our preliminary prospective, non-interventional study to examine the side effects of chemotherapy in patients with breast cancer (NCT03872141), patients with breast cancer who received standard of care single agent weekly taxane-based chemotherapy were assessed at baseline, midpoint, and end of treatment for neurological and cognitive changes and for blood levels of potential protein biomarkers (n = 13). CIPN and CRCI both showed an increase in severity with accumulating taxane and these changes were compared to protein alternations over the course of treatment. Using peripheral blood collected from patients (n = 10) during chemotherapy and tested with an antibody array curated by the MD Anderson RPPA Core), we found that 19 proteins were increased, and 12 proteins decreased over 12 weeks of treatment. Among those downregulate were proteins known to be critical for neuronal viability and function including GRB2 (growth factor receptor-bound protein 2) and NCS1 (neuronal calcium sensor 1). Concurrently, proteins associated with apoptosis, including BAK1 (Bcl-1 homologous antagonist/killer), were upregulated. These results support the proposal that CIPN and CRCI increase with increasing taxane exposure, and identified several proteins that are altered with taxane exposure that could be implicated in their pathogenesis. In conclusion, our study provides evidence for progressive neurological changes and the rationale to investigate the molecular basis for these changes with the goal of target identification for mitigation of these neurological side effects.

The most severe form of autosomal dominant polycystic kidney disease occurs in patients with mutations in the gene (PKD1) encoding polycystin-1 (PC1). PC1 is a complex polytopic membrane protein expressed in cilia that undergoes autoproteolytic cleavage at a G protein-coupled receptor proteolytic site (GPS). A quarter of PKD1 mutations are missense variants, though it is not clear how these mutations promote disease. Here, we established a cell-based system to evaluate these mutations and determined that GPS cleavage is required for PC1 trafficking to cilia. A common feature among a subset of pathogenic missense mutations is a resulting failure of PC1 to traffic to cilia regardless of GPS cleavage. The application of our system also identified a missense mutation in the gene encoding polycystin-2 (PC2) that prevented this protein from properly trafficking to cilia. Using a Pkd1-BAC recombineering approach, we developed murine models to study the effects of these mutations and confirmed that only the cleaved form of PC1 exits the ER and can rescue the embryonically lethal Pkd1-null mutation. Additionally, steady-state expression levels of the intramembranous COOH-terminal fragment of cleaved PC1 required an intact interaction with PC2. The results of this study demonstrate that PC1 trafficking and expression require GPS cleavage and PC2 interaction, respectively, and provide a framework for functional assays to categorize the effects of missense mutations in polycystins.

Neutrophil infiltration occurs in a variety of liver diseases, but it is unclear how neutrophils and hepatocytes interact. Neutrophils generally use granule proteases to digest phagocytosed bacteria and foreign substances or neutralize them in neutrophil extracellular traps. In certain pathological states, granule proteases play a destructive role against the host as well. More recently, nondestructive actions of neutrophil granule proteins have been reported, such as modulation of tissue remodeling and metabolism. Here, we report a completely different mechanism by which neutrophils act nondestructively, by inserting granules directly into hepatocytes. Specifically, elastase-containing granules were transferred to hepatocytes where elastase selectively degraded intracellular calcium channels to reduce cell proliferation without cytotoxicity. In response, hepatocytes increased expression of Serpin E2 and A3, which inhibited elastase activity. Elastase insertion was seen in patient specimens of alcohol-associated hepatitis, and the relationship between elastase-mediated ITPR2 degradation and reduced cell proliferation was confirmed in mouse models. Moreover, neutrophils from patients with alcohol-associated hepatitis were more prone to degranulation and more potent in reducing calcium channel expression than neutrophils from healthy individuals. This nondestructive and reversible action on hepatocytes defines a previously unrecognized role for neutrophils in the transient regulation of epithelial calcium signaling mechanisms.

