It is known that magnesium is the cofactor of 600 and the activator of another 200 enzymatic reactions in the human organism. Hypomagnesemia can be linked to many factors, causing disturbances in energy metabolism, ion channel exchanges, action potential alteration and myocardial cell instability, all mostly leading to ventricular arrhythmia. This review article focuses on identifying evidence-based implications of Mg2+ in cardiac arrhythmias. The main identified benefits of magnesemia correction are linked to controlling ventricular response in atrial fibrillation, decreasing the recurrence of ventricular ectopies and stopping episodes of the particular form of ventricular arrhythmia called torsade de pointes. Magnesium has also been described to have beneficial effects on the incidence of polymorphic ventricular tachycardia and supraventricular tachycardia. The implication of hypomagnesemia in the genesis of atrial fibrillation is well established; however, even if magnesium supplementation for rhythm control, cardioversion facility or cardioversion success/recurrence of AF after cardiac surgery and rate control during AF showed some benefit, it remains controversial. Although small randomised clinical trials showed a reduction in mortality when magnesium was administered to patients with acute myocardial infarction, the large randomised clinical trials failed to show any benefit of the administration of intravenous magnesium over placebo.The importance of magnesium (Mg It is the second intracellular and the fourth extracellular electrolyte in concentration in humans. The adult human organism contains approximately 25 g of magnesium [2+ is stored in the bone system, about 38–40% intracellular in the soft tissue and between 0.3 to 2% can be found in the blood serum [2+) < 0.65 mmol/L, is determined by measuring the total serum concentration by different methods and is often symptomatic [2+ to keep serum concentration within normal limits due to and at the cost of intracellular depletion [2+, which specifically plays an essential role in both the heart and the whole body. However, there is a method that indirectly assesses the intracellular concentration of magnesium based on a reduction in excretion below 80% within 24 h after a loading dose [Magnesium is a micronutrient, an alkaline earth metal occurring as a free cation , asymptomatic hypomagnesemia (1.22–1.82 mg/dL), chronic latent deficiency (1.82–2.06 mg/dL), normal range (2.06–2.33 mg/dL), asymptomatic hypermagnesemia 2.33–4.86 mg/dL) and symptomatic hypermagnesemia (>4.86 mg/dL). This classification introduces two new subclasses (asymptomatic hypomagnesemia and chronic latent deficiency). The new subclasses increase the accuracy of establishing magnesium status and correcting hypomagnesemia from early stages as it is known to date that chronic latent magnesium deficiency increases susceptibility to disease .86 mg/dL.2+ in cellular energy metabolism and other processes influencing the electrophysiological system of the heart. Identifying the implication of magnesium in mechanisms of arrhythmias and the potential causes of hypomagnesaemia, in light of the significant data identified so far, is the key to further management.This review summarises the implications of magnesium in the cardiovascular processes focusing on its impact on the genesis and maintenance of supraventricular and ventricular cardiac arrhythmias. This paper’s main objective is to clarify the aspects related to the involvement of MgHypomagnesaemia can be a consequence of insufficient intake, redistribution from the extracellular to intracellular space and increased loss through the renal or gastrointestinal system ,9.2+, whose scarcity can lead to multiple implications, including a decline in physical performance and cardiovascular health issues represented mainly by hypertension and arrhythmias [2+ from the extracellular to the intracellular compartment can occur after surgical treatment of hyperparathyroidism (hungry bone syndrome) during the treatment of diabetic ketoacidosis, in refeeding syndrome, and during sympathetic stimulation , in acute pancreatitis or other critical illnesses or postoperative states.Reduced magnesium intake can result from insufficient dietary consumption, alcohol dependence or parenteral nutrition that uses products with a poor magnesium content. Malnutrition, especially age-related, is most often associated with deficiency of macro-elements such as Mghythmias ,11. RediMagnesium renal loss due to tubulopathies is associated with hereditary conditions such as Gitelman syndrome, familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), Bartter syndrome, hypomagnesemia with secondary hypocalcemia (HSH), isolated recessive hypomagnesemia (IRH) with normocalcemia, isolated dominant hypomagnesemia (IDH) with hypocalciuria, and autosomal-dominant hypocalcemia with hypercalciuria (ADHH) . AcquireGastrointestinal losses can occur with vomiting, diarrhea, fistulas and nasogastric suction. Chronic malabsorption syndromes usually involve the small intestine and chronic use of protein pump inhibitors reduce the gastrointestinal absorption of magnesium , resulti2+ can be obtained from lymphocytes and erythrocytes that have been correlated to intramyocardial muscle magnesium levels. Samples from buccal tissues can also be used to measure magnesium levels, though only available in the USA; however, such testing is reserved for research [It is worth mentioning that intracellular magnesium depletion can be associated with normal plasma values . Yet, moresearch ,17.2+ can promote increased vulnerability to oxygen-derived free radicals, altering the endothelial function and contributing to the genesis of atherosclerotic plaque formation [2+ supplementation decreases the myocardial infarct size when administered early, before reperfusion therapy, which is rather due to a direct cellular effect than to the regional myocardial blood reflow [The clinical implications of hypomagnesemia in the appropriate functioning of the cardiovascular system have been demonstrated over time. At the level of the vessels, the deficit of Mgormation . An animd reflow . Althougd reflow ,21,22. T2+ is associated with increased vascular tone aggravating arterial hypertension [Besides ion disturbance and a large variety of arrhythmias, low Mgrtension , and appMagnesium strongly affects the myocyte’s homeostasis and maintains a normal action potential. Its use as an adjunctive therapy has demonstrated its importance in electrolyte balance in clinical practice. Recent data confirm a degree of interdependence between hypomagnesemia and cardiac arrhythmias.Changes in the surface electrocardiograms (ECG) associated with hypomagnesemia have been described over time, dependent and varying according to magnesium levels: ST segment depression, peaked and tall or flattened T waves, shortening of the PR interval and QTc, lowering of the QRS voltage, increasing in the QRS duration and the presence of U waves. In a study by Yang et al., isolated hypomagnesemia was found to be associated with increased dispersion of ventricular repolarization evaluated by Tpe /QT ratio , QT-peak interval standard measurement from the beginning of the QRS complex to the peak of the T-wave (QTp)) .Cardiac arrhythmias have various causes and can be associated with a macroscopic structurally normal heart. Frequent examples of these types of causes are inherited conditions, as in the case of the accessory pathway-mediated tachycardias or the normal variant of nodal conduction duality characterized by the presence of a fast and a slow pathway with modified electrophysiologic properties predisposing to atrioventricular nodal reentrant tachycardia. The rest of the known arrhythmias are associated mostly with changes in the heart’s structure found in many pathological conditions and are represented mainly by atrial fibrillation, premature atrial contractions, premature ventricular contractions, ventricular tachycardia and ventricular fibrillation.Hypomagnesemia has many causes and seems to be linked to disturbances in energy metabolism, ion channel exchanges, action potential alteration and myocardial cell electrical instability, all leading to different types of arrhythmia.The implication of hypomagnesemia in the genesis or potentiation of cardiac arrhythmias has several mechanisms . The fir2+ dependent K+ currents playing an essential role against the excessive prolongation of myocardial action potential and having a protecting role against arrhythmia [2+ regulated and increases intracellular sodium and reduces intracellular potassium levels, creating a less negative resting membrane potential. Magnesium deficiency can also lead to hypokalaemia and hypocalcemia, making the role of establishing the link between pure hypomagnesemia and cardiac arrhythmias somehow difficult. There is a strong relationship between Mg2+ and K+; both cations are integral for decreasing cell excitability and stabilizing membrane potentials. Half of the significant hypokalemias seem to be associated with magnesium deficiency; the co-administration of magnesium thus is essential in correcting serum potassium (K+) concentrations [2+ alone also increased the serum K+ level [Another aspect of arrhythmogenesis refers to different types of Mgrhythmia . The mectrations . EnhanceK+ level ,28.2+ repletion is linked to the effect on the ROMK. This inward-rectifying K+ current helps flow the potassium ion inside the cells of the apical membrane of the distal tubule. Intracellular magnesium binding to the channel’s pore causes a temporary block for efflux of K+. On the other hand, the influx of K+ displaces the channel-bent magnesium ion and the maximal needed quantity of K+ enters the cell. As a result, the arrhythmia precipitated by K depletion requires both K+ and Mg2+ repletion for termination [The cellular mechanism behind the reduction of K+ excretion induced by Mgmination .Other hypomagnesemia-dependent effects are the induction of hypokalemia and hypocalcemia and the loss of the direct effect of the normal concentration of magnesium on preventing calcium overload in the myocardial cell. Hypomagnesemia also induces the elaboration of platelet activated factor (PAF), which raises the production of pro-inflammatory cytokines, thrombin and vasoactive mediators, creating and maintaining the inflammation of cardiac tissue that predisposes to arrhythmias .2+ dependent energy metabolism have been described. Mitochondrial Mg2+ regulates reactions in mitochondrial energy metabolism, tricarboxylic acid (TCA) cycle, adenosine diphosphate (ADP)/adenosine