Olaparib as Treatment Versus Nonplatinum Chemotherapy in Patients With Platinum-Sensitive Relapsed Ovarian Cancer: Phase III SOLO3 Study Final Overall Survival Results.

Olaparib treatment significantly improved objective response rate (primary end point) and progression-free survival versus nonplatinum chemotherapy in patients with BRCA-mutated platinum-sensitive relapsed ovarian cancer in the open-label phase III SOLO3 trial (ClinicalTrials.gov identifier: NCT02282020). We report final overall survival (OS; prespecified secondary end point), post hoc OS analysis by number of previous chemotherapy lines, and exploratory BRCA reversion mutation analysis.

Extract Exerts Its Therapeutic Effect through CRAC Channel Inhibition for Atopic Dermatitis Treatment.

Atopic dermatitis (AD) is a common allergic inflammatory skin condition marked by severe itching, skin lichenification, and chronic inflammation. AD results from a complex immune response, primarily driven by T lymphocytes and environmental triggers, leading to a disrupted epidermal barrier function. Traditional treatments, such as topical corticosteroids, have limitations due to long-term side effects, highlighting the need for safer alternatives.

Unraveling the Molecular Reason of Opposing Effects of α-Mangostin and Norfluoxetine on TREK-2 at the Same Binding Site.

TWIK-related K channel (TREK)-2, expressed in sensory neurons, is involved in setting membrane potential, and its modulations contributes to the generation of nociceptive signals. Although acute and chronic pain is a common symptom experienced by patients with various conditions, most existing analgesics exhibit low efficacy and are associated with adverse effects. For this reason, finding the novel modulator of TREK-2 is of significance for the development of new analgesics.

Physiological profiling of cannabidiol reveals profound inhibition of sensory neurons.

Cannabidiol (CBD), the main nonpsychoactive cannabinoid of cannabis, holds promise for nonaddictive treatment of pain. Although preclinical studies have been encouraging, well-controlled human trials have been largely unsuccessful. To investigate this dichotomy and better understand the actions of CBD, we used high-content calcium imaging with automated liquid handling and observed broad inhibition of neuronal activation by a host of ionotropic and metabotropic receptors, including transient receptor potential (Trp) and purinergic receptors, as well as mediators of intracellular calcium cycling.

Regulation of T Lymphocyte Functions through Calcium Signaling Modulation by Nootkatone.

Recent advancements in understanding the intricate molecular mechanisms underlying immunological responses have underscored the critical involvement of ion channels in regulating calcium influx, particularly in inflammation. Nootkatone, a natural sesquiterpenoid found in and various citrus species, has gained attention for its diverse pharmacological properties, including anti-inflammatory effects. This study aimed to elucidate the potential of nootkatone in modulating ion channels associated with calcium signaling, particularly CRAC, K1.

Challenges in the Therapeutic Targeting of KCa Channels: From Basic Physiology to Clinical Applications.

Calcium-activated potassium (KCa) channels are ubiquitously expressed throughout the body and are able to regulate membrane potential and intracellular calcium concentrations, thereby playing key roles in cellular physiology and signal transmission. Consequently, it is unsurprising that KCa channels have been implicated in various diseases, making them potential targets for pharmaceutical interventions. Over the past two decades, numerous studies have been conducted to develop KCa channel-targeting drugs, including those for disorders of the central and peripheral nervous, cardiovascular, and urinary systems and for cancer.

Anti-Inflammatory Effects of Alphitolic Acid Isolated from Nakai Extracts Are Mediated via the Inhibition of I Activity in T Cells.

Ledeb., an important medicinal herb in traditional East Asian medicine, is primarily used to treat abdominal pain, dysentery, and hemostasis. There are ten other reported species of plants, including Nakai-a naturally growing species in South Korea-and Linn.

Inhibition of Ca-permeable TRPV3 and inflammatory cytokine release by honokiol and magnolol in human epidermal keratinocytes.

Transient receptor potential vanilloid-3 (TRPV3) ion channels are prominently expressed in keratinocytes, playing a vital role in skin functions. Honokiol and magnolol (H&M) the primary bioactive constituents in Magnolia officinalis extract, demonstrate anti-inflammatory and skin-protective properties. Nevertheless, the underlying mechanism regarding their effect on Ca-permeable ion channels remain unclear.

