Adenosine Triphosphate Inhibition Research Articles

Automatic metabolism modulator for glycolytic intervention‐induced cascade cancer therapy

AbstractEffective intervention in glycolytic metabolism is a promising way to inhibit tumor malignant invasion. However, the inherent hypoxia environment and unitary regulating model subsequently compromise its therapeutic efficacy. Herein, a facile way to design an automatic metabolism modulator (auto‐MMOD) is developed by loading glucose oxidase (GOx) and DNA‐templated silver nanoclusters (DNA‐AgNCs) into a pH‐responsive zeolitic imidazolate frameworks‐8 (ZIF‐8) nanocarrier, which can activate a cascaded metal ion‐killing effect during GOx‐regulated glycolysis metabolism. When the acidic lysosome microenvironment induces ZIF‐8 decomposition, the released GOx can effectively consume glucose and generate H2O2, thus inhibiting Adenosine Triphosphate synthesis and accelerating tumor starvation. Moreover, the released Ag+ in response to H2O2 can disturb bioenergy metabolism to inhibit tumor proliferation, which further enhances the tumor‐killing effect in hypoxic microenvironments. This study achieves effective tumor suppression in vitro and in vivo by integrating ion therapy into glycolysis intervention, which establish a promising strategy for nano‐theranostics.

Unmasking Protein Phosphatase 2A Regulatory Subunit B as a Crucial Factor in the Progression of Dilated Cardiomyopathy.

Dilated cardiomyopathy (DCM) is one of the major causes of heart failure. Although significant progress has been made in elucidating the underlying mechanisms, further investigation is required for clarifying molecular diagnostic and therapeutic targets. In this study, we found that the mRNA level of protein phosphatase 2 regulatory subunit B' delta (Ppp2r5d) was altered in the peripheral blood plasma of DCM patients. Knockdown of Ppp2r5d in murine cardiomyocytes increased the intracellular levels of reactive oxygen species (ROS) and inhibited adenosine triphosphate (ATP) synthesis. In vivo knockdown of Ppp2r5d in an isoproterenol (ISO)-induced DCM mouse model aggravated the pathogenesis and ultimately led to heart failure. Mechanistically, Ppp2r5d-deficient cardiomyocytes showed an increase in phosphorylation of STAT3 at Y705 and a decrease in phosphorylation of STAT3 at S727. The elevated levels of phosphorylation at Y705 in STAT3 triggered the upregulation of interleukin 6 (IL6) expression. Moreover, the decreased phosphorylation at S727 in STAT3 disrupted mitochondrial electron transport chain function and dysregulated ATP synthesis and ROS levels. These results hereby reveal a novel role for Ppp2r5d in modulating STAT3 pathway in DCM, suggesting it as a potential target for the therapy of the disease.

Tumor-Specific Nano-Herb Delivery System with High L-Arginine Loading for Synergistic Chemo and Gas Therapy against Cervical Cancer.

Cancer metastasis poses significant challenges in current clinical therapy. Osthole (OST) has demonstrated efficacy in treating cervical cancer and inhibiting metastasis. Despite these positive results, its limited solubility, poor oral absorption, low bioavailability, and photosensitivity hinder its clinical application. To address this limitation, a glutathione (GSH)-responded nano-herb delivery system (HA/MOS@OST&L-Arg nanoparticles,HMOA NPs) is devised for the targeted delivery of OST with cascade-activatable nitric oxide (NO) release. The HMOA NPs system is engineered utilizing enhanced permeability and retention (EPR) effects and active targeting mediated by hyaluronic acid (HA) binding to glycoprotein CD44. The cargoes, including OST and L-Arginine (L-Arg), are released rapidly due to the degradation of GSH-responsive mesoporous organic silica (MOS). Then abundant reactive oxygen species (ROS) are produced from OST in the presence of high concentrations of NAD(P)H quinone oxidoreductase 1 (NQO1), resulting in the generation of NO and subsequently highly toxic peroxynitrite (ONOO-) by catalyzing guanidine groups of L-Arg. These ROS, NO, and ONOO- molecules have a direct impact on mitochondrial function by reducing mitochondrial membrane potential and inhibiting adenosine triphosphate (ATP) production, thereby promoting increased apoptosis and inhibiting metastasis. Overall, the results indicated that HMOA NPs has great potential as a promising alternative for the clinical treatment of cervical cancer.