triphosphate (ATP) translocation and the electron transport chain [A series of relationships implicating Mgrt chain .2+) and its various effects on vascular tone, peripheral vascular resistance, myocardial metabolism and Ca2+ homeostasis. Magnesium ions affect the myocyte’s ‘electrical properties by influencing the ion channels’ activity implicated in generating the cell’s action potential, particularly in phases 2 and 3. In phase 2, intracellular Ca2+ overload and therefore cell toxicity are prevented by (Mg2+)-dependent inhibition of the L-type Ca2+ channel. In phase 3, high (Mg2+) concentration seems to block the slow activating component of the rectifier K+ current and the inward rectifier K+ channel. Magnesium ion is a cofactor of the Na+/K+ ATPase pump, which is active in phase 4 of the action potential and necessary for resuming an appropriate resting membrane potential. Magnesium depletion can reduce the activity of the pump, resulting in partial depolarization [2+) plays a role in myocardial excitation-contraction coupling by influencing the intracellular Ca2+ movement [2+ has a role in vasodilation [Cardiac function is heavily influenced by , showed that hypomagnesemia was associated with higher mortality . On the ortality . One recortality ,41. In aortality ,43. ArrhAtrial fibrillation is the most frequent arrhythmia in adults, with a high lifetime risk of 1:3 in persons of European ancestry with an index age of 55 . PostopeAdjunctive therapy with magnesium showed to be helpful in further reducing the incidence of atrial fibrillation in patients with a magnesium deficit.Concerning the relationship between hypomagnesaemia and the development of atrial fibrillation in patients with no baseline cardiovascular disease, a large sample size and long follow-up study (20 years) showed that subjects with lower serum magnesium (≤1.77 mg/dL) had an approximately 50% increased risk of atrial fibrillation compared to those with magnesium levels in the upper limit. However, it should be mentioned that only the baseline serum magnesium was obtained . In patiIn a large study, mild and moderate hypomagnesemia was associated with a significantly increased incidence of atrial fibrillation over a 20-year follow-up .2+ was evaluated at 20 to 40% in several studies. It can also be attributed to the difference in the burden of comorbidities in each study population [Some studies suggest a correlation between a low preoperative intracellular magnesium concentration and an increased risk of developing postoperative atrial fibrillation (AF) in patients undergoing cardiac surgery . Hypomagpulation .A meta-analysis of 35 studies investigated the effect of parenteral magnesium administration as a treatment or prophylaxis for arrhythmias in patients with cardiovascular surgery. The most frequent arrhythmia was atrial fibrillation, followed by ventricular arrhythmic events. Magnesium reduced atrial fibrillation episodes in the absence of significant adverse events; however, it failed to prove its benefit in other arrhythmias .2+ following the effects in a variety of situations, such as the treatment of acute AF vs. placebo, new-onset of AF in the emergency department, prevention of AF during cardiac surgery, before AF cardioversion with a no-treatment control group and pre-electrical cardioversion of AF; however, all the analyses had disappointing results. Other data showed a reduction in the ventricular rate during atrial fibrillation after magnesium administration [Several significant meta-analyses and trials used the randomization of patients to Mgstration ,61,62,632+ associated with increased sympathetic activity, enhanced Mg2+ urinary excretion caused by secondary aldosteronism, and the use of loop diuretics [A study by Khan et al. on more than 3500 participants evaluated the implications of hypomagnesemia on the incidence of atrial fibrillation in a longitudinal community-based cohort, showing a moderate association in patients without cardiovascular disease . Moreoveiuretics .The importance of preventing atrial fibrillation lies mainly in the unfavourable long-term prognosis of this arrhythmia, especially when it becomes permanent and accompanied by comorbidities. Even if 50–87% of the patients with atrial fibrillation are initially asymptomatic, they may develop various symptoms and a less favourable prognosis over time ,68,69,70The number of premature atrial and ventricular contractions increases with age, with a prevalence of 50% in the general population . A low mOne of the first systematic evaluations, a study by Lorenzo et al., showed differences in the myocardial electrical properties evaluated by the invasive electrophysiological study before and after the administration of 6 g, 4% intravenous magnesium in a small cohort of 10 patients. The results included several modifications after magnesium sulphate administration: a decrease in the sinus node function, the prolongation of the atrioventricular (AV) conduction time, a Wenkebach block in the AV node occurring at a larger S1S1 atrial stimulation interval, the increase of the refractory periods of the AV node, and the prolongation of the PR interval on surface ECG. The data provided by this study is important because it indirectly reflects the importance of magnesium in preventing arrhythmias involving the two structures mentioned, the sinoatrial node and the AV node . Another double-blind, randomised, placebo-controlled dose-response study regarding changes in the atrioventricular node electrophysiological properties was provided by Christiansen et al., and showed that a maximal atrioventricular conduction time was obtained by the infusion of 5 mmol magnesium, which was not extended by additional dose escalation .Stiles et al. observed that magnesium supplementation inhibited the conduction primarily over the slow pathway in patients with a dual morphology atrioventricular node, increasing the tachycardia cycle length during atrioventricular nodal reentrant tachycardia . The atrPremature ventricular and atrial contractions have an increased incidence with age, reaching up to 50% prevalence in the general population.Low serum magnesium was linked to a greater incidence of PVCs and a higher risk of ventricular tachycardia and torsades de pointes in obese patients with diabetes and after surgery ,79.An RCT showed that oral magnesium supplementation improved the symptoms and the frequency of premature ventricular and supraventricular contractions in patients without underlying ischemic or structural heart disease .2+ deficiency and ventricular arrhythmia in subjects with structurally normal hearts. A case report published in 2005 presented the situation of a 12-year-old patient with premature ventricular contractions and sustained ventricular tachycardia. While the cardiac evaluation for arrhythmia was normal, the Mg2+ serum level was low. Oral supplementation with magnesium effectively suppressed both PVCs and the episodes of ventricular tachycardia, documented over a follow-up of 5 years [While the role of hypomagnesaemia frequently associated with hypokalaemia has been documented in patients with ventricular tachycardia and an underlying cardiac condition , there i 5 years .Low serum magnesium seems to be a strong predictor of cardiac mortality in patients with atherosclerosis risk or treated with drug-eluting stents for acute myocardial infarction ,84.2+ loss in this specific population; the complex interplay between heart failure and hypomagnesemia was considered to be the cause of ventricular arrhythmic events improved after the infusion of magnesium sulphate [2+ regulates the passing of Na+, K+, and Ca2+ through the voltage-dependent ion channels, generating the action potential as previously described. Hypomagnesemia-induced disturbance of the ion circulation is a cause of repolarization disturbance with QT dispersion and prolongation, the primary substrate of the triggered ventricular arrhythmia known as “torsade de pointes” [ESC Guideline of Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death indicates that hypomagnesemia is associated with ventricular arrhythmias and sudden death; the intravenous administration of magnesium sulphate has been demonstrated to help suppress ventricular arrhythmia even in the presence of a normal magnesemia [Research data shows an exacerbation of ventricular arrhythmia in patients with heart failure NYHA II-IV associated with hypomagnesemia and a benefit from magnesium supplementation, decreasing the number of premature ventricular contractions isolated or organised into couplets and non-sustained ventricular tachycardias . The stusulphate . Mg2+ repointes” ,86. Frompointes” . The 201gnesemia .2+ in the genesis of cardiac arrhythmias is quite limited, with a small number of prospective studies, a significant amount of contradictory data and a failure to highlight its benefit in certain situations. Future directions of research are needed to fill the gaps in the evidence. More extensive randomised, blinded approach studies are required to shed light on the importance of Mg2+ in the genesis of arrhythmias and the role this ion might play in preventing life-threatening arrhythmias in patients with and without cardiovascular diseases in the presence of different acute or chronic comorbidities.The current knowledge regarding the implications of Mg2+ reduces the early after depolarization by influencing the T and L-type calcium channels. This process inhibits the calcium intracellular influx associated with delayed after-depolarizations. Another antiarrhythmic effect of Mg2+ is exerted by promoting potassium intracellular influx, thus correcting the dispersion of ventricular repolarization without shortening the action potential duration. Magnesium sulphate administration decreases the reinitiation of torsade de pointes or other ventricular tachycardia rather than converting the ventricular arrhythmia; however, no randomised controlled studies are yet available for evaluating the benefit of giving magnesium in torsade. Potassium is an important adjunctive therapy together with magnesium sulphate in patients with ventricular dysrhythmias [Kr (delayed rectifier K+ channel) [The American Heart Association’s recommendations indicate adding magnesium sulphate to the therapeutic regimen used in the management of refractory ventricular fibrillation and torsade de pointes . The 202hythmias . Optimalchannel) ,92. Howechannel) .Several studies evaluated the benefits of magnesium supplementation for ventricular tachycardia associated with digoxin therapy. Digoxin inhibits Na+/K+-ATPase, which increases the