Recently, necroptosis, as a programmed cell death pathway, has drawn much attention as it has been implicated in multiple pathologies, especially in the field of inflammatory diseases. Pseudokinase mixed lineage kinase domain-like protein (MLKL) serves as a terminal-known obligate effector in the process of necroptosis. To date, the majority of research on MLKL has focused on its role in necroptosis, and the prevailing view has been that the sole function of MLKL is to mediate necroptosis. However, increasing evidence indicates that MLKL can serve as a regulator of many diseases via its non-necroptotic functions. These functions of MLKL shed light on its functional complexity and diversity. In this review, we briefly introduce the current state of knowledge regarding the structure of MLKL, necroptosis signaling, as well as cross-linkages among necroptosis and other regulated cell death pathways, and we particularly highlight recent progress related to newly identified functions and inhibitors of MLKL. These discussions promote a better understanding of the role of MLKL in diseases, which will foster efforts to pharmacologically target this molecule in clinical treatments.

Periodontitis is a chronic inflammatory disease associated with a dysbiotic bacterial biofilm in the subgingival environment that may disturb the balance between the oral microbiome and its host. The inability of the immune system to eliminate inflammation may result in the progressive destruction of tooth-support tissues. Macrophages are crucial cellular components of the innate immune system and play important roles in diverse physiological and pathological processes. In response to periodontitis-associated bacterial communities, macrophages contribute to inflammation and restoration of tissue homeostasis through pattern recognition receptor-induced signaling cascades; therefore, targeting macrophages can be a feasible strategy to treat patients with periodontitis. Although recent studies indicate that macrophages have a spectrum of activation states, ranging from pro-inflammatory to anti-inflammatory, the regulatory mechanism of the macrophage response to dysbiosis in a tissue-specific manner remains largely unclear. Herein, we attempt to summarize the potential role of macrophage activation in the progression of periodontitis, as well as its relevance to future approaches in the treatment of periodontitis.

As one of the most densely innervated tissues, the dental pulp contains abundant nerve fibres, including sensory, sympathetic and parasympathetic nerve fibres. Studies in animal models and human patients with pulpitis have revealed distinct alterations in protein expression and histological appearance in all types of dental nerve fibres. Various molecules secreted by neurons, such as classical neurotransmitters, neuropeptides and amino acids, not only contribute to the induction, sensitization and maintenance of tooth pain, but also regulate non‐neuronal cells, including fibroblasts, odontoblasts, immune cells and vascular endothelial cells. Dental nerves are particularly important for the microcirculatory and immune responses in pulpitis via their release of a variety of functional substances. Further, nerve fibres are found to be involved in dental soft and hard tissue repair. Thus, understanding how dental nerves participate in pulpitis could have important clinical ramifications for endodontic treatment. In this review, the roles of dental nerves in regulating pulpal inflammatory processes are highlighted and their implications for future research on this topic are discussed.

Peripheral nerve injury (PNI) is one of the most common concerns in trauma patients. Despite significant advances in repair surgeries, the outcome can still be unsatisfactory, resulting in morbidities such as loss of sensory or motor function and reduced quality of life. This highlights the need for more supportive strategies for nerve regrowth and adequate recovery. Multifunctional cytokine transforming growth factor-β (TGF-β) is essential for the development of the nervous system and is known for its neuroprotective functions. Accumulating evidence indicates its involvement in multiple cellular and molecular responses that are critical to peripheral nerve repair. Following PNI, TGF-β is released at the site of injury where it can initiate a series of phenotypic changes in Schwann cells (SCs), modulate immune cells, activate neuronal intrinsic growth capacity, and regulate blood nerve barrier (BNB) permeability, thus enhancing the regeneration of the nerves. Notably, TGF-β has already been applied experimentally in the treatment of PNI. These treatments with encouraging outcomes further demonstrate its regeneration-promoting capacity. Herein, we review the possible roles of TGF-β in peripheral nerve regeneration and discuss the underlying mechanisms, thus providing new cues for better treatment of PNI.

Adenoid cystic carcinoma of the salivary gland (SACC) is a rare malignant tumors of the head and neck region, but it is one of the most common malignant tumors that are prone to perineural invasion (PNI) of the head and neck. The prognosis of patients with SACC is strongly associated with the presence of perineural spread (PNS). Although many contributing factors have been reported, the mechanisms underlying the preferential destruction of the blood-nerve barrier (BNB) by tumors and the infiltration of the tumor microenvironment by nerve fibers in SACC, have received little research attention. This review summarizes the current knowledge concerning the characteristics of SACC in relation to the PNI, and then highlights the interplay between components of the tumor microenvironment and perineural niche, as well as their contributions to the PNI. Finally, we provide new insights into the possible mechanisms underlying the pathogenesis of PNI, with particular emphasis on the role of extracellular vesicles that may serve as an attractive entry point in future studies.