Steroid hormone receptors (SRs) play pivotal roles in the fundamental biological functions related to reproduction, development, and homeostasis. They are also closely associated with various pathophysiologies, including hormone-dependent cancers, metabolic syndromes, and neuropsychiatric disorders. SRs are ligand-dependent transcription factors belonging to the nuclear receptor superfamily. This superfamily also includes orphan nuclear receptors, such as estrogen-related receptors (ERRs) comprising three subtypes of α, β, and γ. Despite their high homology with estrogen receptors (ERs), ERRs cannot bind any endogenous steroid hormones and can activate gene transcription in a ligand-independent manner. Recently, ERRs have attracted considerable attention for their involvement in stem cell pluripotency, senescence, and other poorly understood biological processes. Although subcellular and subnuclear dynamics are crucial for SR function, how ERRs behave in living cells to activate or repress their target genes remains incompletely understood. We have investigated the behaviors of ERRs using fluorescent protein labeling, focusing on whether ERRs exhibit dynamic changes similar to SRs and whether these changes relate to their functional activity. In this review, we summarize findings from studies of molecular behavior, highlighting the coregulation of estrogen signaling by ERs and ERRs, the subnuclear movement of ERRs related to transcriptional repression, and the promotion of lactate metabolism by a novel lactate-responsive protein, LRPGC1, through interaction with ERRγ. We hope these insights contribute to elucidating fundamental biomedical processes and the pathological mechanisms linked to aberrant nuclear receptor signaling pathways.

Chemotherapy-induced peripheral neuropathy (CIPN) frequently develops following treatment of cancer with cytotoxic chemotherapeutics, such as taxanes, platinum-containing agents and vinca alkaloids, and leads to impairment of patients' QOL and dose limitation or cessation of chemotherapy in the worst-case scenario. We have demonstrated that extracellular release of high mobility group box 1 (HMGB1), a nuclear protein, plays a critical role in the developmental process of CIPN, and that thrombomodulin alfa (TMα) capable of degrading HMGB1 in a thrombin-dependent manner prevents CIPN development. Our retrospective cohort study in female patients with breast cancer or gynecological cancer undergoing paclitaxel-based chemotherapy has shown that postmenopausal estrogen decline is a risk factor for the development or aggravation of CIPN. We have also demonstrated that ovariectomy aggravates CIPN in laboratory animals treated with paclitaxel, which is prevented by estrogen supplementation or treatment with TMα. On the other hand, there is evidence from animal studies for inhibition of CIPN by progesterone and of neuropathic pain by androgen. Together, different sex hormones including estrogen may function to limit the development of CIPN, while age-related decline of sex hormones could be a risk for CIPN development. Our study to clarify the effects of sex hormones on HMGB1 behavior during the developmental process of CIPN is still in progress, but we nonetheless propose that TMα capable of inactivating HMGB1 is useful in preventive intervention for cancer patients with high risk of CIPN, e.g., postmenopausal females.

Given the sex differences in pain sensitivity and the prevalence of pain disorders, there is a strong need to elucidate their molecular basis. Because sex differences arise from the interactions between genetic factors and postnatal influences mediated by sex hormones, understanding how sex steroid hormones regulate pain is of particular importance. The mechanical pain threshold is lower in females than in males, whereas no sex differences are observed in thermal, chemical or inflammatory pain, consistent with findings in humans. In gonadectomized male mice, the mechanical threshold is decreased, suggesting a correlation between androgen levels and mechanical pain sensitivity. The androgen receptor (AR) is widely expressed in regions involved in pain transmission, with prominent nuclear localization in the dorsal root ganglia of male mice. In nociceptive primary sensory neuron-specific AR-conditional knockout (AR-cKO) male mice, the mechanical pain threshold is markedly reduced compared with wild-type males, whereas other pain modalities remain unchanged. Moreover, systemic androgen administration to female mice increases nuclear AR localization and elevates the mechanical pain threshold one day after treatment, but these effects are abolished in AR-cKO females. These findings demonstrate that androgen signaling in primary sensory neurons represents a key neural substrate underlying sex differences in mechanical pain sensitivity. Additionally, sex differences observed in neuropathic pain models may also be alleviated by androgen action. Further elucidation of how androgens act on their target neuronal populations is expected to advance our understanding of sex- and individual-specific differences in pain.

Pharmacology role-play is a participatory learning exercise in which students take on the roles of healthcare providers and patients or family members, explaining diseases and pharmacological treatments based on presented case scenarios, and actively learning through mutual communication. Traditionally conducted face-to-face within a single university, this exercise has shifted to online formats during the COVID-19 pandemic, and more recently, attempts have been made to implement inter-university online sessions that utilize remote collaborative learning. In this study, we compared the educational outcomes of online role-play conducted independently at Kochi University and Ehime University in 2020 with those of an inter-university online role-play jointly conducted by both universities in 2021. Participants were third-year medical students at Kochi University and second-year medical students at Ehime University. After completing all assignments, students were asked to complete a post-session questionnaire. Five-point Likert scale responses were analyzed, and free-text comments were further examined using text mining with co-occurrence network analysis. The results indicated that inter-university role-play, compared with single-university sessions, facilitated the recognition of diverse perspectives and promoted deeper reflection through discussion. This experience contributed to enhanced understanding of patients' perspectives, increased motivation for becoming physicians, and improved learning attitudes. These findings suggest that inter-university online role-play is an effective educational approach for enhancing learning outcomes in pharmacology education.