intracellular concentration of Na+ and Ca2+. Magnesium is an essential cofactor for Na+/K+-ATPase; hence, magnesium deficiency can cause a further increase in intracellular sodium while decreasing intracellular potassium .Hypomagnesemia was found to be responsible for an increased risk of digoxin toxicity, which can trigger malignant ventricular arrhythmia in patients with normal digoxin and K+ levels ,96.Liu et al. described the acquired long QT syndrome  associated with an increased risk for ventricular arrhythmia, linked to lowering of the potassium, magnesium and calcium, chlorine and natrium levels in patients with chronic kidney disease . HoweverThe population at risk for ventricular arrhythmia with mild hypomagnesemia includes patients with myocardial ischemia, myocardial infarction, heart failure, post cardiopulmonary bypass and acute illness .In cases of refractory ventricular arrhythmia/torsade de pointes associated with acquired long QT syndrome that are unresponsive to intravenous magnesium and the correction of precipitating factors, the control of the arrhythmia may be obtained with isoproterenol or temporary transvenous pacing .Oral or enteral magnesium is the preferred route of administration in outpatient care, and is used for asymptomatic hypomagnesemia and gastrointestinal tolerance. In contrast, intravenous magnesium repletion is the preferred route of administration in symptomatic hypomagnesemia and/or gastrointestinal intolerance and inpatient care .2+ rises quickly after treatment, intracellular Mg2+ takes much longer to normalize. It has been shown that in patients with normal renal function, magnesium repletion should be continued for two days after magnesemia normalizes [Magnesium supplementation in patients with hypomagnesemia takes three factors into account: kidney function, the presence or absence of hemodynamic stability, and the severity of symptoms. In the case of hemodynamically unstable patients, 1 to 2 g of magnesium sulfate can be infused over 15 min. In symptomatic stable patients with severe hypomagnesemia, 1 to 2 g of magnesium sulfate will be administered over one hour. Magnesium dosage for the adult patient is usually 4 to 8 g of magnesium sulfate, slowly infused over 12 to 24 h. In children, the agreed dose is 25 to 50 mg/kg over 60 s. The dose is recommended to be repeated every 5–15 min up to a maximum of 2 g . After mrmalizes . The mos2+ in this specific population. The cardiovascular effects of hypermagnesemia derive partially from the property of magnesium to behave as a calcium blocker and also to cause the potassium channel block associated with repolarization disturbances responsible for bradycardia, hypotension, prolonged PR interval, QRS and QT interval duration, complete heart block, and worsening of heart failure [To monitor the serum level of magnesium, several strategies have been proposed over time, both to ensure the effectiveness of supplementation and to prevent hypermagnesemia that could increase the risk of adverse cardiovascular events as well as all-cause mortality in patients with critical pathologies admitted to intensive care units ,102,103. failure . The tre failure .2+ concentrations, the blood samples should be accurately prepared to avoid hemolysis since the magnesium stored in the erythrocytes exceeds serum magnesium [2+ status, but it has limitations in patients with kidney and intestinal diseases [To date, monitoring magnesemia may be challenging, especially since there are no available standardized protocols for serum magnesium measurement in different patient populations or the general population. There are no evidence-based reference range values to date, but rather only a consensus-based cut-off value for defining hypomagnesemia, established at 0.85 mmol/L (2.07 mg/dL or 1.7 mEq/L) . For seragnesium . Anticoaagnesium . In patidiseases ,108.80. Future studies are needed to clarify the doses required to adjust the recommended daily dose of magnesium proportionally with increased body weight.The frequency of the determination of serum magnesium still remains at the discretion of the personnel involved in the care of hospitalised patients or subjects monitored in outpatient settings. An important aspect of potential future research is the impact of the increase in body weight on the magnesium necessary Magnesium is involved in multiple metabolic, enzymatic, and electrophysiological reactions and mechanisms which are indispensable or have additional benefits on the electrical stability of the ventricular myocardium. Although some studies reveal the association of hypomagnesemia with supraventricular and ventricular arrhythmias, this remains controversial and requires further research. However, the importance of intravenous magnesium sulphate administration has been shown to be beneficial in reversing “torsade de pointes”, decreasing the incidence of polymorphic ventricular tachycardias (other than the “torsade”) associated with structural heart disease and decreasing the incidence and the ventricular response during atrial fibrillation. The benefit of magnesium for the reduction of cardiac arrhythmias seems to rely on several mechanisms: the regulation of intracellular ionic pumps for K+, Na+ and Ca2+, the reduction of early delayed after-depolarization triggering life-threatening ventricular arrhythmias, the decreasing of PAF- related inflammatory cardiac response linked to arrhythmias, the prevention of shortening of the action potential duration, the increasing of the atrioventricular node conduction time and the atrial and ventricular refractoriness. Magnesium supplementation in cardiac arrhythmias constitutes an interesting and stringent direction to investigate in order to translate knowledge into standardized and effective practical clinical directions.


Stem cell differentiation is of great interest in medical research; however, specifically and effectively regulating stem cell differentiation is still a challenge. In addition to chemical factors, physical signals are an important component of the stem cell ecotone. The mechanical microenvironment of stem cells has a huge role in stem cell differentiation. Herein, we describe the knowledge accumulated to date on the mechanical environment in which stem cells exist, which consists of various factors, including the extracellular matrix and topology, substrate stiffness, shear stress, hydrostatic pressure, tension, and microgravity. We then detail the currently known signalling pathways that stem cells use to perceive the mechanical environment, including those involving nuclear factor-kB, the nicotinic acetylcholine receptor, the piezoelectric mechanosensitive ion channel, and hypoxia-inducible factor 1α. Using this information in clinical settings to treat diseases is the goal of this research, and we describe the progress that has been made. In this review, we examined the effects of mechanical factors in the stem cell growth microenvironment on stem cell differentiation, how mechanical signals are transmitted to and function within the cell, and the influence of mechanical factors on the use of stem cells in clinical applications. Stem cells have unquestionable importance in medicine and are receiving increasing attention due to their role in several diseases , 2. StemThe microenvironment in which stem cells grow contains not only a variety of biochemical molecules, but also a variety of mechanical factors . The mecThe cytoskeleton plays an indispensable role in the cell’s perception of the mechanical environment. Actin senses the stiffness of the environment and controls the persistence of the platelet foot through a specific cluster of actin/proto-myosin filaments, which in turn assembles a focal adhesion . The focThis review aims to summarize the impact of mechanical factors in the stem cell growth microenvironment on stem cell differentiation, describe how stem cells sense and respond to mechanical signals to function, and further explore the clinical implications of the influence of mechanical factors on stem cells.The stem cell microenvironment refers to all the environmental factors surrounding stem cells in tissues as they proliferate, self-renew, and differentiate into tissue cells at their residency sites, including soluble biomolecules, solid ECM with supporting cells, and the mechanical and physicochemical environment surrounding the stem cells. The mechanical microenvironment is an integral part of the stem cell microenvironment and includes the mechanical support of the ECM, the forces exerted on the cell by the environment, and the forces caused by the interaction of the cell with the surrounding support cells . In vivoECM is a three-dimensional network of various extracellular macromolecules, such as collagen, elastin, fibronectin, and laminin proteins, which provide a good environment for cells to survive. Cells cultured in vitro secrete ECM and the cell-derived ECM (dECM) produced after cell removal has great application in cell culture. For example, culturing bone marrow mesenchymal stem cell (MSC) (BMSC) with different combinations of distinct cell types of dECM showed that dECM enhanced the osteogenic and angiogenic potential of BMSC compared to tissue culture polystyrene; the different behaviour of the BMSC is related to the different proportions of cells that make up the dECM . In addiThe topology of the substrate is a physical characteristic of the microenvironment in which the cells are anchored and affects stem cell differentiation in many ways. Nanoscale materials have been widely used to model ECM and their topology has a significant impact on the fate of stem cells , 29. ForUnder physiological conditions, cells in vivo are anchored to tissue substrates of varying stiffness, and their specific stiffness influences the cells that grow on them. Substrate stiffness has a role in a wide range of stem cell differentiation profiles . Cells pAll types of tissue cells in the normal human body are continuously exposed to shear stresses caused by fluid flow in the tissue interstices under load. Shear force treatment of hESC simulated by the Microfluidic Dynamic Culture System promotes the expression of blood progenitors in the hESC lineage, reducing the proportion of mono-competent erythroid and megakaryocyte lineages and increasing the number of bone marrow and bipotent megakaryocyte–erythroid progenitors. Shear force treatment also promoted smooth muscle and cardiomyocyte production, suggesting a role for shear stress in both the haematopoietic spectrum and the arterial vascular system . Human p2 concentration to improve osteogenic