The endoplasmic reticulum (ER) is an essential organelle of eukaryotic cells. Its main functions include protein synthesis, proper protein folding, protein modification, and the transportation of synthesized proteins. Any perturbations in ER function, such as increased demand for protein folding or the accumulation of unfolded or misfolded proteins in the ER lumen, lead to a stress response called the unfolded protein response (UPR). The primary aim of the UPR is to restore cellular homeostasis; however, it triggers apoptotic signaling during prolonged stress. The core mechanisms of the ER stress response, the failure to respond to cellular stress, and the final fate of the cell are not yet clear. Here, we discuss cellular fate during ER stress, cross talk between the ER and mitochondria and its significance, and conditions that can trigger ER stress response failure. We also describe how the redox environment affects the ER stress response, and vice versa, and the aftermath of the ER stress response, integrating a discussion on redox imbalance-induced ER stress response failure progressing to cell death and dynamic pathophysiological changes.

Numerous approaches have been introduced to regenerate artificial dental tissues. However, conventional approaches are limited when producing a construct with three-dimensional patient-specific shapes and compositions of heterogeneous dental tissue. In this research, bioprinting technology was applied to produce a three-dimensional dentin–pulp complex with patient-specific shapes by inducing localized differentiation of human dental pulp stem cells within a single structure. A fibrin-based bio-ink was designed for bioprinting with the human dental pulp stem cells. The effects of fibrinogen concentration within the bio-ink were investigated in terms of printability, human dental pulp stem cell compatibility, and differentiation. The results show that micro-patterns with human dental pulp stem cells could be achieved with more than 88% viability. Its odontogenic differentiation was also regulated according to the fibrinogen concentration. Based on these results, a dentin–pulp complex having patient-specific shape was produced by co-printing the human dental pulp stem cell–laden bio-inks with polycaprolactone, which is a bio-thermoplastic used for producing the overall shape. After culturing with differentiation medium for 15 days, localized differentiation of human dental pulp stem cells in the outer region of the three-dimensional cellular construct was successfully achieved with localized mineralization. This result demonstrates the possibility to produce patient-specific composite tissues for tooth tissue engineering using three-dimensional bioprinting technology.

Inositol-requiring transmembrane kinase endoribonuclease-1α (IRE1α) is the most prominent and evolutionarily conserved unfolded protein response (UPR) signal transducer during endoplasmic reticulum functional upset (ER stress). A IRE1α signal pathway arbitrates yin and yang of cellular fate in objectionable conditions. It plays several roles in fundamental cellular physiology as well as in several pathological conditions such as diabetes, obesity, inflammation, cancer, neurodegeneration, and in many other diseases. Thus, further understanding of its molecular structure and mechanism of action during different cell insults helps in designing and developing better therapeutic strategies for the above-mentioned chronic diseases. In this review, recent insights into structure and mechanism of activation of IRE1α along with its complex regulating network were discussed in relation to their basic cellular physiological function. Addressing different binding partners that can modulate IRE1α function, UPRosome triggers different downstream pathways depending on the cellular backdrop. Furthermore, IRE1α are in normal cell activities outside the dominion of ER stress and activities under the weather of inflammation, diabetes, and obesity-related metaflammation. Thus, IRE1 as an ER stress sensor needs to be understood from a wider perspective for comprehensive functional meaning, which facilitates us with assembling future needs and therapeutic benefits.

Transmembrane B cell lymphoma 2-associated X protein inhibitor motif-containing (TMBIM) 6, a Ca²⁺ channel-like protein, is highly up-regulated in several cancer types. Here, we show that TMBIM6 is closely associated with survival in patients with cervical, breast, lung, and prostate cancer. TMBIM6 deletion or knockdown suppresses primary tumor growth. Further, mTORC2 activation is up-regulated by TMBIM6 and stimulates glycolysis, protein synthesis, and the expression of lipid synthesis genes and glycosylated proteins. Moreover, ER-leaky Ca²⁺ from TMBIM6, a unique characteristic, is shown to affect mTORC2 assembly and its association with ribosomes. In addition, we identify that the BIA compound, a potentialTMBIM6 antagonist, prevents TMBIM6 binding to mTORC2, decreases mTORC2 activity, and also regulates TMBIM6-leaky Ca²⁺, further suppressing tumor formation and progression in cancer xenograft models. This previously unknown signaling cascade in which mTORC2 activity is enhanced via the interaction with TMBIM6 provides potential therapeutic targets for various malignancies.

We developed a novel dentin-pulp-like organoid. It has both stem-cell and odontoblast characteristics using a mesenchymal cell lineage of human dental-pulp stem cells (hDPSCs). The mixture of hDPSCs and Matrigel was transferred into the maintenance medium (MM) and divided into four different groups according to how long they were maintained in the odontogenic differentiation medium (ODM). All organoids were harvested at 21 days and analyzed to find the optimal differentiation condition. To assess the re-fabrication of dentin-pulp-like organoid, after dissociation of the organoids, it was successfully regenerated. Additionally, its biological activity was confirmed by analyzing changes of relevant gene expression and performing a histology analysis after adding Biodentine^® into the ODM. The organoid was cultured for 11 days in the ODM (ODM 11) had the most features of both stem cells and differentiated cells (odontoblasts) as confirmed by relevant gene expression and histology analyses. Micro-computed tomography and an electron microscope also showed mineralization and odontoblastic differentiation. Finally, ODM 11 demonstrated a biologically active response to Biodentine^® treatment. In conclusion, for the first time, we report the fabrication of a dentin-pulp-like organoid using mesenchymal stem cells. This organoid has potential as a future therapeutic strategy for tooth regeneration.

The goal of this study was to fabricate bioactive cell‐laden biocomposites supplemented with bone‐derived decellularized extracellular matrix (dECM) with calcium phosphate ceramic, and to assess the effect of the biocomponents on the osteogenic and odontogenic differentiation of human dental pulp stem cells (hDPSCs). By evaluating the rheological properties and selecting printing parameters, mechanically stable cell‐laden 3D biocomposites with high initial cell‐viability (>90%) and reasonable printability (≈0.9) were manufactured. The cytotoxicity of the biocomposites was evaluated via MTT assay and nuclei/F‐actin fluorescent analyses, while the osteo/odontogenic differentiation of the hDPSCs was assessed using histological and immunofluorescent analyses and various gene expressions. Alkaline phosphate activity and alizarin red staining results indicate that the dECM‐based biocomposites exhibit significantly higher osteogenic activities, including calcification, compared to the collagen‐based biocomposites. Furthermore, immunofluorescence images and gene expressions demonstrated upregulation of dentin matrix acidic phosphoprotein‐1 and dentin sialophosphoprotein in the dECM‐based biocomposites, indicating acceleration of the odontogenic differentiation of hDPSCs in the printed biocomposites. The hDPSC‐laden biocomposite was implanted into the subcutaneous region of mice, and the biocomposite afforded clear induction of osteo/odontogenic ectopic hard tissue formation 8 weeks post‐transplantation. From these results, we suggest that the hDPSC‐laden biocomposite is a promising biomaterial for dental tissue engineering.