Alpha-Mangostin: A Potent Inhibitor of TRPV3 and Pro-Inflammatory Cytokine Secretion in Keratinocytes.

The TRPV3 calcium ion channel is vital for maintaining skin health and has been associated with various skin-related disorders. Since TRPV3 is involved in the development of skin inflammation, inhibiting TRPV3 could be a potential treatment strategy. Alpha-mangostin isolated from L.

Multi-target modulation of ion channels underlying the analgesic effects of α-mangostin in dorsal root ganglion neurons.

Background: α-Mangostin is a xanthone isolated from the pericarps of mangosteen fruit with, and has analgesic properties. Although the effects suggest an interaction of α-mangostin with ion channels in the nociceptive neurons, electrophysiological investigation of the underlying mechanism has not been performed.

Hypothesis: We hypothesized that α-Mangostin exerts its analgesic effects by modulating the activity of various ion channels in dorsal root ganglion (DRG) neurons.

The traditional herbal medicines mixture, Banhasasim-tang, relieves the symptoms of irritable bowel syndrome via modulation of TRPA1, NaV1.5 and NaV1.7 channels.

Ethnopharmacological Relevance: The cause of irritable bowel syndrome (IBS), a functional gastrointestinal (GI) disorder, remains unclear. Banhasasim-tang (BHSST), a traditional herbal medicines mixture, mainly used to treat GI-related diseases, may have a potential in IBS treatment. IBS is characterized by abdominal pain as the main clinical symptom, which seriously affects the quality of life.

Overlooked KCNQ4 variants augment the risk of hearing loss.

Pathogenic variants of KCNQ4 cause symmetrical, late-onset, progressive, high-frequency-affected hearing loss, which eventually involves all frequencies with age. To understand the contribution of KCNQ4 variants to hearing loss, we analyzed whole-exome and genome sequencing data from patients with hearing loss and individuals whose hearing phenotypes were unknown. In KCNQ4, we identified seven missense variants and one deletion variant in 9 hearing loss patients and 14 missense variants in the Korean population with an unknown hearing loss phenotype.

Multiple Effects of Echinochrome A on Selected Ion Channels Implicated in Skin Physiology.

Echinochrome A (Ech A), a naphthoquinoid pigment from sea urchins, is known to have anti-inflammatory and analgesic effects that have been suggested to be mediated by antioxidant activity and intracellular signaling modulation. In addition to these mechanisms, the ion channels in keratinocytes, immune cells, and nociceptive neurons may be the target for the pharmacological effects. Here, using the patch clamp technique, we investigated the effects of Ech A on the Ca-permeable TRPV3, TRPV1 and Orai1 channels and the two-pore domain K (K2P) channels (TREK/TRAAK, TASK-1, and TRESK) overexpressed in HEK 293 cells.

Inhibition of ANO1 by - and -Resveratrol and Their Anticancer Activity in Human Prostate Cancer PC-3 Cells.

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.

NADPH Oxidase 1 Mediates Acute Blood Pressure Response to Angiotensin II by Contributing to Calcium Influx in Vascular Smooth Muscle Cells.

Background: Reactive oxygen species (ROS) and calcium ions (Ca) are among the major effectors of Ang II (angiotensin II) in vascular smooth muscle cells. ROS are related to Ca signaling or contraction induced by Ang II, but little is known about their detailed functions. Here, NOX (NADPH oxidase), a major ROS source responsive to Ang II, was investigated regarding its contribution to Ca signaling.

In-vitro and in-vivo anti-allergic effects of magnolol on allergic rhinitis via inhibition of ORAI1 and ANO1 channels.

Ethnopharmacological Relevance: Flos Magnoliae (the dried flower buds of Magnolia biondii Pamp, FM) is a known herbal traditional medicine used for the symptomatic relief of nasal congestion and rhinorrhea caused by rhinitis and sinusitis. Magnolol, a neolignan from the magnolia family, is a secondary metabolite known to have anti-allergic and anti-inflammatory effects. However, the underlying mechanisms and therapeutic effect of magnolol in the treatment of allergic rhinitis (AR) remain elusive.

