The increasing of intracellular calcium concentration is a fundamental process for mediating osteoclastogenesis, which is involved in osteoclastic bone resorption. Cytosolic calcium binds to calmodulin and subsequently activates calcineurin, leading to NFATc1 activation, a master transcription factor required for osteoclast differentiation. Targeting the various activation processes in osteoclastogenesis provides various therapeutic strategies for bone loss. Diverse compounds that modulate calcium signaling have been applied to regulate osteoclast differentiation and, subsequently, attenuate bone loss. Thus, in this review, we summarized the modulation of the NFATc1 pathway through various compounds that regulate calcium signaling and the calcium influx machinery. Furthermore, we addressed the involvement of transient receptor potential channels in osteoclastogenesis.

Although activating apoptosis in cancer cells by targeting the mitochondria is an effective strategy for cancer therapy, insufficient targeting of the mitochondria in cancer cells restricts the availability in clinical treatment. Here, we report on a polyethylene glycol-coated carbon nanotube (CNT)-ABT737 nanodrug that improves the mitochondrial targeting of lung cancer cells. The polyethylene glycol-coated CNT-ABT737 nanodrug internalized into the early endosomes via macropinocytosis and clathrin-mediated endocytosis in advance of early endosomal escape and delivered into the mitochondria. Cytosol release of the nanodrug led to apoptosis of lung cancer cells by abruption of the mitochondrial membrane potential, inducing Bcl-2-mediated apoptosis and generating intracellular reactive oxygen species. As such, this study provides an effective strategy for increasing the anti-lung cancer efficacy by increasing mitochondria accumulation rate of cytosol released anticancer nanodrugs.

The ubiquitin-mediated degradation system is responsible for controlling various tumor-promoting processes, including DNA repair, cell cycle arrest, cell proliferation, apoptosis, angiogenesis, migration and invasion, metastasis, and drug resistance. The conjugation of ubiquitin to a target protein is mediated sequentially by the E1 (activating)‒E2 (conjugating)‒E3 (ligating) enzyme cascade. Thus, E2 enzymes act as the central players in the ubiquitination system, modulating various pathophysiological processes in the tumor microenvironment. In this review, we summarize the types and functions of E2s in various types of cancer and discuss the possibility of E2s as targets of anticancer therapeutic strategies.

The bicarbonate ion has a fundamental role in vital systems. Impaired bicarbonate transport leads to various diseases, including immune disorders, cystic fibrosis, tumorigenesis, kidney diseases, brain dysfunction, tooth fracture, ischemic reperfusion injury, hypertension, impaired reproductive system, and systemic acidosis. Carbonic anhydrases are involved in the mechanism of bicarbonate movement and consist of complex of bicarbonate transport systems including bicarbonate transporters. This review focused on the convergent regulation of ion homeostasis through various ion transporters including bicarbonate transporters, their regulatory enzymes, such as carbonic anhydrases, pH regulatory role, and the expression pattern of ion transporters in non-secretory systems throughout the body. Understanding the correlation between these systems will be helpful in order to obtain new insights and design potential therapeutic strategies for the treatment of pH-related disorders. In this review, we have discussed the broad prospects and challenges that remain in elucidation of bicarbonate-transport-related biological and developmental systems.

Schematic image illustrates the mechanism of Cl⁻release through the proton sponge by the cationic AuNR induced by TRPM2 activation.

Insulin resistance is a major contributor to the pathogenesis of several human diseases, including type 2 diabetes, hypertension, and hyperlipidemia. Notably, insulin resistance and hypertension share common abnormalities, including increased oxidative stress, inflammation, and organelle dysfunction. Recently, we showed that excess intracellular Ca²⁺, a known pathogenic factor in hypertension, acts as a critical negative regulator of insulin signaling by forming Ca²⁺-phosphoinositides that prevent the membrane localization of AKT, a key serine/threonine kinase signaling molecule. Whether preventing intracellular Ca²⁺ overload improves insulin sensitivity, however, has not yet been investigated. Here, we show that the antihypertensive agent candesartan, compared with other angiotensin-II receptor blockers, has previously unrecognized beneficial effects on attenuating insulin resistance. We found that candesartan markedly reduced palmitic acid (PA)-induced intracellular Ca²⁺ overload and lipid accumulation by normalizing dysregulated store-operated channel (SOC)-mediated Ca²⁺ entry into cells, which alleviated PA-induced insulin resistance by promoting insulin-stimulated AKT membrane localization and increased the phosphorylation of AKT and its downstream substrates. As pharmacological approaches to attenuate intracellular Ca²⁺ overload in vivo, administering candesartan to obese mice successfully decreased insulin resistance, hepatic steatosis, dyslipidemia, and tissue inflammation by inhibiting dysregulated SOC-mediated Ca²⁺ entry and ectopic lipid accumulation. The resulting alterations in the phosphorylation of key signaling molecules consequently alleviate impaired insulin signaling by increasing the postprandial membrane localization and phosphorylation of AKT. Thus, our findings provide robust evidence for the pleiotropic contribution of intracellular Ca²⁺ overload in the pathogenesis of insulin resistance and suggest that there are viable approved drugs that can be repurposed for the treatment of insulin resistance and hypertension.