Lipid raft disruption as an opportunity for peripheral analgesia.

Chronic pain conditions are unmet medical needs, since the available drugs, opioids, non-steroidal anti-inflammatory/analgesic drugs and adjuvant analgesics do not provide satisfactory therapeutic effect in a great proportion of patients. Therefore, there is an urgent need to find novel targets and novel therapeutic approaches that differ from classical pharmacological receptor antagonism. Most ion channels and receptors involved in pain sensation and processing such as Transient Receptor Potential ion channels, opioid receptors, P2X purinoreceptors and neurokinin 1 receptor are located in the lipid raft regions of the plasma membrane. Targeting the membrane lipid composition and structure by sphingolipid or cholesterol depletion might open future perspectives for the therapy of chronic inflammatory, neuropathic or cancer pain, most importantly acting at the periphery.

The Critical Role of The Piezo1/ß-catenin/ATF4 Axis on The Stemness of Gli1+ BMSCs During Simulated Microgravity-Induced Bone Loss.

Disuse osteoporosis is characterized by decreased bone mass caused by abnormal mechanical stimulation of bone. Piezo1 is a major mechanosensitive ion channel in bone homeostasis. However, whether intervening in the action of Piezo1 can rescue disuse osteoporosis remains unresolved. In this study, a commonly-used hindlimb-unloading model is employed to simulate microgravity. By single-cell RNA sequencing, bone marrow-derived mesenchymal stem cells (BMSCs) are the most downregulated cell cluster, and coincidentally, Piezo1 expression is mostly enriched in those cells, and is substantially downregulated by unloading. Importantly, activation of Piezo1 by systemically-introducing yoda1 mimics the effects of mechanical stimulation and thus ameliorates bone loss under simulated microgravity. Mechanistically, Piezo1 activation promotes the proliferation and osteogenic differentiation of Gli1+ BMSCs by activating the ß-catenin and its target gene activating transcription factor 4 (ATF4). Inhibiting ß-catenin expression substantially attenuates the effect of yoda1 on bone loss, possibly due to inhibited proliferation and osteogenic differentiation capability of Gli1+ BMSCs mediated by ATF4. Lastly, Piezo1 activation also slightly alleviates the osteoporosis of OVX and aged mice. In conclusion, impaired function of Piezo1 in BMSCs leads to insufficient bone formation especially caused by abnormal mechanical stimuli, and is thus a potential therapeutic target for osteoporosis.

Targeting Ion Channels for the Treatment of Glioma.

BACKGROUND: Glioma refers to the most aggressive tumor in the central nervous system that starts from support cells or glial cells. The glial cell is the most common cell type in the CNS, and they insulate, surround, as well as feed, oxygen, and nutrition to the neurons. Seizures, headaches, irritability, vision difficulties, and weakness are some of the symptoms. Targeting ion channels is particularly helpful when it comes to glioma treatment because of their substantial activity in glioma genesis through multiple pathways. OBJECTIVE: In this study, we explore how distinct ion channels can be targeted for glioma treatment and summarize the pathogenic ion channels activity in gliomas. RESULTS: Current research found several side effects such as bone marrow suppression, alopecia, insomnia, and cognitive impairments for presently done chemotherapy. The involvement of research on ion channels in the regulation of cellular biology and towards improvements of glioma have expanded recognition of their innovative roles. CONCLUSION: Present review article has expanded knowledge of ion channels as therapeutic targets and detailed cellular mechanisms in the roles of ion channels in gliomas pathogenesis.

The mechanism of ginger and its processed products in the treatment of estradiol valerate coupled with oxytocin-induced dysmenorrhea in mice via regulating the TRP ion channel-mediated ERK1/2/NF-κB signaling pathway.

