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Macrophage plasticity is critical for maintaining immune function and developing solid tumors; however, the macrophage polarization mechanism remains incompletely understood. Our findings reveal that Mg2+ entry through distinct plasma membrane channels is critical to macrophage plasticity. Naïve macrophages displayed a previously unidentified Mg2+ dependent current, and TRPM7-like activity, which modulates its survival. Significantly, in M1 macrophages, Mg2+ entry is facilitated by a novel Mg²-dependent current that relies on extracellular Mg2+, which was crucial for activating iNOS/NFκB pathways and cellular bioenergetics, which drives pro-inflammatory cytokines. Conversely, in M2 macrophages, Mg2+ entry occurs primarily through TRPM7 channels, pivotal for IL-4 and IL-10-mediated anti-inflammatory cytokine secretion. Notably, the Mg2+ deficient diet or addition of TRPM7 agonist Naltriben suppresses the M1 phenotype while promoting angiogenic factors and fostering tumor growth. These findings suggest that Mg2+ flux via specific channels is indispensable for macrophage polarization, with its dysregulation playing a pivotal role in tumor progression. [ABSTRACT FROM AUTHOR]

Purpose: To compare dental students' preparedness in clinical periodontal education following their participation in a discipline‐based predoctoral periodontics clinic with dental students that received a general practice‐based periodontal education. Methods: 114 third‐year dental students and 112 fourth‐year dental students at the University of Texas Health Science Center in San Antonio, were emailed an online survey consisting of questions on their proficiency and confidence levels in diagnosing periodontal diseases and conditions, treatment planning, performing non‐surgical periodontal treatment, identifying the need for referral, and their perceived impediments on their clinical periodontics education. Results: Approximately 97% of third‐year dental students that participated in discipline‐based predoctoral periodontics agree that they are overall confident in providing excellent periodontal care to their patients, and 91% of these students feel that their participation in the predoctoral periodontics clinic has enhanced their knowledge in periodontics as well as their confidence level when providing periodontal patient care. While 95% of fourth‐year dental students agree that they feel confident in providing excellent periodontal care to their patients, only 83% felt that level of confidence during their third‐year in dental school, and 77% believe that given the option to participate in the pre‐doctoral periodontics clinic, their periodontal education would have been strengthened. Conclusions: Our results show that the integration of a discipline based predoctoral periodontics clinic has benefited the dental students and boosted their knowledge and confidence in diagnosing and treating periodontal patients. This model can be improved by addressing space and time limitations. [ABSTRACT FROM AUTHOR]

Clinical studies and structural analyses of salivary stones strongly suggest a linkage between higher saliva calcium (Ca2+) and salivary stone formation, sialolithiasis; however, the process and the mechanism leading to Ca2+ overload during sialolithiasis is not well understood. Here, we show that TRPC3 null (−/−) mice presented with a reduction in Ca2+ entry and current in ductal cells with higher saliva [Ca2+] suggesting diminished transepithelial Ca2+ flux across the salivary ductal cells, leaving more Ca2+ in ductal fluid. Significantly, we found that TRPC3 was expressed in mice and human salivary ductal cells, while intraductal stones were detected in both mice (TRPC3−/−) and patient (sialolithiasis) salivary glands. To identify the mechanism, we found that TRPC3 was crucial in preventing the expression of calcification genes (BMP2/6, Runx2) in ductal cells which may be due to higher extracellular Ca2+ in SMG tissues. Similarly, inflammatory (IL6, NLRP3), fibrotic (FN1, TGFβ1) and apoptotic (Bax1/Bcl2) markers were also elevated, suggesting that the loss of TRPC3 induces genetic changes that leads to salivary gland cell death and induction of inflammatory response. Overall, ablation of TRPC3−/− leads to higher saliva [Ca2+], along with elevated detrimental gene expressions, altogether contributing to salivary gland stone formation. [ABSTRACT FROM AUTHOR]

Background: Primary Sjogren's syndrome (pSS) is a systemic autoimmune disease that is embodied by the loss of salivary gland function and immune cell infiltration, but the mechanism(s) are still unknown. The aim of this study was to understand the mechanisms and identify key factors that leads to the development and progression of pSS. Methods: Immunohistochemistry staining, FACS analysis and cytokine levels were used to detect immune cells infiltration and activation in salivary glands. RNA sequencing was performed to identify the molecular mechanisms involved in the development of pSS. The function assays include in vivo saliva collection along with calcium imaging and electrophysiology on isolated salivary gland cells in mice models of pSS. Western blotting, real‐time PCR, alarmin release, and immunohistochemistry was performed to identify the channels involved in salivary function in pSS. Results: We provide evidence that loss of Ca2+ signaling precedes a decrease in saliva secretion and/or immune cell infiltration in IL14α, a mouse model for pSS. We also showed that Ca2+ homeostasis was mediated by transient receptor potential canonical‐1 (TRPC1) channels and inhibition of TRPC1, resulting in the loss of salivary acinar cells, which promoted alarmin release essential for immune cell infiltration/release of pro‐inflammatory cytokines. In addition, both IL14α and samples from human pSS patients showed a decrease in TRPC1 expression and increased acinar cell death. Finally, paquinimod treatment in IL14α restored Ca2+ homeostasis that inhibited alarmin release thereby reverting the pSS phenotype. Conclusions: These results indicate that loss of Ca2+ signaling is one of the initial factors, which induces loss of salivary gland function along with immune infiltration that exaggerates pSS. Importantly, restoration of Ca2+ signaling upon paquinimod treatment reversed the pSS phenotype thereby inhibiting the progressive development of pSS. [ABSTRACT FROM AUTHOR]

Introduction Parkinson's disease (PD) is the second most common neurodegenerative disorder and is characterized by the selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta region (SNpc). [...], Individuals with Parkinson's disease (PD) experience a progressive decline in motor function as a result of selective loss of dopaminergic (DA) neurons in the substantia nigra. The mechanism(s) underlying the loss of DA neurons is not known. Here, we show that a neurotoxin that causes a disease that mimics PD upon administration to mice, because it induces the selective loss of DA neurons in the substantia nigra, alters [Ca.sup.2+] homeostasis and induces ER stress. In a human neuroblastoma cell line, we found that endogenous store-operated [Ca.sup.2+] entry (SOCE), which is critical for maintaining ER [Ca.sup.2+] levels, is dependent on transient receptor potential channel 1 (TRPC1) activity. Neurotoxin treatment decreased TRPC1 expression, TRPC1 interaction with the SOCE modulator stromal interaction molecule 1 (STIM1), and [Ca.sup.2+] entry into the cells. Overexpression of functional TRPC1 protected against neurotoxin-induced loss of SOCE, the associated decrease in ER [Ca.sup.2+] levels, and the resultant unfolded protein response (UPR). In contrast, silencing of TRPC1 or STIM1 increased the UPR. Furthermore, [Ca.sup.2+] entry via TRPC1 activated the AKT pathway, which has a known role in neuroprotection. Consistent with these in vitro data, Trpc1-/- mice had an increased UPR and a reduced number of DA neurons. Brain lysates of patients with PD also showed an increased UPR and decreased TRPC1 levels. Importantly, overexpression of TRPC1 in mice restored AKT/mTOR signaling and increased DA neuron survival following neurotoxin administration. Overall, these results suggest that TRPC1 is involved in regulating [Ca.sup.2+] homeostasis and inhibiting the UPR and thus contributes to neuronal survival.