Traumatic Brain Injury (TBI) is a major global health concern and a leading cause of death and disability, especially in young adults. It triggers complex secondary injury cascades, e.g., calcium dysregulation, mitochondrial dysfunction and protease activation, that extend well beyond the initial mechanical insult to drive ongoing neurodegeneration. The calcium-dependent protease calpain has emerged as a central mediator of TBI cellular pathology. Calpain cleaves a broad range of cytoskeletal and regulatory proteins across neuronal compartments, disrupting axonal integrity, synaptic function and calcium homeostasis. Despite decades of research, calpain remains an elusive therapeutic target. In this review, we examine the spatial and temporal patterns of calpain activation in the traumatically injured brain, categorize key calpain substrates by structure and location, and assess their mechanistic roles in TBI pathology. We also review recent advances in next-generation calpain-2 selective inhibitors with enhanced specificity and preclinical efficacy and discuss the emerging use of calpain-cleaved protein fragments such as SBDP145 and SNTF as candidate biomarkers for TBI diagnosis and progression. Drawing on molecular, preclinical, and clinical data, we argue that calpain warrants renewed attention as both a therapeutic target and mechanistic biomarker in TBI. It may be time for Cinderella to leave the basement.

Cardiac disorders are the main cause of mortality in autosomal-dominant polycystic kidney disease (ADPKD). However, how mutated polycystins predispose patients with ADPKD to cardiac pathologies before development of renal dysfunction is unknown. We investigate the effect of decreased levels of polycystin 2 (PC2), a calcium channel that interacts with the ryanodine receptor, on myocardial function. We hypothesize that heterozygous PC2 mice ( Pkd2 ⁺/⁻) undergo cardiac remodeling as a result of changes in calcium handling, separate from renal complications. We found that Pkd2 ⁺/⁻ cardiomyocytes have altered calcium handling, independent of desensitized calcium-contraction coupling. Paradoxically, in Pkd2 ⁺/⁻ mice, protein kinase A (PKA) phosphorylation of phospholamban (PLB) was decreased, whereas PKA phosphorylation of troponin I was increased, explaining the decoupling between calcium signaling and contractility. In silico modeling supported this relationship. Echocardiography measurements showed that Pkd2 ⁺/⁻ mice have increased left ventricular ejection fraction after stimulation with isoproterenol (ISO), a β-adrenergic receptor (βAR) agonist. Blockers of βAR-1 and βAR-2 inhibited the ISO response in Pkd2 ⁺/⁻ mice, suggesting that the dephosphorylated state of PLB is primarily by βAR-2 signaling. Importantly, the Pkd2 ⁺/⁻ mice were normotensive and had no evidence of renal cysts. Our results showed that decreased PC2 levels shifted the βAR pathway balance and changed expression of calcium handling proteins, which resulted in altered cardiac contractility. We propose that PC2 levels in the heart may directly contribute to cardiac remodeling in patients with ADPKD in the absence of renal dysfunction. Significance The main cause of death in autosomal-dominant polycystic kidney disease (ADPKD) patients is cardiac-related. However, the reasons why remain unclear. We show that mice lacking one copy of polycystin 2, a protein mutated in ADPKD, have altered calcium signaling and desensitized calcium-contraction coupling in cardiomyocytes. We also show that decreased polycystin 2 levels affect cardiac function by altering responses to adrenergic stimulus. We propose that altering polycystin levels in the heart directly contributes to remodeling of the heart in patients with ADPKD in the absence of renal failure or high blood pressure.

Mutations in the gene for polycystin 2 (Pkd2) lead to polycystic kidney disease, however the main cause of mortality in humans is cardiac related. We previously showed that 5 month old Pkd2+/- mice have altered calcium-contractile activity in cardiomyocytes, but have preserved cardiac function. Here, we examined 1 and 9 month old Pkd2+/- mice to determine if decreased amounts of functional polycystin 2 leads to impaired cardiac function with aging. We observed changes in calcium handling proteins in 1 month old Pkd2+/- mice, and these changes were exacerbated in 9 month old Pkd2+/- mice. Anatomically, the 9 month old Pkd2+/- mice had thinner left ventricular walls, consistent with dilated cardiomyopathy, and the left ventricular ejection fraction was decreased. Intriguingly, in response to acute isoproterenol stimulation to examine β-adrenergic responses, the 9 month old Pkd2+/- mice exhibited a stronger contractile response, which also coincided with preserved localization of the β2 adrenergic receptor. Importantly, the Pkd2+/- mice did not have any renal impairment. We conclude that the cardiac-related impact of decreased polycystin 2 progresses over time towards cardiac dysfunction and altered adrenergic signaling. These results provide further evidence that polycystin 2 provides a critical function in the heart, independent of renal involvement.