Anti-Inflammatory Effect of Licochalcone A via Regulation of ORAI1 and K Channels in T-Lymphocytes.

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.

constituent fargesin has an anti-allergic effect ORAI1 channel inhibition.

magnoliae (FM), the dry flower buds of or its related species, is a traditional herbal medicine commonly used in Asia for symptomatic relief of and treating allergic rhinitis, headache, and sinusitis. Although several studies have reported the effects of FM on store-operated calcium entry (SOCE) the ORAI1 channel, which is essential during intracellular calcium signaling cascade generation for T cell activation and mast cell degranulation, the effects of its isolated constituents on SOCE remain unidentified. Therefore, we investigated which of the five major constituents of 30% ethanoic FM (vanillic acid, tiliroside, eudesmin, magnolin, and fargesin) inhibit SOCE and their physiological effects on immune cells.

Inhibitory effects of -Mangostin on T cell cytokine secretion ORAI1 calcium channel and K channels inhibition.

Background: As one of the main components of mangosteen (), a tropical fruit, -mangostin has been reported to have numerous pharmacological benefits such as anti-cancer, anti-inflammatory, and anti-allergic effects through various mechanisms of action. The effects of -mangostin on intracellular signaling proteins is well studied, but the effects of -mangostin on ion channels and its physiological effects in immune cells are unknown. Generation of intracellular calcium signaling is a fundamental step for T cell receptor stimulation.

Ca Sensitivity of Anoctamin 6/TMEM16F Is Regulated by the Putative Ca-Binding Reservoir at the N-Terminal Domain.

Anoctamin 6/TMEM16F (ANO6) is a dual-function protein with Ca-activated ion channel and Ca-activated phospholipid scramblase activities, requiring a high intracellular Ca concentration (e.g., half-maximal effective Ca concentration [EC] of [Ca]i > 10 μM), and strong and sustained depolarization above 0 mV.

Apoptotic effects of alisol B 23‑acetate on gastric cancer cells.

Alisol B 23‑acetate (AB23A) is a natural triterpenoid isolated from , which exhibits a number of pharmacological activities. In the present study, AB23A‑induced anticancer efficacy was examined in AGS gastric cancer cells. Cell viability assay, cell cycle analysis, caspase activity assay, western blotting and reactive oxygen species (ROS) assay were used to investigate the anticancer effects of AB23A on AGS cells.

Nootkatol prevents ultraviolet radiation-induced photoaging ORAI1 and TRPV1 inhibition in melanocytes and keratinocytes.

Skin photoaging occurs due to chronic exposure to solar ultraviolet radiation (UV), the main factor contributing to extrinsic skin aging. Clinical signs of photoaging include the formation of deep, coarse skin wrinkles and hyperpigmentation. Although melanogenesis and skin wrinkling occur in different skin cells and have different underlying mechanisms, their initiation involves intracellular calcium signaling via calcium ion channels.

Allosteric modulation of alternatively spliced Ca-activated Cl channels TMEM16A by PI(4,5)P and CaMKII.

Transmembrane 16A (TMEM16A, anoctamin1), 1 of 10 TMEM16 family proteins, is a Cl channel activated by intracellular Ca and membrane voltage. This channel is also regulated by the membrane phospholipid phosphatidylinositol 4,5-bisphosphate [PI(4,5)P]. We find that two splice variants of TMEM16A show different sensitivity to endogenous PI(4,5)P degradation, where TMEM16A(ac) displays higher channel activity and more current inhibition by PI(4,5)P depletion than TMEM16A(a).

Bicarbonate permeation through anion channels: its role in health and disease.

Many anion channels, frequently referred as Cl channels, are permeable to different anions in addition to Cl. As the second-most abundant anion in the human body, HCO permeation via anion channels has many important physiological roles. In addition to its classical role as an intracellular pH regulator, HCO also controls the activity and stability of dissolved proteins in bodily fluids such as saliva, pancreatic juice, intestinal fluid, and airway surface liquid.