Potential Role of Dipeptidyl Peptidase-4 in Regulating Mitochondria and Oxidative Stress in Cardiomyocytes.

Oxidative stress causes mitochondrial damage and bioenergetic dysfunction and inhibits adenosine triphosphate production, contributing to the pathogenesis of cardiac diseases. Dipeptidyl peptidase 4 (DPP4) is primarily a membrane-bound extracellular peptidase that cleaves Xaa-Pro or Xaa-Ala dipeptides from the N terminus of polypeptides. DPP4 inhibitors have been used in patients with diabetes and heart failure; however, they have led to inconsistent results. Although the enzymatic properties of DPP4 have been well studied, the substrate-independent functions of DPP4 have not. In the present study, we knocked down DPP4 in cultured cardiomyocytes to exclude the effects of differential alteration in the substrates and metabolites of DPP4 then compared the response between the knocked-down and wild-type cardiomyocytes during exposure to oxidative stress. H2O2 exposure induced DPP4 expression in both types of cardiomyocytes. However, knocking down DPP4 substantially reduced the loss of cell viability by preserving mitochondrial bioenergy, reducing intracellular reactive oxygen species production, and reducing apoptosis-associated protein expression. These findings demonstrate that inhibiting DPP4 improves the body's defense against oxidative stress by enhancing Nrf2 and PGC-1α signaling and increasing superoxide dismutase and catalase activity. Our results indicate that DPP4 mediates the body's response to oxidative stress in individuals with heart disease.

ATP Inhibition for Starvation/Mild Photothermal/Photodynamic Synergy Therapy Using Polypeptide Nanoparticles Conjugating 2-Deoxy-D-Glucose and Dye under NIR Phototheranostic Strategy.

Rapid propagation of tumor cells requires plenty of energy, which is adenosine triphosphate (ATP) dependent. ATP inhibition in tumors not only results in the starvation of tumor cells but also down-regulation of the level of heat shock proteins (HSPs), which usually increase during traditional photothermal therapy (PTT), especially when the temperature is up 50°C. 2-deoxy-D-glucose (2DG) is an anti-glycolytic reagent and can be used as an efficient agent for ATP inhibition in tumors. Compared with typical PTT, low-temperature mild photothermal therapy (MPTT) is receiving more and more attention because it avoids the high temperatures causing damage to the normal tissue, and the increase of HSPs which decrease PTT. Here, multifunctional polypeptide nanoparticles pDG@Ahx conjugating both a NIR probe Ahx-BDP and 2DG into the side chain of the amphiphilic polypeptide have been prepared. In vitro and in vivo studies reveal that the as-prepared nanoparticles achieve a synergistic effect of starvation/MPTT/PDT (photodynamic therapy), and it provides a new strategy to NIR-I/II fluorescence imaging-guided starvation/MPTT/PDT synergy therapy for tumors.

Polydopamine-encapsulated zinc peroxide nanoparticles to target the metabolism-redox circuit against tumor adaptability for mild photothermal therapy.

Regulating the metabolism-redox circuit of cancer cells has emerged as an attractive strategy to improve the therapeutic outcome, while often confronting the glaring issue of resistance due to the multiple adaptive responses of tumor cells. This study presents a simple yet efficient approach to regulate this circuit simultaneously against tumor adaptability by utilizing polydopamine-encapsulated zinc peroxide nanoparticles (ZnO2@PDA NPs). The nanoparticles could deliver large amounts of Zn2+ and H2O2 into tumor cells to unfold an intracellular self-amplifying loop for breaking the balance in zinc and redox homeostasis by H2O2-mediated endogenous Zn2+ release from metallothioneins due to its oxidation by H2O2 and Zn2+-induced in situ H2O2 production by disturbing mitochondrial respiration, ultimately disrupting tumor adaptability to exogenous stimuli. The elevated levels of Zn2+ and H2O2 also inhibited adenosine triphosphate (ATP) generation from glycolysis and mitochondrial respiration to disrupt energy adaptability. Furthermore, insufficient ATP supply could reduce glutathione and heat shock protein expression, thereby sensitizing oxidative stress and enabling PDA-mediated mild photothermal therapy (PTT). Consequently, this trinity nanoplatform, which integrated dual-starvation therapy, amplified oxidative stress, and mild PTT, demonstrated outstanding therapeutic effects and a facile strategy.

