Menthol is an important flavoring additive that triggers a cooling sensation. Under physiological condition, low to moderate concentrations of menthol activate transient receptor potential cation channel subfamily M member 8 (TRPM8) in the primary nociceptors, such as dorsal root ganglion (DRG) and trigeminal ganglion, generating a cooling sensation, whereas menthol at higher concentration could induce cold allodynia, and cold hyperalgesia mediated by TRPM8 sensitization. In addition, the paradoxical irritating properties of high concentrations of menthol is associated with its activation of transient receptor potential cation channel subfamily A member 1 (TRPA1). Under pathological situation, menthol activates TRPM8 to attenuate mechanical allodynia and thermal hyperalgesia following nerve injury or chemical stimuli. Recent reports have recapitulated the requirement of central group II/III metabotropic glutamate receptors (mGluR) with endogenous κ-opioid signaling pathways for menthol analgesia. Additionally, blockage of sodium channels and calcium influx is a determinant step after menthol exposure, suggesting the possibility of menthol for pain management. In this review, we will also discuss and summarize the advances in menthol-related drugs for pathological pain treatment in clinical trials, especially in neuropathic pain, musculoskeletal pain, cancer pain and postoperative pain, with the aim to find the promising therapeutic candidates for the resolution of pain to better manage patients with pain in clinics.

Chemotherapy-induced thrombocytopenia (CIT) is a common condition that frequently results in reduced chemotherapy dosages, postponed treatment, bleeding, and unfavorable oncological outcomes. At present, there is no clear suggestions for preventing or treating CIT. Thrombopoietin (TPO) replacement therapy has been invented and used to treat CIT to promote the production of megakaryocytes and stimulate the formation of platelets. However, this treatment is limited to the risk of immunogenicity and cancer progression. Therefore, an unmet need exists for exploring alternatives to TPO to address the clinical issue of CIT. Application of appropriate therapeutic drugs may be due to understanding the potential mechanisms of CIT. Studies have shown that chemotherapy significantly affects various cells in bone marrow (BM) microenvironment, reduces their ability to support normal hematopoiesis, and may lead to BM damage, including CIT in cancer patients. This review focuses on the epidemiology and treatment of cancer patients with CIT. We also introduce some recent progress to understand the cellular and molecular mechanisms of chemotherapy inhibiting normal hematopoiesis and causing thrombocytopenia.

CNS inflammation is known to be an important pathogenetic mechanism of perioperative neurocognitive disorder (PND), and iron overload was reported to participate in this process accompanied by oxidative stress. Ferroptosis is an iron-dependent form of cell death, and occurs in multiple neurodegenerative diseases with cognitive disorder. However, the effect of ferroptosis in inflammation-related PND is unknown. In this study, we found that the ferroptosis inhibitor liproxstatin-1 ameliorated memory deficits in the mouse model of lipopolysaccharide (LPS)-induced cognitive impairment. Moreover, liproxstatin-1 decreased the activation of microglia and the release of interleukin (IL)-6 and tumor necrosis factor-alpha (TNF)-α, attenuated oxidative stress and lipid peroxidation, and further weakened mitochondrial injury and neuronal damage after LPS exposure. Additionally, the protective effect of liproxstatin-1 was related to the alleviation of iron deposition and the regulation of the ferroptosis-related protein family TF, xCT, Fth, Gpx4, and FtMt. These findings enhance our understanding of inflammation-involved cognitive dysfunction and shed light on future preclinical studies.

Chronic pain is a common, complex and unpleasant sensation following nerve injury, tissue trauma, inflammatory diseases, infection and cancer. It affects up to 25% of adults and is increasingly recognized as the leading cause of distress, disability and disease burden globally. Chronic pain is often refractory to most current analgesics, thus emphasizing the requirement for improved therapeutic medications. It is of great importance to elucidate the specific pathogenesis of chronic pain with different etiologies. Recent progress has advanced our understanding in the contribution of neuroinflammation and glial cells (microglia and astrocyte) activation in the plasticity of excitatory nociceptive synapses and the development of chronic pain phenotypes. Oxidative stress-associated neuronal apoptosis is also identified to be a pivotal step for central pain sensitization. The family of cysteine aspartate specific proteases (Caspases) has been well known to be key signaling molecules for inflammation and apoptosis in several neurological conditions. Recent studies have highlighted the unconventional and emerging role of caspases in microgliosis, astrocytes morphogenesis, chemokines release, cytokines secretion and neuronal apoptosis in initiating and maintaining synaptogenesis, synaptic strength and signal transduction in persistent pain hypersensitivity, suggesting the possibility of targeting caspases pathway for prevention and treatment of chronic pain. In this review, we will discuss and summarize the advances in the distinctive properties of caspases family in the pathophysiology of chronic pain, especially in neuropathic pain, inflammatory pain, cancer pain and musculoskeletal pain, with the aim to find the promising therapeutic candidates for the resolution of chronic pain to better manage patients undergoing chronic pain in clinics.