Intracellular calcium (Ca2+) signaling controls myoblast proliferation, fusion, and myofiber formation. In myoblasts, Transient Receptor Potential Canonical (TRPC) channels, with TRPC1 as a predominant isoform, mediate store-operated Ca²⁺ entry (SOCE) and are essential for myogenesis. PDLIM5 (ENH1), a PDZ-LIM scaffold protein, organizes signaling events, including ion channel regulation and transcriptional control in muscles. This study aims to test the hypothesis that PDLIM5 regulates TRPC1-mediated Ca2+ entry in myoblasts. Thapsigargin-induced SOCE was suppressed by the SOCE inhibitors Gd3+ and 2-APB, as well as by TRPC1 siRNA, supporting the involvement of TRPC1 in SOCE in C2C12 myoblasts. Additionally, SOCE inhibition decreased the number of nuclei per myotube and reduced the size of myotubes. ENH1 siRNA knockdown significantly downregulated TRPC1 and STIM1 mRNA expression, increased basal cytosolic Ca2+ level, and impaired SOCE response and myotube maturation. Overexpression of ENH4, a skeletal muscle-specific short splice variant of ENH1, similarly repressed TRPC1-mediated SOCE and myotube formation. Conversely, ENH1 overexpression enhanced SOCE without altering the mRNA levels of TRPC1, Orai1, or STIM1. Immunoprecipitation showed a physical interaction between ENH1/ENH4 and TRPC1. In differentiated myotubes, TRPC1 also contributed to thapsigargin-induced SOCE, as evidenced by the reduced Ca2+ entry following TRPC1 knockdown. ENH1 knockdown and ENH4 overexpression significantly attenuated SOCE in myotubes; notably, ENH1 knockdown also increased basal cytosolic Ca2+ level. In contrast to myoblasts, ENH1 overexpression did not enhance SOCE in myotubes, concomitant with the absence of a detectable interaction between ENH1 and TRPC1, whereas ENH4 retained its association with TRPC1. These findings suggest that ENH1 and ENH4 differentially modulate TRPC1-dependent Ca2+ entry in C2C12 cells, thereby regulating myogenic differentiation and contributing to skeletal muscle formation and development.

Intervertebral disc degeneration (IDD) is a major cause of chronic low back pain. Its pathogenesis is highly complex and encompasses multiple pathological processes, including cellular dysfunction, extracellular matrix (ECM) degradation, inflammatory responses, oxidative stress, and aberrant mechanical loading. Traditionally, programmed cell death (PCD), particularly apoptosis and autophagy, has been regarded as a key contributor to IDD. However, with ongoing advances in this field, an expanding number of emerging forms of regulated cell death (RCD) have been identified and demonstrated to play critical roles in the initiation and progression of IDD. These advances have also provided new insights into the key molecular events underlying disc degeneration and have facilitated the identification of potential disease-modifying therapeutic targets. This review systematically summarizes five emerging RCD modalities, namely ferroptosis, cuproptosis, necroptosis, PANoptosis, and disulfidptosis, with particular emphasis on their mechanistic roles, key regulatory factors, signaling pathways, and patterns of interaction in IDD. Current evidence indicates that these RCD modalities not only independently contribute to cell death but may also converge through shared pathological nodes, including oxidative stress, mitochondrial dysfunction, and inflammatory signaling, thereby producing synergistic amplification effects that further aggravate cell loss and matrix destruction. Regarding therapeutic strategies, a range of RCD-targeted pharmacological approaches has been reported to exhibit potential therapeutic value, including iron chelators, modulators of copper metabolism, inhibitors of the RIPK signaling pathway, antioxidants, and agents targeting PANoptosis-related signaling. These findings provide novel perspectives for the precision treatment of IDD. Nevertheless, most available studies remain limited to cellular and animal models, and the spatiotemporal expression patterns of the relevant signaling networks, their mechanisms of interaction, and their dynamic changes across different stages of degeneration remain to be further elucidated. Taken together, the identification of emerging RCD mechanisms has provided a more comprehensive framework for understanding the complex pathological processes of IDD. Furthermore, it has established a theoretical basis for the development of multi-target combinatorial intervention strategies and disease-modifying therapeutic paradigms, and may ultimately facilitate a shift in IDD management from symptomatic relief alone toward etiology-oriented and precision-based interventions.

