Modulation Of Ion Channels Research Articles

The VRAC blocker DCPIB directly gates the BK channels and increases intracellular Ca2+ in melanoma and pancreatic duct adenocarcinoma cell lines.

The volume regulated anion channel (VRAC) is known to be involved in different aspects of cancer cell behaviour and response to therapies. For this reason, we investigated the effect of DCPIB, a presumably specific blocker of VRAC, in two types of cancer: pancreatic duct adenocarcinoma (PDAC) and melanoma. We used patch-clamp electrophysiology, supported by Ca2+ imaging, gene expression analysis, docking simulation and mutagenesis. We employed two PDAC lines (Panc-1 and MiaPaCa-2), as well as a primary (IGR39) and a metastatic (IGR37) melanoma line. DCPIB markedly increased whole-cell currents in Panc-1, MiaPaca2 and IGR39, but not in IGR37 cells. The currents were mostly mediated by KCa 1.1 channels, commonly known as BK channels. We confirmed DCPIB activation of BK channels also in HEK293 cells transfected with α subunits of this channel. Further experiments showed that in IGR39, and to a smaller degree also in Panc-1 cells, DCPIB induced a rapid Ca2+ influx. This, in turn, indirectly potentiated BK channels and, in IGR39 cells, additionally activated other Ca2+ -dependent channels. However, Ca2+ influx was not required for activation of BK channels by DCPIB, as such activation involved the extracellular part of the protein and we have identified a residue crucial for binding. DCPIB directly targeted BK channels and, also, acutely increased intracellular Ca2+ . Our findings extend the list of DCPIB effects that should be taken into consideration for future development of DCPIB-based modulators of ion channels and other membrane proteins.

Therapeutic potential of viral vectors that express venom peptides for neurological diseases

The venoms of arachnids, cone snails, and snakes consist of many peptides that have varieties of physiological activities, e.g., modulation of ion channels. We have recently prepared lentiviral vectors that express spider venom peptides and successfully observed their expression and secretion by the transduced cells. We expect that this expression method can be applied to neurological diseases. Because most neurological and psychiatric symptoms are caused by the dysregulations of neuronal activities and/or synaptic transmission, a single injection of a viral vector that expresses venom peptides would compensate for the dysregulations and thereby exert a therapeutic effect. Here, we discuss the details of application methods, and how and what venom peptide would exert therapeutic potential for a given disorder, e.g., chronic pain, epilepsy, and Parkinson’s and Huntington’s diseases. We also discuss the potential obstacles, i.e., lack of genetic information, side effects, and immune response, and methods to circumvent them.

P2Y1 purinergic receptor identified as a diabetes target in a small-molecule screen to reverse circadian β-cell failure.

The mammalian circadian clock drives daily oscillations in physiology and behavior through an autoregulatory transcription feedback loop present in central and peripheral cells. Ablation of the core clock within the endocrine pancreas of adult animals impairs the transcription and splicing of genes involved in hormone exocytosis and causes hypoinsulinemic diabetes. Here, we developed a genetically sensitized small-molecule screen to identify druggable proteins and mechanistic pathways involved in circadian β-cell failure. Our approach was to generate β-cells expressing a nanoluciferase reporter within the proinsulin polypeptide to screen 2640 pharmacologically active compounds and identify insulinotropic molecules that bypass the secretory defect in CRISPR-Cas9-targeted clock mutant β-cells. We validated hit compounds in primary mouse islets and identified known modulators of ligand-gated ion channels and G-protein-coupled receptors, including the antihelmintic ivermectin. Single-cell electrophysiology in circadian mutant mouse and human cadaveric islets revealed ivermectin as a glucose-dependent secretagogue. Genetic, genomic, and pharmacological analyses established the P2Y1 receptor as a clock-controlled mediator of the insulinotropic activity of ivermectin. These findings identify the P2Y1 purinergic receptor as a diabetes target based upon a genetically sensitized phenotypic screen.

A Review of Targeted Therapies for Monogenic Epilepsy Syndromes.