differentiation. This bioreactor is used to precisely control the fate of stem cells in terms of osteogenesis and has potential applications in the healthcare industry, for example in the prevention of osteoporosis [Perfusion flow-induced shear stress in a fully automated bioreactor enhances osteogenic differentiation in hBMSC and modulates Ooporosis . Howeveroporosis . Intermioporosis . The ratoporosis . The effHowever, a single application of shear stress is not sufficient. In practice, a combination of other culture conditions should be considered to improve the efficiency of targeted differentiation. Shear stress combined with polymeric biomaterials can enhance the osteogenic differentiation of MSCs . This coHydrostatic pressure (HP) is a mechanical force that is widely present in the environment in which cells live. Using autologous platelet-rich fibrin (PRF) membranes as a growth factor-rich scaffold and culturing BMSCs pre-conditioned with HP prior to transplantation greatly enhanced the chondrogenic potential of the BMSC/PRF constructs. Further studies showed that the pressurized pretreated BMSC/PRF graft group showed a significant improvement in the integration of the regenerated cartilage with the host cartilage environment . HP is tHP combined with the stromal microenvironment can induce directed differentiation of stem cells. Intermittent HP (IHP) and 3D microenvironments modified with ECM proteins, especially collagen, have a synergistic effect on the expression of chondrogenic genes by MSCs . HP and Tension is the force exerted on an object by means of pulling in a certain direction, such as the pulling force produced on the cells in the body by the tissues. For example, muscle contraction is a movement produced by the cells being subjected to traction. Multiple studies confirm that cyclic mechanical tension can promote osteogenic differentiation of human periodontal stem cells –63. FurtIn addition, the frequency and amplitude as well as the duration of stretching led to the differentiation of cells in different directions . For exaA microgravity environment is one in which the apparent weight of a system is much less than its actual weight in the presence of gravity. Microgravity is not common in daily life, but it has a major impact on astronauts conducting space operations. Microgravity can up- or downregulate differentiation-related genes , 71, whiMany studies have demonstrated that microgravity inhibits the osteogenic differentiation of hBMSCs while promoting adipogenesis and chondrogenic differentiation , 76. HowMicrogravity has a positive effect in some ways. Mouse embryonic stem cell (mESC) cultured in a rotating bioreactor under simulated microgravity conditions can differentiate towards stereotyped endoderm, and these cells can further differentiate into cells from other related organs such as the pancreas, liver, and thyroid . SimulatAs described in the previous section, mechanical stimuli, or the mechanical properties of the pericellular matrix material, play an important role in regulating the morphological development and function of stem cells. However, the exact mechanisms of how mechanical signals are sensed by and transmitted to and within stem cells, ultimately leading to a range of biological effects in stem cells, need to be further explored. There are two main mechanisms regarding the cellular perception of mechanical signals: transmission and transduction mechanisms. Signal transmission mechanisms occur when changes in the microenvironment are transmitted via sensors into the cell to cause rearrangement of the cytoskeleton, which in turn transmits signals to the cytoskeleton in the nucleus. Signal transduction mechanisms occur when changes in the microenvironment alter the permeability of ion channels or the activity of associated intracellular receptors, transducing mechanical signals into chemical signals to regulate the expression of associated genes. The two mechanisms work in synergy to transmit and convert mechanical signals. The cytoskeleton, integrins, and ion channels, among others, play important roles in perception . In addiNuclear factor κ-B (NF-κB) is a ubiquitous, inducible nuclear transcriptional activator that binds to enhancer elements in many different cell types and can also be activated by pathogenic stimuli. RANKL is a ligand for NF-κB receptor activator (RANK), which binds specifically to and activates RANK. RANKL-stimulated cells exhibit marked translocation of p65 from the cytoplasm to the nucleus, phosphorylating and activating NF-κB pathway-associated proteins. Activated NF-κB/p65 translocation to the nucleus reduces the expression of runt-related transcription factor 2 (RUNX2), alkaline phosphatase (ALP), and osteoprotegerin (OPG). At the same time, OPG is a decoy receptor for RANKL, which competitively inhibits the binding of RANKL to RANK, inhibiting osteoclast production and its survival time. Therefore, the relative ratio of RANKL/OPG, which coordinates osteoblast/osteoclast production, is of great importance .Binding of NF-κB dimers to NF-κB inhibitor (IκB) in the cytoplasm renders NF-κB dimers inactive. IκB proteins are phosphorylated and degraded following physical or chemical stimulation of cells. Subsequently, NF-κB dimers are transformed into an activated state, released, and transferred to the nucleus, leading to nuclear localization of p65 and increased expression of RANKL mRNA, resulting in an increased RANKL/OPG ratio, which in turn induces target gene transcription . MechaniNF-κB is expressed in rat growth plate chondrogenesis, stimulates chondrocyte proliferation and differentiation, prevents apoptosis, and promotes longitudinal bone growth , whereasBone formation requires a balance between bone formation by osteoblasts and bone resorption by osteoclasts, the absence of either of which can cause specific corresponding diseases or abnormalities. Therefore, the effects of different mechanical forces on osteoblasts and osteoclasts were investigated. Fluid shear stress reduced RANKL expression and increased OPG expression in cells, which significantly reduced the RANKL/OPG ratio, upregulating the expression of osteoblast marker genes  Fig. 1)1). MechaThe nicotinic acetylcholine (ACh) receptor (nAChR) is a ligand-gated ion channel that signals through endogenous ACh and its agonists to drive organoid growth and differentiation . Among tTumour necrosis factor-α (TNF-α) and IL-1β significantly increased phosphorylated glycogen synthase kinase-3β (GSK-3β) levels in BMSCs and periodontal stem cells (PDLSCs), and increased expression of phosphorylated GSK-3β (p-GSK-3 β) upregulated α7 nAChR expression and promoted its function, which in turn upregulated RANKL, downregulated OPG, and decreased ALP, RUNX2, and OCN, leading to decreased osteogenic differentiation and increased osteoclast formation  At the same time, the nAChR signalling pathway has synergistic effects with a variety of signalling pathways. Upregulation of α7nAChR activates the NF-κB signalling pathway. The receptor activator of RANKL is upregulated, which in turn induces osteoclast effects . The nAC2+ influx [2+ usually occurs first in the cilia, but the exact mechanism is not known [2+ influx into the cell, acting as a second messenger and activating the Notch1 signalling pathway, upregulating the expression of ALP, Runx2, and OCN, thereby promoting the osteogenic differentiation of human periodontal stem cells (hPDLSC) [The piezoelectric mechanosensitive ion channel (PIEZO) acts as a mechanosensor and is a key receptor for sensing mechanical stimuli . PIEZO s+ influx , which iot known . Increas(hPDLSC) .Fig. 3Me2+. PIEZO 1 responds to shear stress-induced stretching of the cell membrane after mechanical loading, leading to the release of ATP in the extracellular environment. Sarcoplasmic reticulum (SR) Ca2+ ATPase 2 (SERCA2) is an ATPase that interacts with PIEZO 1 in the membrane bilayer at the endoplasmic reticulum (ER)-plasma membrane junction and inhibits the mechanosensitivity of PIEZO 1. Specific mechanical forces can also transport cytosolic Ca2+ into the SR/ER for storage, maintain Ca2+ homeostasis, and regulate the PIEZO pathway [Shear stress associated with local blood flow is a key piezoelectric channel activator , and sti pathway .2+ influx from PIEZO to chondrocytes [2+, and elevated resting-state Ca2+ in turn alters the F-actin cytoskeleton and amplifies mechanically induced trauma [Chondrocytes in articular cartilage are one of the terminal cells of MSC differentiation, and PIEZO channels exhibit a key signal transduction role in the fate of chondrocytes. During endochondral ossification, PIEZO 1 inactivation in chondrocytes impairs trabecular bone formation, resulting in reduced ossification . PIEZO 1drocytes  Fig. 3)2+ influxdrocytes . In addid trauma .Hypoxia-inducible factor 1 (HIF-1) is a basic helix–loop–helix transcription factor that plays a role in apoptosis, and TWIST is also a helix–loop–helix transcription factor that controls gene expression during embryogenesis and the epithelial-mesenchymal transition. The HIF-1α/TWIST-mediated cellular response to oxygen affects stem cell differentiation and bone and cartilage histogenesis . NaturalUnder hypoxic conditions, HIF-1ɑ levels in bone marrow macrophages (BMM) are upregulated and can promote osteoclast formation . HIF-1α Mechanical stimulation also induces osteogenic differentiation of BMSCs via the TWIST/E2A/p21 axis. Mechanical cyclic strain promotes TWIST and inhibits E2A, and TWIST and E2A interact to activate p21 expression. p21 has different regulatory effects on RUNX2 and BMP2, maintaining a relative balance between osteogenic factors. Meanwhile, p21 acts as a downstream gene of TWIST and E2A, regulating TWIST expression positively and E2A expression negatively  Fig. 4)4). HIF-1Stem cells are receiving increasing attention in the fields of regenerative medicine and tissue engineering and are important for a wide range of diseases , 2. OsteHuman adipose mesenchymal progenitor cells (haMPCs) are stem cells with multiple differentiation potentials and immunomodulatory functions. Significant improvements in joint function, pain, quality of life, and cartilage regeneration were observed in patients with knee osteoarthritis after receiving intra-articular injections of ex vivo-expanded haMPCs from their own adipose tissue . MSCs haDiabetes mellitus (DM) is a serious metabolic disease characterized by hyperglycaemia and beta-cell dysfunction. Although medication is available to control the progression of the disease, it is difficult to cure it, so there is a real need for