Maribavir: Mechanism of action, clinical, and translational science.

Maribavir is an oral benzimidazole riboside for treatment of post-transplant cytomegalovirus (CMV) infection/disease that is refractory to prior antiviral treatment (with or without resistance). Through competitive inhibition of adenosine triphosphate, maribavir prevents the phosphorylation actions of UL97 to inhibit CMV DNA replication, encapsidation, and nuclear egress. Maribavir is active against CMV strains with viral DNA polymerase mutations that confer resistance to other CMV antivirals. After oral administration, maribavir is rapidly and highly absorbed (fraction absorbed >90%). The approved dose of 400 mg twice daily (b.i.d.) achieves a steady-state area under the curve per dosing interval of 128 h*μg/mL and trough concentration of 4.90 μg/mL (13.0 μM). Maribavir is highly bound to human plasma proteins (98%) with a small apparent volume of distribution of 27.3 L. Maribavir is primarily cleared by hepatic CYP3A4 metabolism; its major metabolite, VP44669 (pharmacologically inactive), is excreted in the urine and feces. There is no clinically relevant impact on maribavir pharmacokinetics by age, sex, race/ethnicity, body weight, transplant type, or hepatic/renal impairment status. In phase II dose-ranging studies, maribavir showed similar rates of CMV viral clearance across 400, 800, or 1200 mg b.i.d. groups, ranging from 62.5-70% in study 202 (NCT01611974) and 74-83% in study 203 (EudraCT 2010-024247-32). In the phase III SOLSTICE trial (NCT02931539), maribavir 400 mg b.i.d. demonstrated superior CMV viremia clearance at week 8 versus investigator-assigned treatments, with lower treatment discontinuation rates. Dysgeusia, nausea, vomiting, and diarrhea were commonly experienced adverse events among patients treated with maribavir in clinical trials.

IN SILICO STUDY OF APTAMER SPECIFICITY FOR DETECTION OF ADENOSINE TRIPHOSPHATE (ATP) AS BIOSENSOR DEVELOPMENT FOR MITOCHONDRIA DIABETES DIAGNOSIS

Diabetes Mellitus (DM) is characterized by increased blood glucose levels. It is generally caused by the pancreas' inability to produce insulin due to cell damage or insulin resistance. Due to the inhibition of adenosine triphosphate (ATP) production, which is essential for insulin secretion, one clinical pathology of this complication is insulin secretion dysfunction. Common methods of blood sugar diagnostics cannot distinguish mitochondrial diabetes and can lead to medication errors. Furthermore, an approach was developed through ATP biomarkers using an electrochemical biosensor with the help of an aptamer. However, it remains unknown precisely how and where the molecular interactions between the modified aptamer and ATP occur. Simulations were conducted in this study for 100 ns in silico using the amber18 computer program to determine the stability of the interaction and specificity between aptamer-ATP were compared to ADP and AMP. The results showed that the significant interactions are three hydrogen bonds between ATP and G7, G8, and A24. It was discovered that the aptamer-ATP complex had moderately good interaction and better potential for specificity than ADP and AMP. According to the RMSD, RMSF, and binding energy profiles, the system is still searching for the best conformation, necessitating a longer simulation time and additional studies to optimize the system. As a result, the system can reach a stable state and determine a more accurate energy calculation, hence, it is interpreted according to real applications.

Synergistic glycolysis disturbance for cancer therapy by a MOF-based nanospoiler.

