Anoctamin1 (ANO1), a calcium-activated chloride channel, is involved in the proliferation, migration, and invasion of various cancer cells including head and neck squamous cell carcinoma, lung cancer, and prostate cancer. Inhibition of ANO1 activity or downregulation of ANO1 expression in these cancer cells is known to exhibit anticancer effects. Resveratrol, a natural polyphenol abundant in wines, grapes, berries, soybeans, and peanuts, shows a wide variety of biological effects including anti-inflammatory, antioxidant, and anticancer activities. In this study, we investigated the effects of two stereoisomers of resveratrol on ANO1 activity and found that cis- and trans-resveratrol inhibited ANO1 activity with different potencies. Cis- and trans-resveratrol inhibited ANO1 channel activity with IC₅₀ values of 10.6 and 102 μM, respectively, and had no significant effect on intracellular calcium signaling at 10 and 100 μM, respectively. In addition, cis-resveratrol downregulated mRNA and protein expression levels of ANO1 more potently than trans-resveratrol in PC-3 prostate cancer cells. Cis- and trans-resveratrol significantly reduced cell proliferation and cell migration in an ANO1-dependent manner, and both resveratrol isomers strongly increased caspase-3 activity, PARP cleavage, and apoptotic sub-G1 phase ratio in PC-3 cells. These results revealed that cis-resveratrol is a potent inhibitor of ANO1 and exhibits ANO1-dependent anticancer activity against human metastatic prostate cancer PC-3 cells.

Calcium signaling plays a vital role in the regulation of various cellular processes, including activation, proliferation, and differentiation of T-lymphocytes, which is mediated by ORAI1 and potassium (K⁺) channels. These channels have also been identified as highly attractive therapeutic targets for immune-related diseases. Licochalcone A is a licorice-derived chalconoid known for its multifaceted beneficial effects in pharmacological treatments, including its anti-inflammatory, anti-asthmatic, antioxidant, antimicrobial, and antitumorigenic properties. However, its anti-inflammatory effects involving ion channels in lymphocytes remain unclear. Thus, the present study aimed to investigate whether licochalcone A inhibits ORAI1 and K⁺ channels in T-lymphocytes. Our results indicated that licochalcone A suppressed all three channels (ORAI1, Kv1.3, and KCa3.1) in a concentration-dependent matter, with IC₅₀ values of 2.97 ± 1.217 µM, 0.83 ± 1.222 µM, and 11.21 ± 1.07 µM, respectively. Of note, licochalcone A exerted its suppressive effects on the IL-2 secretion and proliferation in CD3 and CD28 antibody-induced T-cells. These results indicate that the use of licochalcone A may provide an effective treatment strategy for inflammation-related immune diseases.

Phan Thi Lam Hong, Hyun Jong Kim, Woo Kyung Kim, and Joo Hyun Nam. Korean J Physiol Pharmacol 2021;25:251-8. https://doi.org/10.4196/kjpp.2021.25.3.251

Programmable nucleases, such as zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas, are widely accepted because of their diversity and enormous potential for targeted genomic modifications in eukaryotes and other animals. Moreover, rapid advances in genome editing tools have accelerated the ability to produce various genetically modified animal models for studying human diseases. Given the advances in gene editing tools, these animal models are gradually evolving toward mimicking human diseases through the introduction of human pathogenic mutations in their genome rather than the conventional gene knockout. In the present review, we summarize the current progress in and discuss the prospects for developing mouse models of human diseases and their therapeutic applications based on advances in the study of programmable nucleases.

Post-inflammatory hyperpigmentation (PIH) is a common pigmentary disorder characterized by excessive melanin production following skin inflammation. Histamine, a key inflammatory mediator, is known to stimulate melanogenesis via H₂ receptors; however, the underlying calcium (Ca²⁺) signaling mechanisms remain largely unexplored. In this study, we investigated the role of the ORAI1-STIM1 complex in histamine-induced melanogenesis using B16F10 melanoma cells and normal human epidermal melanocytes (NHEMs). Histamine (10–30 μM) significantly increased melanin content (2.5–2.8-fold), an effect specifically abolished by the H₂ antagonist famotidine. Notably, while acute histamine application failed to trigger immediate Ca²⁺ influx, chronic exposure significantly enhanced store-operated Ca²⁺ entry (SOCE) capacity by approximately 2.8-fold, providing evidence for a functional remodeling of the Ca²⁺ signaling machinery. Histamine-induced melanogenesis was significantly suppressed by intracellular Ca²⁺ chelation, pharmacological inhibition of ORAI1 (BTP-2 or Synta-66), and siRNA-mediated silencing of ORAI1 or STIM1, but not ORAI2, ORAI3, or STIM2. Our findings demonstrate that chronic histamine exposure drives hyperpigmentation through ORAI1-STIM1-mediated SOCE remodeling, establishing this complex as a promising therapeutic target for the treatment of PIH and related inflammatory pigmentary disorders.