new and effective treatment modalities for DM. Stem cell therapy holds great promise for people with DM . Stem ceOsteoporosis is a widespread progressive bone disease that can pose a serious risk to people’s health and quality of life. Not only does it appear in older adults, but it also commonly afflicts space people who work in outer space. Researchers were inspired by the fact that exercise reduces the risk of osteoporosis in the population. Studies have shown that BMSCs can accelerate bone healing, ossification, and restoration of bone mechanical properties in osteoporotic fractures . BMSCs hTo overcome the limitations of the small amount of umbilical cord blood stem cells (UCB), intra-bone transfer of UCB (IB-UCB) is used. Intact haematopoietic stem cells were maintained by direct delivery of UCB into hypoxic HSC ecotopes, with rapid haematopoietic recovery and low incidence of graft-versus-host disease . In addiIn addition to these common diseases, stem cells have a wide range of applications, including periodontitis , acute lMechanical signals act as important influences on the fate of living organisms in a number of areas, including the circulatory system , neural The external force generated using an in vitro mechanical device increases the stiffness of adipose tissue, thus affecting the migration and differentiation of ASCs. Different tissue stiffnesses have different effects in promoting the regeneration of adipose tissue. The use of mechanical devices to expand soft tissue holds promise for treating large soft tissue defects that are difficult to reconstruct through surgery . Mechani2 concentration and controlling shear stress [Shear stress can cause a variety of clinical conditions. Platelet activation induced by shear stress is thought to be an important mechanism in acute coronary syndromes . Shear sr stress . Also, ar stress .Intermittent shear flow has the potential to induce both circumferential stretch caused by HP of the fluid and shear stress caused by flow at the inner surface, while having a role in the simultaneous differentiation of MSC into epithelial and muscular lineages. Intermittent shear flow is more effective than steady shear flow for the development of oesophageal tissue engineering scaffolds . The intThe high HP in the periodontal ligament generated by the orthodontic force recruits the tooth cells and leaves a resorption pit on the root surface. Root resorption is more likely to occur when HP exceeds capillary blood pressure . This fiMicrogravity has many well-known adverse effects on the human body. Prolonged exposure to microgravity during spaceflight can lead to severe osteoblast dysfunction, resulting in bone loss and causing conditions similar to osteoporosis  and discThis paper summarises the impact of mechanical signals, including structural and force signals, in the microenvironment in which stem cells grow on stem cell differentiation and the mechanisms of how stem cells sense mechanical signals, and further discusses how mechanical factors affecting stem cells can be modified for clinical and disease applications. Existing studies on stem cell differentiation mostly ignore the role of mechanical cues in the environment. This review provides a timely summary of the impact of mechanical cues from the microenvironment in which stem cells reside. Mechanical signalling is an integral part of the study of stem cell differentiation that cannot be ignored and provides an important basis for future studies on the specialized differentiation of stem cells. However, the environmental components of stem cell growth are complex, and the mechanical signals generated by the interactions are also complex and diverse . This arIn addition, the performance of implanted stem cells depends not only on differentiation but also on migration, adhesion, proliferation, and paracrine secretion, which deserve to be explored in depth in the future. Different ECM stiffness affects cell-ECM adhesion, cell spreading and migration . The dirExperiments in which stem cells respond to a mechanical environment sometimes show results that are contrary to previous studies , possiblIn conclusion, this review summarizes the effects of the mechanical microenvironment of stem cell growth on stem cell differentiation and the corresponding mechanisms, which have important implications for clinical disease treatment.


The Aminoacyl-tRNA Synthetases (aaRSs) are an evolutionarily ancient family of enzymes that catalyze the esterification reaction linking a transfer RNA (tRNA) with its cognate amino acid matching the anticodon triplet of the tRNA. Proper functioning of the aaRSs to create aminoacylated (or “charged”) tRNAs is required for efficient and accurate protein synthesis. Beyond their basic canonical function in protein biosynthesis, aaRSs have a surprisingly diverse array of non-canonical functions that are actively being defined. The human genome contains 37 genes that encode unique aaRS proteins. To date, 56 human genetic diseases caused by damaging variants in aaRS genes have been described: 46 are autosomal recessive biallelic disorders and 10 are autosomal dominant monoallelic disorders. Our appreciation of human diseases caused by damaging genetic variants in the aaRSs has been greatly accelerated by the advent of next-generation sequencing, with 89% of these gene discoveries made since 2010. In addition to these genetic disorders of the aaRSs, anti-synthetase syndrome (ASSD) is a rare autoimmune inflammatory myopathy that involves the production of autoantibodies that disrupt aaRS proteins. This review provides an overview of the basic biology of aaRS proteins and describes the rapidly growing list of human diseases known to be caused by genetic variants or autoimmune targeting that affect both the canonical and non-canonical functions of these essential proteins. The Central Dogma of molecular biology explains the flow of genetic information in a biological system from DNA through RNA to proteins . The AmiGiven their central role in human biology, it is unsurprising that genetic variants that disrupt aaRS protein structure and function cause disease. Damaging variants in aaRSs have now been linked to over 50 human diseases . NotablyThe synthesis of functional proteins relies on the accurate transfer of genetic information from DNA, through mRNA, to protein. To generate new proteins, DNA is first transcribed to mRNA using the complementarity of nucleotide bases. The mRNA is then translated into a protein by the ribosome. The ribosome reads the mRNA in groups of triplet codons with each codon corresponding to one amino acid.Once the ribosome reads a codon, elongation factors bring a tRNA containing the three bases complementary to a codon (anticodon) and charged with the correct amino acid. The amino acid delivered by the tRNA is then added to the growing polypeptide chain following the order of codons specified by the mRNA. This elongating polypeptide eventually becomes a functional protein within the cell.The sequence of amino acids in a protein is defined by what amino acid is brought to the ribosome by the tRNA cognate to each codon. The essential step in this process involves linking the appropriate amino acid with its matching tRNA. This is the reaction catalyzed by the aaRSs, the esterification that links each tRNA molecule with its cognate amino acid creating an aminoacylated, or “charged” tRNA . In addiWith few exceptions, all living organisms contain genes for the 20 aaRSs, one for each amino acid. The degeneracy of the genetic code means that there are more codons than amino acids. Therefore, the aaRS for an amino acid can recognize several tRNAs cognate to that amino acid. Eukaryotes contain genes for cytoplasmic and mitochondrial aaRSs . All of these proteins are nuclear encoded and synthesized in the cytoplasm with the organellar aaRSs being imported to their final destinations following translation.In humans and other higher eukaryotes, 9 of the aaRS proteins  bind together to form the cytoplasmic multi-tRNA synthetase complex (MSC) . While tDuring evolution, most eukaryotic cytoplasmic aaRSs gained noncatalytic domains not found in their respective orthologs in bacteria or archaea . These aOur understanding of these non-canonical functions of aaRSs is growing rapidly. As we try to understand how pathogenic genetic changes in the aaRS genes cause human disease, it is essential that we look beyond the canonical aminoacylation role of aaRSs and consider how alterations in non-canonical functions may also contribute to pathophysiology .aaRS nomenclature is somewhat complex as it integrates functional classes, subcellular localization, and gene names. Here we clarify and summarize this nomenclature. First, aaRS proteins are divided into two classes based on their specific structural and functional properties . Class IA for alanine; Y for tyrosine); 2) this is followed by ARS1 or ARS2 depending on whether the aaRS is located in the cytoplasm or mitochondria, respectively. For example, LARS2 specifies leucyl-tRNA synthetase 2, which charges a tRNA molecule with leucine in the mitochondria of the cell.The naming convention for genes encoding aaRSs is as follows: 1) gene names begin with the one-letter symbol for the amino acid the aaRS recognizes , 17 encode mitochondrial synthetases, and two genes encode proteins that will exist in both locations .Next-generation sequencing (NGS) technology has transformed our ability to make genetic diagnoses. Since the first successful application of NGS for gene identification in 2010 , the disTo date, 56 human diseases caused by damaging variants in aaRS genes have been described see . EmphasiNARS1, HARS1, GARS1, AARS1, MARS1, WARS1, YARS1) have been identified  disease. CMT is a clinically and genetically heterogeneous neurodegenerative disorder that affects the peripheral nervous system in roughly 1 in 2,500 individuals . SymptomCMT is divided into various subtypes, with demyelinating Type 1 CMT (CMT1) and axonal Type 2 CMT (CMT2) containing the majority of cases. Demyelinating Type 1 CMT occurs from breakdown of the myelin sheath of nerves, while Type 2 axonal CMT occurs from direct damage to the axons of nerves . IntermeYARS1, MARS1, KARS1, WARS1, AARS1, GARS1, HARS1). All of these genes except YARS1 and KARS1 are associated with monoallelic axonal CMT (CMT2). YARS1 causes dominant intermediate C CMT. KARS1 is an outlier in that it causes autosomal recessive CMT, and specifically the intermediate B subtype.While over 90 genes have been linked to the pathogenesis of CMT, aaRS-encoding genes constitute the largest gene