Increased glycolysis for promoting adenosine triphosphate (ATP) generation is one of the hallmarks of cancer. Although reducing glucose intake or depriving cellular glucose can delay the growth of tumors to some extent, their therapeutic efficacy is a highly needed improvement for clinical translation. Herein, we found that mannose synergistic with glucose oxidase (GOx) can induce cell death by ATP inhibition, autophagy activation, and apoptosis protein upgradation. By using biodegradable zeolitic imidazolate frameworks (ZIF-8) as a nanocarrier (denoted as ZIF-8/M&G), the mannose and GOx can accumulate at the tumor site while having no obvious long-term toxicity. At the tumor site, GOx inhibits glycolysis by converting glucose and oxygen to H 2O 2 and gluconic acid, realizing oxidation therapy and expediting the degradation of the pH-responsive ZIF-8 nanoparticles, respectively. Simultaneously, mannose disturbs sugar metabolism and reduces oxygen consumption, which in turn promotes the GOx oxidation process. The concerted glycolysis inhibition through interactions between mannose and GOx endows ZIF-8/M&G nanospolier with excellent therapeutic efficacy both in vitro and in vivo. Synergistic glycolysis disturbance by the designed nanospoiler in this work proposes a versatile approach for metabolism disturbance to tumor treatment.

Peripheral blood mononuclear cell mitochondrial copy number and adenosine triphosphate inhibition test in NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is associated with mitochondrial dysfunction. This study aims to develop biomarkers for assessing mitochondrial dysfunction in patients with NAFLD. Mitochondrion-associated transcriptome analysis was performed. Peripheral blood mononuclear cells obtained from patients with NAFLD (69) and healthy controls (19) were used to determine the mitochondrial DNA (mtDNA) copy number. A mitochondrial inhibition substrate test (ATP assay) was performed in HepG2 cells using the patient serum. Hepatic mRNA transcriptome analysis showed that the gene expression related to mitochondrial functions (mitochondrial fusion, apoptotic signal, and mitochondrial envelope) increased in patients with steatohepatitis, but not in those with NAFL. Gene set enrichment analysis revealed that the upregulated expression of genes is related to the pathways of the tricarboxylic (TCA) cycle and deoxyribonucleic acid (DNA) replication in patients with steatohepatitis, but not in healthy controls. The mtDNA copy number in the peripheral blood mononuclear cells was 1.28-fold lower in patients with NAFLD than that in healthy controls (P <.0001). The mitochondrial inhibition substrate test showed that the cellular adenosine triphosphate (ATP) concentration was 1.2-fold times less in NAFLD patients than that in healthy controls (P <.0001). The mtDNA copy number and mitochondrial ATP inhibition substrate test demonstrated negative correlations with the degree of hepatic steatosis, whereas the ATP concentration showed a positive correlation with the mtDNA copy number. The mitochondrial copy number of peripheral blood mononuclear cells and mitochondrial ATP inhibition substrate can be used as biomarkers for assessing the mitochondrial dysfunction in patients with NAFLD.

Propofol-Related Infusion Syndrome: A Clinical Review

Propofol-related infusion syndrome (PRIS) is a lethal condition characterized by multiple organ system failures. It can occur due to prolonged administration of propofol (an anesthetic) in mechanically intubated patients. The main presenting features of this condition include cardiovascular dysfunction with particular emphasis on impairment of cardiovascular contractility, metabolic acidosis, lactic acidosis, rhabdomyolysis, hyperkalaemia, lipidaemia, hepatomegaly, acute renal failure, and eventually mortality in most cases. The significant risk factors that predispose one to PRIS are: critical illnesses, increased serum catecholamines, steroid therapy, obesity, young age (significantly below three years), depleted carbohydrate stores in the body, increased serum lipids, and most importantly, heavy or extended dosage of propofol. The primary pathophysiology behind PRIS is the disruption of the mitochondrial respiratory chain that causes inhibition of adenosine triphosphate (ATP)synthesis and cellular hypoxia. Further, excess lipolysis of adipose tissue occurs, especially in critically ill patients where the energy source is lipid breakdown instead of carbohydrates. This process generates excess free fatty acids (FFAs) that cannot undergo adequate beta-oxidation. These FFAs contribute to the clinical pathology of PRIS. It requires prompt management as it is a fatal condition. The clinicians must observe the patient's electrocardiogram (ECG), serum creatine kinase, lipase, amylase, lactate, liver enzymes, and myoglobin levels in urine, under propofol sedation. Doctors should immediately stop propofol infusion upon noticing any abnormality in these parameters. The other essentials of management of various manifestations of PRIS will be discussed in this article, along with a detailed explanation of the condition, its risk factors, diagnosis, pathophysiology, and presenting features. This article aims to make clinicians more aware of the occurrence of this syndrome so that better ways to manage and treat this condition can be formulated in the future.

