The endoplasmic reticulum (ER) is a central hub of cellular proteostasis, coordinating protein folding, lipid metabolism, calcium signaling, and inter-organelle communication. Disruptions in ER function activate the unfolded protein response (UPR), an evolutionarily conserved signaling network mediated by PERK, IRE1α, and ATF6. Initially viewed primarily as a stress-mitigating mechanism, the UPR is now recognized as a central coordinator of diverse cellular stress-response pathways. This review focuses on mechanistic insights into UPR signaling, with particular emphasis on its crosstalk with oxidative stress regulation, mitochondrial function and mitochondria–ER contact sites, autophagy, inflammatory signaling, and metabolic sensing. The analysis integrates evidence from biochemical and structural studies, genetic and pharmacological perturbation models, and selected in vivo investigations from PubMed and Google Scholar between 2000 and 2025, focusing on mechanistic, experimental and translational studies addressing UPR signaling and ER stress. Together, these studies demonstrate how transient UPR activation promotes cellular adaptation through coordinated transcriptional, translational, and organelle-specific responses. We further discuss how sustained or unresolved ER stress alters UPR outputs, shifting signaling toward maladaptive outcomes such as mitochondrial dysfunction, dysregulated autophagy, oxidative imbalance, and apoptosis. By placing the UPR within a network of interconnected stress pathways, this work provides a framework for understanding how ER proteostasis is linked to cell fate decisions under stress.

Endoplasmic reticulum (ER) stress is a significant player in the pathophysiology of various neurodegenerative and neuropsychiatric disorders. Despite the established link between ER stress and inflammatory pathways, there remains a need for deeper exploration of the specific cellular mechanisms underlying ER stress-mediated neuroinflammation. This study aimed to investigate how the severity of ER stress (triggered by different concentrations of tunicamycin) can impact the release of proinflammatory cytokines IL-6 and IL-8 from astrocytes and microglia, comparing the effects with those induced by well-known immunostimulants—tumor necrosis factor alpha (TNF-α) or lipopolysaccharide (LPS). Mild ER stress has a distinct effect on the cytokine release compared to more intense stress levels, i.e., diminished IL-6 production was accompanied by an increase in IL-8 level, which was significantly more pronounced in astrocytes than in microglia. On the contrary, prolonged or more severe ER stress induced inflammation in glial cells, leading to a time- and concentration-dependent buildup of proinflammatory IL-6, but unlike inflammatory agents, an ER stress inducer diminished IL-8 secretions by glial cells. The differences could hold importance in identifying ER stress markers as potential drug targets for the treatment of neurodegenerative diseases or mood disorders, yet this requires confirmation in more complex animal studies.

Periodontal disease is a prevalent inflammatory disorder that can lead to severe oral complications. Recent studies increasingly underline the role of endoplasmic reticulum (ER) stress in its pathogenesis. Experimental models using inflammatory agents such as lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF-α), and ligature-induced periodontitis in rodents, as well as chemical hypoxia, have consistently demonstrated the activation of unfolded protein response (UPR) pathways in periodontal cells. Key ER stress markers, including CHOP, GRP78, PERK, and ATF6, were upregulated in periodontal ligament cells, stem cells, and gingival epithelial cells under these conditions. While ER stress in periodontitis is primarily associated with detrimental outcomes such as apoptosis and inflammation, it may also have a physiological role in bone remodeling via the PERK-eIF2α-ATF4 axis. Importantly, several ER stress-modulating agents—such as oridonin, melatonin, and exosomes derived from M2 macrophages—have shown therapeutic potential by reducing stress marker expression and limiting periodontal damage. These findings suggest that targeting ER stress may offer a novel therapeutic strategy. Future human studies are essential to determine whether a combined approach targeting inflammation and ER stress could more effectively halt or reverse periodontal tissue destruction, while also assessing the long-term safety of ER stress modulation.