Genetic sequencing technologies have led to an increase in the identification and characterization of monogenic epilepsy syndromes. This increase has, in turn, generated strong interest in developing “precision therapies” based on the unique molecular genetics of a given monogenic epilepsy syndrome. These therapies include diets, vitamins, cell-signaling regulators, ion channel modulators, repurposed medications, molecular chaperones, and gene therapies. In this review, we evaluate these therapies from the perspective of their clinical validity and discuss the future of these therapies for individual syndromes.

Activation and peptide modulation of an acid-sensing ion channel involves conformationally decoupled states

Acid-sensing ion channels (ASICs) contribute to fast synaptic transmission and are controlled by protonation of residues in the extracellular domain (ECD) that lead to opening of the cation-selective pore in the transmembrane domain (TMD) of this trimeric channel. By binding to the subunit interface of the ASIC1a ECD, the cysteine knot toxin Psalmotoxin-1 (PcTx1) can potently and selectively inhibit the channel leading to reduce neurotoxicity during ischemic strokes. However, the conformational consequences of this interaction and the number of toxin molecules required for inhibition have remained unknown.

Disease associated CaM variants interact with KCNQ1 to confer aberrant membrane trafficking and function

Calmodulin (CaM) is a ubiquitous auxiliary subunit and a potent modulator of key ion channels underlying the cardiac action potential (AP). Missense variants in calmodulin (CaM) have emerged to underly arrhythmias associated with high mortality rates. As CaM regulates several key cardiac ion channels, mechanistic understanding of CaM variant-associated arrhythmias requires elucidating individual CaM variant's effect on distinct channels. One key CaM regulatory target is the KCNQ1 (KV7.1) voltage-gated potassium channel that underly the repolarizing IKs current.

Bidirectional modulation of ion channels with divalent nanobodies

Ion channels are essential for myriad cellular functions and their regulation is a critical pharmacological strategy for many diseases. However, traditional small-molecule and peptide-based therapeutics that target these channels are often inadequate, as their systemic distribution can lead to modulation of their target protein in off-target tissues. Gene therapy is an alluring alternative, with the potential to restrict transgene expression to a defined tissue. Here, we create a toolset to modulate the ubiquitin status of a target protein with divalent nanobodies (‘Divas’) that recruit the HECT domain of Nedd4L to a protein of interest.

A novel peptide from the venom of Centruroides margaritatus has unique primary structure and inhibits Kv1.2 and Kv1.3 with high affinity

Scorpion venoms are rich in ion channel modulator peptides toxins. Proteomic analysis of soluble venom of the Colombian scorpion Centruroides margaritatus revealed that it contains mainly peptides with molecular weights ranging between 2.5-8 kDa. Among them, a novel short peptide (named Cm28) consists of 27 amino acids with MW of 2820 Da inhibited voltage-gated potassium channels Kv1.2 and Kv1.3 with Kd value of 0.96 and 1.3 nM, respectively. There was no significant shift in the conductance-voltage (G-V) relationship for both channels in the presence of toxin.

Integrating In-silico with In-vitro Studies of Rutin as an Anti Hypertensive

Rutin was evaluated for its antihypertensive effect by In vitro ACE inhibitory activity using Captopril as standard. For molecular docking the proteins namely PDB ID: 1UZE, 1O86, 2XY9 and 3L3N are selected and modelled. The abilities of the 3D model were assessed via the PROCHECK database and considered with the Ramachandran plot. The G-score of rutin was found to be more than the glide score of standard drug captopril affirming that the compound had similar affinity to impasse to the proteins. Proteins with PDB ID 1UZE, 1O86, 2XY9, and 3L3N showed more than 90% favoured area which evidently specifies that the designated protein in the current research is of noble eminence. ADME (Absorption, Distribution, Metabolism and Excretion outcome shown the three violations of rutin out of the five and the Captopril has got zero violations which noticeably shown the possibility for its greater oral bioavailability. The results of bioactive score revealed that rutin and captopril showed moderately active against GPCR ligand, ion channel modulator, kinase inhibitor and nuclear receptor but both rutin and the standard captopril were found to be highly dynamic counter to protease inhibitor and enzyme inhibitor. The PASS results clearly stated that rutin and captopril as cardio protectant, vasoprotector, vasodilator, antihypertensive. Rutin was predicted with hepatoxicity and nephrotoxicity while captopril was predicted with myocardial infarction, hepatotoxicity and nephrotoxicity. The direct targets of rutin have interventions with Cytochrome P4503A, Carbonic anhydrase II, Sodium /glucose cotransporter/2 and TNF-alpha for direct targets. The possible targets were with vascular endothelial growth factor receptor 1, and Sodium /glucose cotransporter/2. In vitro ACE inhibition assay demonstrated that rutin has shown antihypertensive activity by inhibiting angiotensin converting enzyme. From the above results the mechanism of action of rutin was validated through in silico interactions with the suitable PDB’s from MCULE software.