Structure-Activity Relationship and Mechanistic Studies of Bisaryl Urea Anticancer Agents Indicate Mitochondrial Uncoupling by a Fatty Acid-Activated Mechanism.

Targeting the cancer cell mitochondrion is a promising approach for developing novel anticancer agents. The experimental anticancer agent N,N'-bis(3,5-dichlorophenyl)urea (SR4) induces apoptotic cell death in several cancer cell lines by uncoupling mitochondrial oxidative phosphorylation (OxPhos) using a protein-free mechanism. However, the precise mechanism by which SR4 depolarizes mitochondria is unclear because SR4 lacks an acidic functional group typically found in protein-independent uncouplers. Recently, it was shown that structurally related thioureas can facilitate proton transport across lipid bilayers by a fatty acid-activated mechanism, in which the fatty acid acts as the site of protonation/deprotonation and the thiourea acts as an anion transporter that shuttles deprotonated fatty acids across the phospholipid bilayer to enable proton leak. In this paper, we show that SR4-mediated proton transport is enhanced by the presence of free fatty acids in the lipid bilayer, indicating that SR4 uncouples mitochondria through the fatty acid-activated mechanism. This mechanistic insight was used to develop a library of substituted bisaryl ureas for structure-activity relationship studies and subsequent cell testing. It was found that lipophilic electron-withdrawing groups on bisaryl ureas enhanced electrogenic proton transport via the fatty acid-activated mechanism and had the capacity to depolarize mitochondria and reduce the viability of MDA-MB-231 breast cancer cells. The most active compound in the series reduced cell viability with greater potency than SR4 and was more effective at inhibiting adenosine triphosphate production.

FRI082 - Peripheral blood mononuclear cells mitochondrial copy number and adenosine triphosphate inhibition test in non-alcoholic fatty liver disease

FRI082 - Peripheral blood mononuclear cells mitochondrial copy number and adenosine triphosphate inhibition test in non-alcoholic fatty liver disease

The functional activity of donor kidneys is negatively regulated by microribonucleic acid-451 in different perfusion methods to inhibit adenosine triphosphate metabolism and the proliferation of HK2 cells

ABSTRACT This study explored the regulation of different perfusion methods on ischemia-reperfusion injury in donor kidneys. In this study, renal cortical/medullary tissue specimens were collected from porcine kidneys donors using different perfusion methods at various time points. Hematoxylin and eosin (H&E) staining was used to test the histological differences. Differentially expressed micro-ribonucleic acids (miRNAs) were identified by miRNA transcriptome sequencing. Reverse transcription-polymerase chain reaction (RT-PCR) tests were used to verify the changes in miRNAs in the kidney tissue taken from different perfusion groups. The related signaling pathways and the changes in the cell functions of different perfusion groups were analyzed by Kyoto Encyclopedia of Genes and Genomes (KEGG) /Gene Ontology (GO) bioinformatics analyses. The effects of miRNA overexpression on the metabolism and proliferation of HK2 cells were detected by ATP kit and MTT assay. The H&E staining results showed that there were essentially no differences in the tissue samples among different perfusion groups at and before 12 h compared with a control group. The quantitative PCR results revealed that there was essentially no change in the expression of ssc-miR-451, ssc-miR-1285, and ssc-miR-486 in the cis infusion or joint infusion kidney groups, and their expression was significantly down-regulated over time in the trans-infusion kidney group. The bioinformatics analysis showed that the cellular component, molecular function, and biological processes of the kidney tissue, which had been perfused using three methods, had been consistently affected. The most significant changes after perfusion occurred in the intracellular metabolism signaling pathways. Furthermore, the energy metabolism and proliferation of the HK2 cells were significantly inhibited after the overexpression of miR-451. Specific miRNA markers, such as miR-451, may play a negative regulatory role in cell metabolism following the perfusion of kidney transplants using different methods.