Dental caries is a prevalent oral health problem that significantly reduces an individual's quality of life; although, it can be effectively managed through restorative treatments. Even in cases where the caries does not reach the pulp, released microbial products from the lesion can still penetrate the pulp chamber, potentially inducing stress on pulp cells. In this study, we conducted a comparative analysis of the biological and proteomic profiles of dental pulp stem cells (DPSCs) isolated from clinically asymptomatic teeth with dentinal caries that had not reached the pulp and isolated from healthy teeth. Following biological evaluations, we examined proteomes of these DPSCs by conducting a shotgun proteomics approach. Our findings show that DPSCs from decayed teeth exhibit a significantly higher proportion of senescent cells. Proteomic profiling revealed upregulation of inflammatory signaling, extracellular matrix remodeling, and senescence-associated secretory phenotype (SASP) related proteins. Additionally, we observed an upregulation in the expression of proteins associated with extracellular matrix (ECM) remodeling and components of the SASP, which are hallmarks of the senescence process. The study reveals that DPSCs can be affected by stress from carious lesions, even when the pulp appears clinically intact. Senescence and inflammatory response in these affected cells may have deleterious effects on other tissues within the organism. Consequently, restorative treatments should consider targeting not only the decayed tissue but also the senescent cells within the pulp that may have been affected by the stress induced by caries.

Y. Zhao, H. Wang, X. Li, M. Cao, H. Lu, Q. Meng, H. Pang, H. Li, C. Nadolny, X. Dong, and L. Cai, "Ang II-AT1R Increases Cell Migration Through PI3K/AKT and NF-κB Pathways in Breast Cancer," Journal of Cellular Physiology 229, no. 11 (2014): 1855-1862, https://doi.org/10.1002/jcp.24639. The above article, published online on 01 April 2014 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors; the journal Editor-in-Chief, Robert Heath; and Wiley Periodicals LLC. The retraction has been agreed due to concerns raised by third parties. Image duplications have been identified within Figure 1a and across Figures 1a, 1b, 2 f, 3a, 3c, 3 d, 4a, and 4e. The scope of the corrections proposed by the authors extended beyond the panels implicated in the identified issues, thereby further undermining the editors' confidence in the accuracy and integrity of the whole body of work presented in the article. Accordingly, the article has been retracted, as the editors consider the conclusions to be invalid.

ABSTRACTPatients with chronic kidney disease, and particularly those under hemodialysis, are prone to develop cardiovascular complications, mostly due to the exacerbation of vascular calcification. Vascular calcification relies on the transdifferentiation of vascular smooth muscle cells into calcifying cells. Sphingosine 1‐phosphate is a pleiotropic sphingolipid and an important regulator of osteogenesis and the cardiovascular system. Therefore, we explored the role of sphingosine 1‐phosphate metabolism in chronic kidney disease‐derived vascular calcification. Vascular calcification progression in chronic kidney disease and sphingosine 1‐phosphate signaling were examined in calcified vascular smooth muscle cells, in aortic explants, in rats with adenine‐induced chronic kidney disease, as well as in serum from hemodialysis patients. Sphingosine kinase 2 activity and sphingosine 1‐phosphate secretion, under the control of phospholipase D1, were exacerbated in calcified vascular smooth muscle cells. Furthermore, phospholipase D1 knockout mice display significantly less circulating sphingosine 1‐phosphate, supporting intertwined signalization cascades. Overall, sphingosine kinase expression and activity were upregulated in calcified aortic explants and in calcified aortas from rats. Sphingosine 1‐phosphate was increased in the serum of rats with mild vascular calcification. The Food and Drug Administration‐approved immunosuppressant drug fingolimod, a general modulator of S1P metabolism, strongly inhibited calcification in vascular smooth muscle cells and aortic explants. Additionally, fingolimod significantly reduced inflammation, attenuated metabolic syndrome and moderately inhibited aortic calcification in rats. Finally, we demonstrated for the first time that serum sphingosine 1‐phosphate was significantly increased in hemodialysis patients with mild abdominal aortic calcification. Our findings open an unexplored therapeutic option, which is targeting sphingosine 1‐phosphate metabolism, eventually with fingolimod, for the prevention and treatment of vascular calcification in chronic kidney disease patients.

ABSTRACTPodocytes are not only the key regulators of glomerular filtration barrier dynamics but also exhibit immunological properties. They are capable of antigen presentation and possess a receptor system recognizing pathogen‐associated molecular patterns. Our earlier study further demonstrated that podocytes share additional similarities with immune cells, as they can synthesize and secrete the active form of cathepsin C – an enzyme that controls the activation of neutrophil serine proteases (NSPs). In this study, we established that podocytes synthesize neutrophil elastase (NE), proteinase 3 (PR 3), and cathepsin G (CatG) but also release their active forms into the extracellular environment. We found that NSPs contribute to podocyte dysfunction upon inflammation induction by PMA and under conditions of insulin insensitivity. Moreover, actin cytoskeleton rearrangement and increased albumin permeability of the podocyte monolayer were triggered by nucleotide‐binding and oligomerization domain‐containing protein 2 (NOD2) activation via muramyl dipeptide (MDP), which consequently enhanced NE and PR 3 activity. Notably, silencing the ELANE gene, which encodes NE, exerted a protective effect on podocytes even after NOD2 activation. These findings indicate that NSPs, especially NE, contribute to podocyte dysfunction in diabetes and diabetic kidney disease, a condition characterized by chronic inflammation and insulin resistance.