Background: Endoplasmic reticulum (ER) stress is a significant player in the pathophysiology of various neurodegenerative and neuropsychiatric disorders. Despite the established link between ER stress and inflammatory pathways, there remains a need for deeper exploration of the specific cellular mechanisms underlying ER stress-mediated neuroinflammation. Methods: This study aimed to investigate how severity of ER stress can impact the release of proinflammatory cyto-kines IL-6 and IL-8 from astrocytes and microglia, comparing the effects with those induced by well-known immunostimulants - tumor necrosis factor alpha (TNF-α) or lipopolysaccharide (LPS). Results: Mild ER stress has a distinct effect on the cytokine release compared to more intense stress levels, i.e. diminished IL-6 production was accompanied by an increase in IL-8 level, which was significantly more pronounced in astrocytes than in microglia. On the contrary, prolonged or more severe ER stress induced inflammation in glial cells, leading to a time- and concentration-dependent buildup of pro-inflammatory IL-6 but unlike inflammatory agents, ER stress inducer diminished IL-8 secretions by glial cells. Conclusion: The differences could hold importance in identifying ER stress markers as potential drug targets for treatment of neurodegenerative diseases or mood disorders, yet it requires confirmation in more complex animal studies.

Vitamin D₃ is a fat-soluble steroid essential for bone metabolism, immune modulation, and inflammation control, all critical for periodontal health. Its active form, 1,25-dihydroxyvitamin D₃, binds to the vitamin D receptor (VDR) in periodontal cells, including periodontal ligament stromal cells, fibroblasts, osteoblasts, and macrophages, enhancing osteogenesis, antimicrobial defenses, and anti-inflammatory responses. Clinical and experimental evidence demonstrates that adequate systemic vitamin D₃ levels and local activation in gingival tissues improve outcomes of nonsurgical and surgical periodontal therapies, reducing probing pocket depth (PPD), clinical attachment loss (CAL), and gingival inflammation. Dose-dependent supplementation shows greater clinical efficacy, and emerging evidence supports potential topical applications. This review integrates molecular mechanisms with clinical findings, highlighting the therapeutic potential of vitamin D₃ in periodontal disease management.

Background: Periodontitis is a multifactorial, chronic inflammatory disease that leads to progressive destruction of the periodontal apparatus. Despite the effectiveness of scaling and root planing (SRP), residual inflammation and limited regenerative potential justify the search for adjunctive biologic therapies. Platelet-derived concentrates, including platelet-rich plasma (PRP), platelet-rich fibrin (PRF), concentrated growth factors (CGF), and platelet-poor plasma (PPP), have gained attention as autologous sources of growth factors enhancing periodontal regeneration. Aim: This narrative review provides a comparative analysis of the biological mechanisms, preparation protocols, and clinical outcomes associated with the adjunctive use of platelet-derived concentrates in non-surgical periodontal therapy. Methods: A narrative literature review was conducted using English-language publications retrieved from PubMed and Google Scholar, covering studies published from 2012 onward. The search strategy was based on combinations of keywords related to platelet-derived concentrates and non-surgical periodontal therapy. In vitro, in vivo, and clinical studies, as well as relevant narrative, systematic, and umbrella reviews evaluating the adjunctive use of platelet-derived concentrates (PRP, PRF, CGF, and PPP) were considered. Studies focusing on biological mechanisms, preparation protocols, and clinical periodontal outcomes were included, whereas case reports, studies unrelated to periodontal therapy, and publications lacking relevant clinical or biological outcome data were excluded. Results: Most clinical studies reported improvements in probing depth reduction, clinical attachment level gain, and bleeding indices following adjunctive use of platelet-derived concentrates with SRP. PRF tended to demonstrate more consistent clinical outcomes compared to PRP, potentially related to its simplified preparation and sustained release of bioactive molecules. CGF showed promising osteogenic and angiogenic properties in preclinical and early clinical studies. PPP, although less extensively investigated, exhibited regenerative and antimicrobial potential in preliminary reports. Conclusions: Platelet-derived concentrates may serve as valuable adjuncts in non-surgical periodontal therapy; however, the current evidence is characterized by methodological heterogeneity and variable study quality. While PRF appears to yield more consistent clinical results, definitive conclusions regarding superiority among different platelet concentrates cannot be drawn. Further well-designed randomized controlled trials are required, particularly for CGF and PPP.