Magnetoelectric Polymer Membrane-Based Electrical Microenvironment with Magnetically Controlled Antibacterial Activity.

The "hard to clean" parts of food processing devices (e.g., the corners of pipes) are difficult to disinfect. This challenge might be overcome through the application of a positive electrical environment. However, the chemical modification of a material surface is complex and difficult. In this work, we developed a smart electroactive TbxDy1-xFe alloy/poly(vinylidene fluoride-trifluoroethylene) (TD/P(VDF-TrFE)) magnetoelectric coating to endow stainless steel with the function of a smart adjustable electrical environment, which was realized by the introduction of a magnetic field of various intensities (0-1800 Oe). An antibacterial assay showed that the polarized coating@stainless steel (P-CS) exhibited antibacterial effects, with the highest antibacterial effect observed at 1800 Oe. Furthermore, in this study, we have, for the first time, explored the antibacterial mechanism of TD/P(VDF-TrFE)-assisted electrical stimulation based on the bacterial intracellular reactive oxygen species (ROS) level, cell respiratory chain, and membrane potential. The results showed that a microelectric field was formed on the P-CS sample in an aqueous solution, which not only generated ROS on the cathode surface but also caused H+ consumption in the electrochemical gradient of the bacterial membrane, leading to OH- production and inhibition of adenosine triphosphate (ATP) synthesis. In addition, the electric field also induced hyperpolarization of the membrane potential in Escherichia coli cells via a K+ efflux, thus inducing rearrangement of the outer membrane. In conclusion, an adjustable surface potential was established through the introduction of magnetoelectric polymer coatings, which endowed stainless steel with magnetically controlled antibacterial effects.

Molecular Docking andin silicoEvaluation of Phytochemicals of Bioactive Methanolic Extract ofIpomoea mauritianaJacq. as Anti-Bacterial Agents

Antibacterial treatment has grown difficult due to the increasing growth in bacterial infections, as well as their tolerance to most first-line antibiotics. This is a severe danger to the world’s human health in the 21st century, necessitating further research to identify drugs with improved antibacterial effects and broad-spectrum functions. This study aimed to discover anti-bacterial agents through the molecular docking and in silico approach. Most responsive thirty (32) compounds on UPLC-Q-TOF/MS analysis were selected from our previous report to get the hit compound(s) against inhibition of cell wall synthesis, inhibition of protein synthesis, interference with nucleic acid synthesis, inhibition of a metabolic pathway, inhibition of membrane function and inhibition of adenosine triphosphate (ATP) synthase. From the molecular docking results, we afforded six compounds for cell wall synthesis protein, four compounds for protein synthesis protein, five for nucleic acid synthesis protein, three for metabolic pathway protein, four for membrane function protein and three for ATP synthase protein which eventually undergoes the pharmacokinetic and drug-likeness properties to obtain lead compound(s). Finally, we discovered that compounds Turpinionosides B, Polydatin, Ledebouriellol, and Pterodontoside A have the strongest binding interactions with cell wall synthesis, inhibition of protein synthesis and inhibition of metabolic pathway synthesis, interference with nucleic acid synthesis and inhibition of ATP synthase, inhibition of membrane function proteins, respectively. These compounds have the potential to become an anti-bacterial therapeutic candidate due to their promising pharmacological properties.