Noninvasive Manipulation of Ion Channels for Neuromodulation and Theranostics

ConspectusFunctional and structural studies of ion channels have deepened our understanding of their mechanisms and important role in regulating neuronal activity and treating disease. Manipulation of ion channels can directly control electrochemical signals in the nervous and cardiovascular systems for advanced neuromodulation and theranostics. Manipulation tools based on ion channel control, such as optogenetics, electrical stimulation, chemogenetics, and gene editing, have advanced basic biomedical research and enabled unprecedented treatment strategies. Nevertheless, conventional approaches are associated with limitations such as invasiveness, irreversibility, or low spatiotemporal resolution, which limit their clinical application. Therefore, targeted noninvasive or minimally invasive modulation of various ion channel activities is highly desirable.In recent years, nanomaterials have enabled noninvasive and precise modulation of ion channels due to their tunable morphology and physicochemical properties. Based on activation modes, current nanomaterial-based methods for ion channel control include light stimulation, thermal regulation, and mechanical manipulation. Nanomaterials can serve as energy transducers to convert macroscopic signals that penetrate deep into tissue, such as near-infrared light or magnetic fields, into local stimuli for ion channel manipulation. For photomodulation, lanthanide-doped nanoparticles convert near-infrared light into visible energy by upconversion, enabling bidirectional control of excitatory and inhibitory opsins in deep tissues. For thermal modulation, photothermal nanoparticles transform absorbed light, such as near-infrared, into heat to activate thermosensitive channels in deep targets. For mechanical manipulation, magnetic nanoparticles convert external magnetic fields into local attractive and torque forces to regulate the functionality of mechanosensitive channels without concern for penetration depth. Moreover, nanomaterial-based strategies can realize targeted and minimally invasive control over the activities of various ion channels even at the single-cell level, maximizing their feasibility and application potential.In this Account, we focus on the manipulation of ion channels using nanomaterials and categorize current approaches into photoconversion optogenetics, thermogenetics, and magnetogenetics. We first introduce the biological principles of various opsins, discuss thermo- and mechanosensitive ion channels and describe their molecular mechanisms in the context of channel structures. We also outline the general principles of emerging nanomaterials in terms of energy conversion capability. We highlight the major advances in nanoprobe-enabled systems and their modern applications in neuromodulation and theranostics. We conclude the Account with a discussion of existing challenges and future prospects.

Role of Ion Channel Modulator in Diabetes Mellitus

Role of Ion Channel Modulator in Diabetes Mellitus

Rapid Drug-Screening Platform Using Field-Effect Transistor-Based Biosensors: A Study of Extracellular Drug Effects on Transmembrane Potentials.