family connected with this disorder . So far,CMT is specifically associated with monoallelic pathogenic variants in cytoplasmic aaRSs, indicating a special sensitivity of the peripheral nervous system to this type of genetic change. Given the estimate that only ∼20% of the CMT-related variants affect canonical catalytic function , the simet al. and Spaulding et al. expanded our understanding of disease mechanisms in CMT  in affected motor neurons through the sensor kinase GCN2. Importantly, these complementary studies identified two strategies with potential therapeutic benefit: 1) overexpression of tRNAGly to rescue protein synthesis, avoiding ISR activation and the ensuing peripheral neuropathy; or 2) inhibiting GCN2 to avoid activation of the neurotoxic ISR. Currently, the mechanism(s) linking aaRS variants to human CMT remains an area of intense investigation with the ultimate goal of developing treatments that will prevent neurodegeneration in patients born with aaRS variants that cause CMT.In recent studies, a complementary pair of papers by Zuko s in CMT . The invWhile CMT is the most common monoallelic condition associated with aaRS variants, several other related neurological conditions are caused by damaging aaRS variants. It is helpful to appreciate that borders between these disease definitions are rather ‘porous’ and that these additional monoallelic aaRS-related conditions share features with CMT and with each other.WARS1 and GARS1 have been associated with dHMN  is a pure motor neuropathy characterized by progressive distal muscle weakness and muscular atrophy without sensory impairment. Pathogenic variants in both ith dHMN .de novo heterozygous variants in the NARS1 gene  is reported to be caused by RS1 gene . Notablyde novo heterozygous variants in GARS1  is a severe neuromuscular disorder with symptoms beginning in the first weeks or months of life. Several unrelated children with SMAJI have been found to have in GARS1 .Biallelic diseases arising from the disruption of both alleles of genes encoding the aaRSs cause severe, early-onset disorders affecting multiple organ systems. Biallelic disease can be caused by homozygous or compound heterozygous variants.Autosomal recessive aaRS deficiencies represent a rapidly growing group of severe inherited diseases  involvinet al. to trial a personalized intervention in four patients based on oral supplementation with the cognate amino acid matching the patients’ aaRS deficiency   . This amet al. emphasized the importance of deep phenotyping of patients with aaRS-related diseases and reporting all clinical features, so the full extent of the phenotypes can be appreciated . All forms of this COXPD caused by pathogenic aaRS variants cause damage to the CNS (which requires an abundant and constant energy supply)  is a unifying umbrella term describing a large group of multisystem disorders caused by defects in the mitochondrial oxidative phosphorylation system. Currently more than 50 different types of COXPD have been described, each caused by damaging variants in genes critical to the integrity of mitochondrial oxidative phosphorylation. The most common biallelic disease category associated with mitochondrial aaRSs is COXPD. To date, eight mitochondrial aaRS-encoding genes have been found to cause various forms of COXPD ( supply) . Other cmyopathy .HARS2 and LARS2 cause Perrault syndrome, an autosomal recessive disorder characterized by sensorineural deafness in both males and females, and ovarian dysgenesis in affected females . However, other organs systems are also affected, manifesting as liver disease, myopathies, and ovarian failure . Hence,  females . While t females .KARS1) and leukodystrophies . Interestingly, a damaging monoallelic variant in the AARS1 gene has also been found to cause leukoencephalopathy in two members of an affected Swedish family  and one monoallelic variant (NARS1) in cytosolic aaRS genes. Symptoms of these disorders include intellectual disability, delayed language development and ability to walk, microcephaly, movement disorders, and in some cases seizures . ASSD is a rare condition that involves the production of autoantibodies that bind with, and mount a response against, aaRS proteins . ASSD isThe recent rapid advances in defining the role of aaRSs in human disease opens many avenues for life changing improvements in diagnosis and targeted treatment. The ability to provide a complete genetic diagnosis for individuals with monoallelic or biallelic aaRS diseases is transformative in many ways—new treatments can be explored based on the genetic findings , new potential medical issues or risks can be anticipated and avoided, and accurate genetic counselling can be provided for the patient and their extended family. Ultimately, our current understanding of aaRSs in health and disease represents a powerful integration of knowledge that has emerged through the study of evolutionary science, basic biochemistry, and clinical medicine.


Fas Activated Serine/Threonine Kinase (FASTK) family is a protein family encoded in the nuclear genome that spans the mitochondria and executes numerous functions, and consists of FASTK, the founding member along with 5 homologous proteins FASTKD1-5.Up regulation of FASTK family members have not only been implicated in tumour progression and invasion but also in increased resistance to chemotherapy proven by their knockdown leading to increased sensitivity to drugs. Thus, this review reports theimplication of FASTK proteins in cancer and hence provides a scope to emphasise the role of these proteins in Oral Cancer. Cancer is characterised by a pathological breakdown in the processes that control cell proliferation, differentiation, and death Earlier quoted as an emerging hallmark and now included in the main component is the metabolic reprogramming of mitochondria is critical in cancer development . MitochoNumerous protein families have been significant in maintaining mitochondrial organisation and stability which are crucial for disease prevention, one such family which is now under the radar is the Fas-activated serine/threonine kinase (FASTK) family ofproteins that has emerged as key regulators in post-transcriptional gene expression in the mitochondria -11. It cThe mechanism of action of FASTK proteins is under continuous research due to their unique structural characteristics. Mitochondrial FASTK isoform has been reported to be necessary for the biogenesis of the mitochondrial ND6 mRNA, which encodes anessential subunit of mitochondrial respiratory complex I. The mitFASTKD1 controls the ND3 domain in the mitochondria and has a putative role in RNA stability-related processes. The down-regulation of mitochondrial MT-ND3 mRNA levels leads to decreased respiratory complex I abundance and activity. Owing tFASTKD2 has a unique role in mitochondrial respiration, RNA processing and translation and interacts with a defined set of mitochondrial transcripts including 16S ribosomal RNA (RNR2) and NADH dehydrogenase subunit 6 (ND6) messenger RNA. FASTKD2FASTKD3 is another protein which localises to the mitochondrial matrix but is not expressed in the MRGs unlike the other members of the FASTK family but plays a role in controlling mRNA stability of various molecules including MT-ND2, MT-ND3,MT-CO2, MT-CYB, and MT-ATP8/6 and also essential for effective COX1 mRNA translation . AccordiAnother interesting player in the FASTK family is FASTKD4 also called the TBRG4 (Transforming growth factor beta regulator) or cell cycle progression restoration protein 2 (CPR2) is a key regulator in mt-RNA functions and also implicated in numerouscancers. Activation of non-canonical processing site between MT-ND5 and MT-CYB may be involved with FASTKD4 protein . Upon FAFASTKD5 is a bonafide component of MRGs, and colocalizes with MRGs which differentially regulate the processing of mitochondrial RNAs and an essential component of protein synthesis . DepletiFASTK family is an intriguing group of proteins who have a discernible role in cancer but their role in oral cancer is still unexplored. FASTK, FASTKD2 and FASTKD4 are upregulated in cancer tissue compared to healthy tissue or cell lines in numerouscancers as mentioned in the table (Table 1 - see PDF). Silencing of FASTK has decreased the proliferation and induced activation of the apoptotic pathway. Additionally, increased expression of FASTK in astrocytoma led to upregulated migration and invasion.These findings demonstrate that FASTK can be used as a prognostic biomarker but also as a therapeutic target .The otheMitochondrial biogenesis is an intriguing functional enigma in the cell as they are the only organelle which has a two way control, they possess their own genome, the mt-DNA, which requires dedicated gene expression machinery as well the control fromthe various nuclear encoded proteins which control and express within the mitochondria . MitochoAs mentioned earlier, many nuclear encoded proteins are essential for mitochondrial transcription, RNA processing, degradation and translation. Emerging players in the post-transcriptional mitochondrial gene expression regulation concerns members ofthe FASTK family of proteins, which also controls non-canonical RNA processing and are structurally related to RNA binding proteins (RBP) 33] Mito Mito33] In many cancers as already discussed, differential expression of FASTKs has been observed and some of them have been used as prognostic biomarkers. A large number of FASTKs have also been implicated in cancer development and in decreased drug sensitivity,suggesting that the FASTK family is a putative candidate for oncology research. Furthermore, some of these proteins act as tumour suppressors, by proapoptotic and increasing cell survival   while otThere is increased recognition that genetic alterations affecting RNA splicing and polyadenylation are common in cancer and may generate novel therapeutic opportunities  Supek etThis review has concisely spotlighted the physiological and pathological roles of the relatively unexplored FASTK family and accentuated the mechanisms by which their functional alterations can lead to cancer development. Despite the substantial progressmade in the field of mtRNA processing and its regulation, many concepts regarding their role in malignancies remain camouflaged. Our discussion is a sliver of the entire scope, with mitochondrial proteins engaging in a plethora of roles in almost every facetof cancer biology and thus optimistically unearths a whole new arena in drug design therapeutic strategies by imploring the roles of FASTK proteins, particularly in cancers.