Multifunctional liquid metal-based nanoparticles with glycolysis and mitochondrial metabolism inhibition for tumor photothermal therapy

Tumor cells obtain energy supply from different metabolic pathways to maintain survival. In this study, a tumor acidity-responsive spherical nanoparticle (called as LMGC) was designed by attaching glucose oxidase (GOx) and mineralizing calcium carbonate on the surface of liquid metal nanoparticles to integrate the synergistic effect of adenosine triphosphate (ATP) generation inhibition and photothermal therapy (PTT) for enhanced tumor therapy. After GOx catalysis, the process of glycolysis was inhibited, and the increased H2O2 level enhanced the intratumoral oxidative stress. Besides, the gluconic acid production accelerated the degradation of LMGC and promoted Ca2+-mediated mitochondrial dysfunction. The inhibition of glycolysis and mitochondrial metabolism could significantly reduce ATP production and down-regulate heat shock protein (HSP) expression, which would reduce tumor cells heat resistance and improve PTT therapeutic effect. This liquid metal-based ATP inhibition system with enhanced therapeutic effect will find great potential for tumor treatment.

Bempedoic acid: A nonstatin drug for the management of hypercholesterolemia.

Bempedoic acid: A nonstatin drug for the management of hypercholesterolemia.

Study of the bioenergetics to identify the novel pathways as a drug target against Mycobacterium tuberculosis using Petri net

Tuberculosis is one of the life-threatening diseases globally, caused by the bacteria Mycobacterium tuberculosis. In order to control this epidemic globally, there is an urgent need to discover new drugs with novel mechanism of action that can help in shortening the duration of treatment for both drug resistant and drug sensitive tuberculosis. Mycobacterium essentially depends on oxidative phosphorylation for its growth and establishment of pathogenesis. This pathway is unique in Mycobacterium tuberculosis as compared to host due to the differences in some of the enzyme complexes carrying electron transfer. Hence, it serves as an important drug target area. The uncouplers which inhibit adenosine triphosphate synthesis, could play a vital role in serving as antimycobacterial agents and thus could help in eradicating this deadly disease. In this article, the bioenergetics of Mycobacterium tuberculosis are studied with and without uncouplers using Petri net. Petri net is among the most widely used mathematical and computational tools to model and study the complex biochemical networks. We first represented the bioenergetic pathway as a Petri net which is then validated and analyzed using invariant analysis techniques of Petri net. The valid mathematical models presented here are capable to explain the molecular mechanism of uncouplers and the processes occurring within the electron transport chain of Mycobacterium tuberculosis. The results explained the net behavior in agreement with the biological results and also suggested some possible processes and pathways to be studied as a drug target for developing antimycobacterials.

Bempedoic Acid: A New Non-statin Drug for the Treatment of Dyslipidemia.

Statins are currently the first-line drugs for managing dyslipidemia due to their substantial clinical efficacy in reducing low-density lipoprotein cholesterol (LDL-C) and the risk of atherosclerotic cardiovascular disease (ASCVD). However, many patients do not reach their LDL-C target despite taking high-dose statins and some patients are intolerant of these drugs. Therefore, an additional or alternative pharmacological intervention may be required. Bempedoic acid is a novel lipid-lowering drug recently approved for the treatment of dyslipidemia. This review describes the pharmacology of bempedoic acid and its clinical role in patients with dyslipidemia. Bempedoic acid, via its active coenzyme A (CoA) form, inhibits adenosine triphosphate (ATP)-citrate lyase, and reduces hepatic cholesterol synthesis through the mevalonate pathway. The reduction in plasma LDL-C by bempedoic acid is approximately 20%. In addition, this drug is able to lower the level of high-sensitivity C-reactive protein (hs-CRP) by 20%, which suggests anti-inflammatory activity. Bempedoic acid is well tolerated by the majority of patients. Possible common adverse drug reactions include upper respiratory tract infection, urinary tract infection and arthralgia. Serum creatinine and uric acid should be monitored since increased creatinine and hyperuricemia-associated new onset of gout and gout flares have been reported in patients taking bempedoic acid. Decreased hemoglobin levels and rare tendon ruptures have also been observed. Due to its efficacy and good safety profile, bempedoic acid might serve as a potential therapeutic alternative for the management of dyslipidemia.