Ion channel-modulating drugs play an important role in treating cardiovascular diseases. Facing the demands for continuous monitoring of drug effectiveness, the conventional techniques have become limited when investigating a long-term cellular physiology. To address the challenge, we propose a drug-screening platform using the stretch-out electrical double layer (EDL)-gated field-effect transistor-based biosensors (BioFETs). In this work, BioFETs were utilized to amplify electrophysiological signals from the mammalian cardiomyocytes (H9c2). The stretch-out configuration avoided a chemical corrosion on FETs and prolonged the lifetime of a BioFET system. A physical model is presented to elucidate the signal response to a drug effect on a cell. Fibronectin and gelatin were coated on sensors and served as the adhesive layers where H9c2 cells attached. BioFETs demonstrated an ability to qualitatively distinguish a depolarization and a polarization of the cytomembranes. The signal responses to the changes of transmembrane potentials were monitored in real-time, and they were highly correlated. The effects of nifedipine and calcium ions on cellular electrophysiology were examined and discussed. Due to the capability of a rapid detection, a prolonged lifetime, and an excellent sensitivity to an electrical change, a stretch-out EDL-gated BioFET can be a drug-screening platform for ion channel modulators.

Virus-Host Interactions of Enteroviruses and Parvovirus B19 in Myocarditis

Viral diseases are a major threat to modern society and the global health system. It is therefore of utter relevance to understand the way viruses affect the host as a basis to find new treatment solutions. The understanding of viral myocarditis (VMC) is incomplete and effective treatment options are lacking. This review will discuss the mechanism, effects, and treatment options of the most frequent myocarditis-causing viruses namely enteroviruses such as Coxsackievirus B3 (CVB3) and Parvovirus B19 (PVB19) on the human heart. Thereby, we focus on: 1. Viral entry: CVB3 use Coxsackievirus-Adenovirus-Receptor (CAR) and Decay Accelerating Factor (DAF) to enter cardiac myocytes while PVB19 use the receptor globoside (Gb4) to enter cardiac endothelial cells. 2. Immune system responses: The innate immune system mediated by activated cardiac toll-like receptors (TLRs) worsen inflammation in CVB3-infected mouse hearts. Different types of cells of the adaptive immune system are recruited to the site of inflammation that have either protective or adverse effects during VMC. 3. Autophagy: CVB3 evades autophagosomal degradation and misuses the autophasomal pathway for viral replication and release. 4. Viral replication sites: CVB3 promotes the formation of double membrane vesicles (DMVs), which it uses as replication sites. PVB19 uses the host cell nucleus as the replication site and uses the host cell DNA replication system. 5. Cell cycle manipulation: CVB3 attenuates the cell cycle at the G1/S phase, which promotes viral transcription and replication. PVB19 exerts cell cycle arrest in the S phase using its viral endonuclease activity. 6. Regulation of apoptosis: Enteroviruses prevent apoptosis during early stages of infection and promote cell death during later stages by using the viral proteases 2A and 3C, and viroporin 2B. PVB19 promotes apoptosis using the non-structural proteins NS1 and the 11 kDa protein. 7. Energy metabolism: Dysregulation of respiratory chain complex expression, activity and ROS production may be altered in CVB3- and PVB19-mediated myocarditis. 8. Ion channel modulation: CVB3-expression was indicated to alter calcium and potassium currents in Xenopus laevis oocytes and rodent cardiomyocytes. The phospholipase 2-like activity of PVB19 may alter several calcium, potassium and sodium channels. By understanding the general pathophysiological mechanisms of well-studied myocarditis-linked viruses, we might be provided with a guideline to handle other less-studied human viruses.

Immunomodulatory Proteins in Tick Saliva From a Structural Perspective.

To feed successfully, ticks must bypass or suppress the host’s defense mechanisms, particularly the immune system. To accomplish this, ticks secrete specialized immunomodulatory proteins into their saliva, just like many other blood-sucking parasites. However, the strategy of ticks is rather unique compared to their counterparts. Ticks’ tendency for gene duplication has led to a diverse arsenal of dozens of closely related proteins from several classes to modulate the immune system’s response. Among these are chemokine-binding proteins, complement pathways inhibitors, ion channels modulators, and numerous poorly characterized proteins whose functions are yet to be uncovered. Studying tick immunomodulatory proteins would not only help to elucidate tick-host relationships but would also provide a rich pool of potential candidates for the development of immunomodulatory intervention drugs and potentially new vaccines. In the present review, we will attempt to summarize novel findings on the salivary immunomodulatory proteins of ticks, focusing on biomolecular targets, structure-activity relationships, and the perspective of their development into therapeutics.