Oxidative stress has been implicated in the pathogenesis and progression of many neurodegenerative disorders including Parkinson’s disease and Alzheimer’s disease. One of the major enzyme systems involved in the defense against reactive oxygen species are the tripeptide glutathione and oxidoreductase glutaredoxin. Glutathione and glutaredoxin system are very important in the brain because of the oxidative modification of protein thiols to protein glutathione mixed disulfides with the concomitant formation of oxidized glutathione during oxidative stress. Formation of Pr-SSG acts as a sink in the brain and is reduced back to protein thiols during recovery, thus restoring protein functions. This is unlike in the liver, which has a high turnover of glutathione, and formation of Pr-SSG is very minimal as liver is able to quickly quench the prooxidant species. Given the important role glutathione and glutaredoxin play in the brain, both in normal and pathologic states, it is necessary to study ways to augment the system to help maintain the protein thiol status. This review details the importance of glutathione and glutaredoxin systems in several neurodegenerative disorders and emphasizes the potential augmentation of this system as a target to effectively protect the brain during aging. The brain is highly sensitive to oxidative stress due to its high oxygen consumption, abundance of unsaturated fatty acids which are prone to oxidation, and low antioxidant levels. It is a metabolically active and a high energy demanding organ that relies heavily on mitochondria for its energy needs ,2. MajorOxidative stress results from the excess accumulation of reactive oxygen species, such as superoxides, hydrogen peroxides, hydroxyl radicals and nitric oxide when they are not effectively counteracted by antioxidants . OxidatiReactive oxygen species are detoxified through a set of enzymes including superoxide dismutase, catalase and glutathione peroxidase. Super oxide dismutase (SOD) catalyzes the conversion of superoxide molecules to hydrogen peroxide . It is pGlutathione (GSH), the tripeptide in the form of γ-glutamyl cysteinyl glycine, is a major thiol antioxidant responsible for the maintenance of protein thiol status in the cells. During the detoxification of ROS, glutathione peroxidase (GPx) oxidizes GSH to GSSG. The oxidized form GSSG connected by an intermolecular disulfide bond is reduced back by glutathione reductase (GR) utilizing the reducing equivalents of NADPH  Figure . The ratOne of the major changes that occur even under low levels of oxidative stress is the changes in protein thiols leading to their successive oxidation to disulfides, sulfenic, sulfinic and sulfonic acid . SulfeniGlutaredoxins (Grx) are evolutionarily conserved GSH-dependent oxidoreductase involved in the regulation of several cellular processes . Grx1 reOxidative stress and a dysfunctional redox system are implicated in the initiation and progression of many neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) . SelecteGSH has critical roles in maintaining the brain redox status and protecting brain cells from oxidative damage . It is tAstrocytes have higher GSH concentration compared to neurons, and both have a differential preference for the precursors of GSH synthesis. Secretion of GSH into the extracellular space by astrocytes provides GSH precursors to neurons  Figure . In addiReplenishing GSH in the brain could be a promising treatment strategy for neurodegenerative disorders. GSH does not cross blood-brain-barrier and its systemic administration is not effective to increase the concentration in the brain as most of the GSH are metabolized in blood. Several studies have investigated the effect of GSH precursors in a mouse model in restoring GSH. Treatment with GSH precursors has been shown to protect from Aβ induced neurotoxicity  and cognGlutaredoxins are ubiquitously expressed thiol oxidoreductases that regulate protein thiol homeostasis by reversing protein S-glutathionylation using GSH as a substrate. Grx1 regulates proteins involved in cell survival and death including Akt, cjun, ion transporters, NFκB, intracellular signaling molecule Ras and transcription factor nuclear factor-1 (NF1) . A majorThe glutaredoxin-mediated reduction of protein mixed disulfides to protein thiols is critical in the brain where glutathionylation of protein is more prominent. In the brain, under conditions of oxidative stress such as that seen during reperfusion following ischemia or in animal models of MPTP, there is a predominant formation of Pr-SS-Pr. During recovery following these insults, Pr-SSG is reduced back to Pr-SH by Grx1, thus restoring protein function.Glutaredoxin was first purified by Mieyal et al. from human erythrocytes as thioltransferase specific for GSH containing mixed disulfides  and clonMaintaining protein thiol homeostasis is important for mitochondrial functions. Loss of GSH and formation of Pr-SSG in the brain contributes to various dysfunctions including loss of activity of mitochondrial enzymes, structural damage to mitochondrial membranes and deregulation of cell survival pathways. Mitochondria are prone to oxidative damage as ROS generated during oxidative phosphorylation can in turn releases more reactive oxygen species that can damage the macromolecules essential for its normal function. The percentage of total cell GSH present in mitochondria is 10–15% .The response of brain mitochondria to oxidative stress is very different from the liver mitochondria. In the brain, the GSH lost during oxidative stress is recovered as Pr-SSG and only less than 5% of GSH is recovered as GSSG . HoweverMitochondrial enzymes are particularly vulnerable to oxidative damage, complex Ⅰ being the most affected as it increases the oxidation of the GSH pool. Protein thiol groups on 75 and 51 KDa subunits of complex Ⅰ undergo glutathionylation and forms mixed disulfide with GSH  Figure . Thiol m+ in mitochondria [Glutaredoxin 2 (Grx2) was first identified and cloned by Holmgren et al., which is 34% identical to cytosolic Grx1 . It has chondria .Further, overexpression of Grx2 attenuatesthe mutant superoxide dismutase (SOD1) mediated degeneration of motor neurons. MutSOD1 accumulates in the mitochondria of motor neurons, and impairs respiratory complexes and ATP production. Grx2 is required for normal mitochondrial function and viability, whereas overexpression of Grx1 is shown to be beneficial in the cytosol and does not preserve mitochondrial dynamics or apoptosis induced by mutSOD1 .Increased Pr-SSG formation due to loss of Grx1 activity in the cytosol is known to impair mitochondrial dynamics in the brain. Pr-SSG formed by the oxidation of sulfhydryl groups of cysteine increases the permeability of the inner mitochondrial membrane and opens upa mitochondrial transition pore, resulting in the uncoupling of oxidative phosphorylation and ATP hydrolysis. In addition, the oxidation of voltage-dependent anion channel (VDAC), a mitochondrial outer membrane protein results in the loss of mitochondrial membrane potential MMP . The redOverall, glutaredoxin acts as a potential neuroprotective mediator to maintain mitochondrial function during oxidative stress, excitatory amino acid toxicity and MPTP mediated neurotoxicity. The role of glutaredoxins will be discussed under each of the disease conditions that follow.Neurolathyrism is a human neurological disorder caused by the ingestion of plant toxin, 3-oxalylamino-L-alanine (L-BOAA) present in Lathyrus sativus. Neurolathyrism affects motor neurons, and anterior horn cells and results in the loss of axons in the pyramidal tract of the lumbar spinal cord in humans. It has been more commonly seen in men, while women are protected from the disease .Animal models of L-BOAA toxicity showed GSH depletion and loss of mitochondrial complex Ⅰ activity  that canA gender specific effect of L-BOAA is seen in human as well as in animal models. L-BOAA mediated GSH depletion and mitochondrial dysregulation are identified only in male  and ovarGSH homeostasis in the brain during cerebral ischemia has been studied. Reactive oxygen species formed during reperfusion injury following ischemia cause damage to the brain which generally occurs in conditions such as stroke, head trauma and cardiac arrest in humans . ReperfuReperfusion following severe ischemia, induced by bilateral carotid artery occlusion and systemic hypotension results in massive loss of GSH along with an increased mortality rate . PartialMaintenance of thiol homeostasis is important during reperfusion as it can leads to the oxidation of protein thiols, damage to membrane structures and loss of activity of critical enzymes with active thiol groups such as Na+/K+-ATPase. Thus, the administration of thiol antioxidants such as α-lipoic acid was shown to restore and maintain thiol homeostasis to recover from reperfusion injury. α-lipoic acid shows a remarkable neuroprotective effect during severe ischemic-reperfusion injury with the mortality rate in rats reduced from 78% to 26% accompanied by attenuation of brain GSH loss .PD is a movement disorder, characterized by the presence of Lewy bodies as intracellular aggregates of α-synuclein and loss of dopaminegic neurons from substantia nigra pars compacta regions (SNpc) . Althoug2+) and ferric states (Fe3+) of iron are present in Lewy bodies and iron content is higher in the SNpc regions of the PD brain. When an excess amount of redox-active iron is present in a cell, it generates more ROS, such as superoxides and hydroxyl radicals or lipid peroxides via fenton reaction [Dopaminergic neurons produce dopamine (DA), a neurotransmitter that modulates synaptic transmission to control motor activity. Dopaminergic neurons are rich in neuromelanin and iron content ,74. Bothreaction . The fenIron is mostly associated with proteins in the cell and readily incorporated into mitochondria. Iron-containing enzymes in mitochondria also generates a substantial amount of ROS through a biological process ,77. AddiSeveral animal models are utilized to study different aspects of PD pathology, which include genetic and neurotoxin-induced models. Genetic models, linked to monogenic PD, include a mutation in genes SNCA, LRRK2, UCH-L1, PRKN, and PINK1, and exhibit dopaminergic cell loss, motor deficit and mostly formation of Lewy bodies. Animal models utilizing neurotoxins such as MPTP, rotenone, diamide, and herbicide paraquat, induce loss of dopaminergic neurons and elicit motor symptoms, but mostly lack α-synuclein aggregation seen as Lewy body formation .