Ginger (Rhizoma zingiberis, RZ) has been used as a food, spice, supplement, flavoring agent, and as an edible herbal medicine. It is characterized by its pungency and aroma, and is rich in nutrients with remarkable pharmacological effects. It is used in traditional medicine clinics to treat diseases and symptoms, such as colds, headache, and primary dysmenorrhea (PD). In China, a variety of processed products of RZ are used as herbal medicines, such as baked ginger (BG) or ginger charcoal (GC) to treat different diseases and symptoms. However, the molecular mechanism of the therapeutic effect of RZ and its processed products (RZPPs, including BG or GC) against PD has not been well characterized. Moreover, whether the transient receptor potential (TRP) ion channels are involved in this process is not clear. In the present study, UHPLC-Q-TOF MS was adopted to analyse the differential quality markers (DQMs) between RZ and RZPPs. In addition, differential metabolomics (DMs) was acquired between RZ- and RZPPs-treated estradiol valerate coupled with an oxytocin-induced PD mouse uterus using untargeted metabolomics (UM). A correlation analysis between DQMs and DMs was also conducted. Benzenoids, lipids, and lipid-like molecules were the main DQMs between RZ and RZPPs. RZ and RZPPs were found to improve the pathological status of the uterus of a PD mouse, with significantly decreased serum levels of E2, PGF2α, TXB2 and remarkably increased levels of PROG and 6-keto-PGF1α. Moreover, RZ and RZPPs alleviated PD in mice via regulating the TRP ion channel-mediated ERK1/2/NF-κB signaling pathway. Our results indicate that the therapeutic effect of RZ and RZPPs against PD may be mediated by regulating the TRP ion channel-mediated ERK1/2/NF-κB signaling pathway, and provide a reference for the development of new dietary supplements or medicines.

Pathophysiological role of ion channels and transporters in HER2-positive breast cancer.

The incidence of breast cancer (BC) has been increasing each year, and BC is now the most common malignant tumor in women. Among the numerous BC subtypes, HER2-positive BC can be treated with a variety of strategies based on targeting HER2. Although there has been great progress in the treatment of HER2-positive BC, recurrence, metastasis and drug resistance remain considerable challenges. The dysfunction of ion channels and transporters can affect the development and progression of HER2-positive BC, so these entities are expected to be new therapeutic targets. This review summarizes various ion channels and transporters associated with HER2-positive BC and suggests potential targets for the development of new and effective therapies.

Ion channel-targeting near-infrared photothermal switch with synergistic effect for specific cancer therapy.

Despite significant achievement in chemotherapy, the off-target actions and low pharmaceutical selectivity of the therapeutic agents still limit their clinical efficacy. Herein, a multifunctional nanoplatform which integrates chemotherapy, chemodynamic therapy (CDT) and photoactivation of TRPV1 channels has been successfully established for specific cancer therapy. Polydopamine (PDA) coated hollow prussian blue nanocages (hPBNCs) are used as the photothermal switches and drug carriers for loading chemotherapeutic drug, doxorubicin (Dox). Conjugating with the TRPV1 antibodies enables the nanoplatform to bind specifically to TRPV1 channels on the plasma membrane of the TRPV1-positive cancer cells and then activate them by local heating upon NIR irradiation, leading to the over-influx of Ca2+. Critically, the laser irradiation can be carefully controlled to not only open the TRPV1 channels but also avoid burning of tumors by hyperthermia. Moreover, the exposed hPBNCs in the acidic tumor cells can decompose endogenous H2O2 into ˙OH by Fenton reaction to realize CDT, which further aggravates cancer cell apoptosis. Together with the chemotherapy caused by Dox, our nanoplatform displays an enhanced anticancer effect both in vitro and in vivo. Our work provides a powerful means for site-specific cancer synergetic therapy with high spatial and temporal resolution.

A novel strategy for cancer therapy by mutated mammalian degenerin gene transfer.

Mammalian degenerin (MDEG) is a member of the amiloride-sensitive sodium ion channel family, and its site-directed active mutant (MDEG-G430F) induces massive Na+ influx into cells, leading to cell ballooning and cell bursting. We attempted a novel therapeutic approach for gastric cancers by transferring MDEG-G430F into cancer cells using tumor-specific promoters. In carcinoembryonic antigen (CEA)-producing gastric cancer cells, the level of cell death observed when MDEG-G430F was used with a CEA promoter was similar to that observed when using a potent nonspecific promoter such as the cytomegalovirus promoter. In an in vivo study, fusogenic liposome complexes containing MDEG-G430F driven by the CEA promoter were injected intraperitoneally into CEA-producing gastric cancer cells in a mouse peritoneal dissemination model. Although all 15 of the control mice were dead by 50 days postinoculation, 13 of the 15 mice treated with MDEG-G430F survived. These results indicate that transferring MDEG-G430F into cancer tissues using tumor-specific promoters can achieve striking and selective cancer cell death irrespective of the transcriptional efficiency of the promoters used in vivo, and suggest that this approach is a promising new strategy for cancer gene therapy.