Comparative Investigation of Five Cobras’ Venoms Analgesic Capacity

Every day, a lot of people suffer from different types and intensity pain. Pain is probably the most common symptomatic reason to seek medical consultation. Unfortunately, despite improved knowledge of underlying mechanisms and better treatments, many people who have any type of pain receive inadequate care and non-effective drugs. Although the pain transmission channels are intensively studied, and the drug market is constantly replenished with new analgesics, it is well known that existing medications for the treatment of pain are often associated with serious side effects and rapid development of tolerance (moderate efficiency, physical dependence, respiratory arrest, suffocation, cardiac arrest, etc.). Thus, there is a need for new, more effective remedies. For this reason, despite the presence of a large number of anti-pain drugs, research and development of more effective and safe means for anaesthesia continue. Natural resources, particularly venoms, are a perspective supplier of antinociceptive and anti-inflammatory medicines. Venoms are complex mixtures of bioactive substances with high selectivity for physiological processes, including modulation of different ion channels, receptors function, and metabolic pathways. Thus, venoms represent an extensive source of molecules for the development of therapeutic agents. The goal of this study was the comparison of antinociceptive effects of five different cobras' venom antinociceptive action of cobras’ venoms was carried out under the same experimental conditions, at the same doses, during acute and inflammatory pain in mice in “formalin test”. To avoid toxic effects, the sublethal dose of each cobra venom (approximately 1/10 LD 50 ) was selected. The behavioural study showed that all tested venoms had a slight sensitizing effect in the acute phase during the first 5 min. In the second, inflammatory phase (16*25min), all tested cobra’s venoms (3μg/0.1ml, intraperitoneal) showed significant antinociceptive action, particularly the Naja naja oxiana venom decreased pain sensitivity by 48.4%, the Naja naja pallida venom by 75.4%, the Naja naja nigricincta venom by 38.5%, the Naja naja kaouthia venom by 33.2%, and the Ophiophagus Hannah venom by 78.3%, (p<0.05). The analgesic capacity of Analgin and Diclofenac under the same conditions were 77.9% and 88.7%, respectively. Thus, the Naja n. pallida and Ophiophagus Hannah venoms have shown the most expressed antinociceptive action, and they have competitive effectiveness compared to classic analgesics. They may be chosen as the most effective from tested venoms for further development of pain relief remedies.

Investigations regarding the role of NOS1AP in the heart using a conditional overexpression mouse model

Abstract Background 35.3% of deaths in 2019 in Germany are caused by cardiovascular diseases (Destatis). 95% of these people were 60 years and older. To increase survival rate in elderly patients we investigate the relevance of altered expression of neuronal nitric oxide synthase 1 (NOS1) adaptor protein (NOS1AP) acting as an L-type calcium channel (CaV1.2) modulator via directing NOS1 to CaV1.2 on cardiac electrophysiology. Genome-wide association studies have linked genetic polymorphisms in NOS1AP to variations in QT interval duration (QTc). The QT interval reflects ventricular de- and repolarization. It may predispose individuals to ventricular tachycardia and sudden cardiac death (SCD) if prolonged, shortened or otherwise unregularly. In addition, about 20% of families with a clinically proven diagnosis of long QT syndrome (LQTS) host no mutation in any of the 16 associated genes. Methods and results Transgenic mice with conditional overexpression of NOS1AP in cardiac myocytes were used as model organism. We confirmed the interaction of NOS1AP with NOS1 and CaV1.2. Electrocardiography in NOS1AP overexpressing mice showed atrial and ventricular tachycardia both spontaneously and upon programmed stimulation associated with a significant decrease in QTc. Heart rates in NOS1AP overexpressing mice were similar to non-induced animals. Survival was significantly reduced (only 60% after 12 weeks vs. 100% in non-induced mice). Induced QTc alterations and accompanied deaths subsided upon re-administration of doxycycline. Whole-cell patch-clamp measurements in isolated adult ventricular myocytes were performed and action potential duration at 90% of repolarization (APD90) was significantly reduced in induced transgenic NOS1AP overexpressing mice compared to control littermates. In addition, we investigated the functional effect of the human SNP rs16847548 (T/C) located within the NOS1AP promoter. The SNP was found to decrease the transcriptional activity of NOS1AP in vitro and therefore, potentially leading to a decrease in NOS1AP expression in humans. Conclusion Myocardial overexpression of NOS1AP leads to short QT syndrome with increased susceptibility to atrial and ventricular arrhythmias and cardiac death. In accordance, APD90 is significantly shortened in overexpressing animals. The human SNP rs16847548, which is located in the promoter region of NOS1AP, results in a reduced NOS1AP promoter activity in vitro, hereby providing an explanation for the frequently published elongation of QT intervals. In summary, not only mutations in ion channels themselves but also genetic alterations in the expression of ion channel modulators such as NOS1AP, have an impact on QTc and arrhythmogenesis and represent a promising therapeutic target for LQTS patients. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Gesundheitscampus Brandenburg (MWFK)