+, an active metabolite of MPTP  , would aFurthermore, the selective downregulation of Grx1 in SNpc shows a loss of TH positive neurons and the development of motor deficits. A recent study concludes that the knockdown of Grx1 in substantia nigra could selectively degenerate SNpc DA neurons without affecting them in the VTA region. Moreover, significant downregulation of Grx1 mRNA was also observed in the SNpc region of human PD autopsy tissue .It is very well known that typical neuroleptic such as haloperidol, while being a very effective anti-psychotic drug, is known to cause tardive dyskinesia in a subset of patients. Symptoms of dyskinesia overlapping with PD is a very big concern that led to the development of atypical anti-psychotic drugs such as clozapine, quetiapine, etc . Haloper+, also induces dopaminegic neurodegeneration and mitochondrial dysfunction via oxidative stress, mimicking features of pathological PD [Paraquat, a herbicide with structural similarity to MPPgical PD   across different PD models with a motor deficit and neuroinflammation found promising results in alleviating the symptoms of PD. ALA regulates ferroptosis, a programmed cell death that depends on iron and increased lipid peroxides via activating PI3K/Akt/Nrf2 pathway . ALA redAlzheimer’s disease is an age-related progressive form of dementia, characterized by the presence of extracellular amyloid-β deposition, neurofibrillary tangle formations, loss of synapses and neurodegeneration. Multiple pathways contribute to AD pathogenesis and oxidative stress is one of the early events ,106. Aβ-Synaptic dysfunction including loss of dendritic spines is one of the major consequences of AD  which afRegulating actin dynamics is critical to synaptic functions including synaptic plasticity, memory and learning. The G-actin/F-actin equilibrium is maintained by several actin binding proteins, mainly Cofilin . CofilinThe increased S-glutathionylationin proteins has been identified  along wiMaintaining protein thiol homeostasis during oxidative stress is critical in the brain. Over the years, the role of glutathione and glutaredoxin in alleviating oxidative damage has been studied extensively across models of neurodegeneration. Most of the antioxidants do not cross the blood-brain barrier to reverse protein thiol oxidation. Treatment strategies using GSH precursors and common antioxidants such as α-lipoic acid, vitamin E and vitamin C have shown only minimal effects in patients. Hence, it is critical to augment the intrinsic system such as the transcription of glutaredoxins early in the disease progression to effectively combat oxidative stress.


Background: Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease that can affect patients’ quality of life. Dupilumab is the first biologic agent approved for the treatment of patients with inadequately controlled moderate-to-severe AD and its mechanism of action is based on the inhibition of the interleukin (IL)-4 and IL-13 signaling. There are only a few data on the safety of dupilumab in AD patients with comorbidities, including kidney disorders. Materials and Methods: Descriptive retrospective series of three patients with chronic kidney diseases  receiving dupilumab for their concomitant severe AD. Results: Treatment with a standard dosage of dupilumab caused a relevant improvement of AD in all patients without any adverse events or worsening of renal function. In a patient with severe renal failure, the drug was effective and well tolerated without the need for any dose adjustments, also after the initiation of peritoneal dialytic treatment. Conclusion: Our case series suggests the use of dupilumab as an effective and safe treatment for AD patients suffering from renal diseases, although additional studies are required to confirm such preliminary findings. Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease that can have a significant impact on the quality of life of affected patients and their families. Dupilumab is a human monoclonal antibody that inhibits interleukin (IL)-4 and IL-13 signaling by binding the shared alpha-subunit of the IL-4 receptor, thus reducing the Th2 response [We describe three male adult patients with severe AD and kidney disease who were safely and successfully treated with a standard dosage of dupilumab (600 mg induction dose followed by 300 mg every 2 weeks thereafter).The first patient reported a long personal history of allergic rhinitis, asthma and severe AD, secondary arterial hypertension, and chronic kidney disease due to Alport syndrome, a rare hereditary disease caused by mutations in the type IV collagen genes COL4A3, COL4A4, and COL4A5, affecting the renal glomerular basement membrane [The second patient, affected by IgA nephropathy, reported a 10-year history of pollen allergy and a 4-year history of severe AD. AD manifestations rapidly improved with dupilumab leading to the achievement of EASI 90 in two months. After one year, a consistent reduction in AD scores was registered, while serum creatinine and glomerular filtration rate did not show remarkable changes; a slight reduction in proteinuria was observed . Such reThe third patient was an elderly subject with severe AD, chronic kidney disease probably due to hypertensive nephrosclerosis, and chronic obstructive pulmonary disease. After one year of therapy with dupilumab, AD scores dramatically improved and renal function remained stable . ClinicaAll patients applied emollients and used short courses of topical corticosteroids on an as-needed basis, especially in the initial treatment phases.Dupilumab proved to be safe and effective in these three patients with severe AD and concomitant kidney disease, without any adverse events or worsening of renal function during treatment. Moreover, in the third patient affected by severe renal failure, the renal function remained stable during treatment with dupilumab, and no dose adjustments were required, even after the initiation of peritoneal dialytic treatment.Only a few publications described the use of dupilumab for AD in patients with severe systemic comorbidities, including renal diseases ,4. HowevRenal disease is an obvious contraindication to cyclosporine, one of the most common therapeutic options for severe AD. Moreover, patients with chronic kidney disease, especially those with end-stage renal failure or on renal replacement treatment, frequently complain of chronic pruritus . TherefoKha et al. described a renal transplant man with uremic pruritus, acute flare of AD and superimposed prurigo nodularis coinciding with recent transplant failure who was treated with dupilumab for 8 months . TreatmeVarma et al. presented the case of a 22-month-old child with a history of hydronephrosis and other pathological conditions, whose AD dramatically improved after receiving three doses of dupilumab . A recenAnecdotal and contrasting findings exist regarding the safety of dupilumab in patients with IgA nephropathy. IgA nephropathy is the most common primary glomerulonephritis in the world and is characterized by the deposition of IgA1-containing immune complexes in the glomerular mesangium responsible for glomerular injury. Pathogenesis of IgA nephropathy is only partially known and appears to be complex. Excessive activity of T lymphocytes, especially the Th2, Tfh, Th17, and Th22 subpopulations, is likely to have a relevant pathogenic role . MoreoveIn our patient with IgA nephropathy, a slight reduction in proteinuria was detected during treatment with dupilumab. IgE levels were only slightly above the normal range at baseline and marginally decreased after one year of dupilumab treatment . TanczosIn another report 14), a relevant decline in serum IgE levels and an unexpected rapid deterioration in renal function were described during treatment with dupilumab in a patient with severe AD and minimal renal dysfunction. After stopping dupilumab, a renal biopsy was performed, and primary IgA nephropathy was diagnosed. The authors of this report suspected the involvement of IL-4 neutralization in IgA nephropathy exacerbation through the possible activation of Th17 cells or Toll-like receptor signaling [, a relevIn conclusion, the present cases suggest that dupilumab can be an effective and safe option in AD patients suffering from renal diseases. However, more data are necessary to better define the safety profile in subjects with relevant comorbidities and special patient populations, including patients with chronic kidney disease and subjects treated with dialysis.