In-silico discovery of antidiabetic drug potential of <i>Balanites aegyptiaca</i> leaf’s phenolic compounds

<i>Balanites aegyptiaca</i> leaf is very effective in managing diabetes and rich in phenolic compounds. However, the modes of action of the phytochemicals are mainly unknown. Thus, the present in silico drug discovery study on some phenolic compounds was designed to evaluate potential mechanisms of action of the antihyperglycemic phytochemicals of <i>B. aegyptiaca</i> leaf extract. The study deployed in silico drug-like studying techniques such as; predicted activity spectra of substances (PASS), molecular docking, prediction of adsorption, distribution, metabolism, excretion, and toxicity (ADMET), Lipinski’s rule of 5 (PLOP). The study reveals six compounds with good drug-like properties: cLogp, hydrogen bond donor/acceptor (<5/ < 10), and molar refractivity. In addition, ADMET and drug properties like kinase inhibitors, ion channel modulators, and nuclear receptors were positive for the compounds. Each phenolic compound showed one or more antidiabetic activities like insulin promoter, insulin sensitizer and inhibitors of α-amylase and α-glucosidase. Docking result predicted that the phenolic compounds inhibited either α-amylase or α-glucosidase while one of the compounds; 2-methoxy-4-(1-propenyl)-phenol inhibited both α-amylase and α-glucosidase with binding energies of -4.4 and -4.2 kcal/mol against -3.8 and -4.8 kcal/mol by Acarbose. The study revealed that phenolic compounds from <i>B. aegyptiaca</i> leaf possessed drug-like properties, including the ability to interact with α-amylase and α-glucosidase, a vital target protein in the management of diabetes mellitus. The data from the in silico study is a step toward the pharmaceutical discovery of the antidiabetic drug potential of <i>B. aegyptiaca</i> leaf.

ACUTE RESPIRATORY FAILURE FROM HYPERMAGNESEMIA REQUIRING PROLONGED MECHANICAL VENTILATION

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Magnesium is a major intra-cellular divalent cation. It is essential for multiple metabolic and physiological processes. It plays a crucial role in enzymatic actions, electron transporters, and the synthesis of nucleic acids. CASE PRESENTATION: A 73-year-old Caucasian male patient with a past medical history of Hypertension, Diabetes Mellitus type two, chronic constipation and chronic lower back pain presented to emergency department with 2-day history of diffuse abdominal pain. Acute abdominal series failed to show significant abnormality other than constipation and hence he was given one dose of oral magnesium citrate, one dose of GI cocktail (contains Maalox) and a fleets enema on day one of hospital stay. Overnight patient had a near syncopal episode and worsening of his abdominal pain while having a bowel movement. He was noted to be hypotensive with blood pressure of 84/47 mmhg, heart rate 132 and with a lactic acidosis level of 8.3 mmol/l, hence an abdominopelvic CT was done and showed free air in abdomen (Figures 1 and 2). Patient was taken to emergent laparotomy and underwent pyloric ulcer perforation repair with omental patch.On post-operative day 1 he was noted to have flaccid paralysis including lack of deep tendon and brain stem refluxes. Due to concerns of anoxic brain injury, brain imaging was done with no acute findings. Ionized Calcium, Phosphate levels and Potassium levels were within normal limits. He was noted to have Magnesium level of 9.2 mg/dl. This was thought to be cause of his flaccid paralysis and hence was initiated on Intravenous fluids along with Lasix. In view of oliguric kidney injury, emergent Hemodialysis was initiated. Patient received two hemodialysis sessions with Magnesium levels returning to physiologic levels. Over the next 48-72 hours patient has significant improvement in his hypotension and bradycardia. His mentation and muscle strength and acute kidney injury also improved. He was successfully liberated from the ventilator and subsequently discharged to rehab DISCUSSION: Our patient had acute respiratory failure with failure to extubate due to flaccid paralysis of his respiratory muscles. This was found to be a result of extremely high serum magnesium levels which was unexpected given he received only two doses of magnesium containing agents (magnesium citrate and Maalox) within the last 2 weeks. Hypermagnesemia is most commonly seen in the setting of renal impairment along with concomitant excessive magnesium intake. Neuromuscular and cardiac toxicity are common complications of hypermagnesemia. [2] Our patient had all the features usually described in hypermagnesmia but with only a small intake of Magnesium in setting of acute kidney injury. We hypothesize that the pyloric perforation allowed for increased uptake of magnesium through the inflamed peritoneum CONCLUSIONS: N/A REFERENCE #1: Cascella, Marco, Sarosh Vaqar et al. "Hypermagnesemia." StatPearls, StatPearls Publishing, 2020. REFERENCE #2: Agus, Z. S., M. Morad et al. "Modulation of cardiac ion channels by magnesium." Annual review of physiology 53.1 (1991):299-307. REFERENCE #3: Lee, Jay Wook. "Fluid and electrolyte disturbances in critically ill patients." Electrolytes & Blood Pressure 8.2 (2010):72-81. DISCLOSURES: No relevant relationships by Khalid Sawalha, source=Web Response

A Self‐Powered Piezo‐Bioelectric Device Regulates Tendon Repair‐Associated Signaling Pathways through Modulation of Mechanosensitive Ion Channels (Adv. Mater. 40/2021)

Tendon Repair Piezoelectricity is present in all living beings and provides the basis for mechanisms of tissue regeneration. In article number 2008788, Marc A. Fernandez-Yague, Manus J. Biggs, and co-workers show that tendon cell function can be controlled by electrical stimulation and introduce a new implantable stimulator device powered by body movement paving the way for a new class of regenerative electrical therapies without the use of drugs or external stimulation.

Cardiovascular Drugs and Osteoarthritis: Effects of Targeting Ion Channels

Osteoarthritis (OA) and cardiovascular diseases (CVD) share many similar features, including similar risk factors and molecular mechanisms. A great number of cardiovascular drugs act via different ion channels and change ion balance, thus modulating cell metabolism, osmotic responses, turnover of cartilage extracellular matrix and inflammation. These drugs are consumed by patients with CVD for many years; however, information about their effects on the joint tissues has not been fully clarified. Nevertheless, it is becoming increasingly likely that different cardiovascular drugs may have an impact on articular tissues in OA. Here, we discuss the potential effects of direct and indirect ion channel modulating drugs, including inhibitors of voltage gated calcium and sodium channels, hyperpolarization-activated cyclic nucleotide-gated channels, β-adrenoreceptor inhibitors and angiotensin-aldosterone system affecting drugs. The aim of this review was to summarize the information about activities of cardiovascular drugs on cartilage and subchondral bone and to discuss their possible consequences on the progression of OA, focusing on the modulation of ion channels in chondrocytes and other joint cells, pain control and regulation of inflammation. The implication of cardiovascular drug consumption in aetiopathogenesis of OA should be considered when prescribing ion channel modulators, particularly in long-term therapy protocols.