Drug Biotransformation Research Articles

How Antiretroviral Drug Concentrations Could Be Affected by Oxidative Stress, Physical Capacities and Genetics: A Focus on Dolutegravir Treated Male PLWH

High levels of reactive oxygen species (ROS) are present in people living with HIV (PLWH), produced by intense physical activity; in response, our body produces antioxidant molecules. ROS influence the expression of gene-encoding enzymes and transporters involved in drug biotransformation. In addition, pharmacogenetics can influence transporter activity, and thus drug exposure. Currently, no studies concerning this topic are present in the literature. The aim of this study was to investigate whether some antioxidant molecules, physical exercise, and genetic variants could affect dolutegravir (DTG) concentrations in PLWH, switching from triple to dual therapy. Thirty PLWH were recruited and analyzed at baseline (triple therapy), and 6 months after (dual therapy). Physical capacities were investigated using validated tools. Drug concentrations and oxidative stress biomarkers levels were evaluated through liquid chromatography coupled with tandem mass spectrometry, while genetic variants through real-time PCR. No statistical differences were suggested for drug concentrations, with the exception of intracellular DTG (p = 0.047). Statistically significant correlations between DTG plasma concentrations and white blood cells (p = 0.011; S = 0.480) and cytoplasmic N-acetyl-cysteine (p = 0.033; S = −0.419) were observed. Finally, white blood cells and BMI remained in the final multivariate regression model as predictors of DTG concentrations. This is the first study showing possible factors related to oxidative stress impacting DTG exposure.

Effects of CYP3A4 Variants on Methadone Metabolism InVitro.

In hepatic drug metabolism, cytochrome P450 (CYP450) enzymes, particularly CYP3A4, catalyze the majority of drug biotransformations, accounting for over 50% of the CYP450 family's metabolic capacity. This study aimed to assess the catalytic efficiency of 22 CYP3A4 allelic variants on the invitro oxidative metabolism of methadone. We utilized a baculovirus-insect cell expression system to produce recombinant CYP3A4 variants and subsequently assessed their catalytic activity in the N-demethylation of methadone. Of the 23 tested CYP3A4 allelic variants, CYP3A4*1 represents the wild type. Compared with CYP3A4*1, 12 variants displayed significantly lower intrinsic clearance of methadone, while 3 variants showed increased intrinsic clearance of methadone. Additionally, six variants demonstrated no significant difference in intrinsic clearance of methadone compared to CYP3A4*1, and one variant showed no detectable expression. Our evaluation of the enzymatic activity of CYP3A4 gene polymorphisms on methadone can aid in the personalized clinical use of methadone and facilitate the investigation into the relationship between genetic variations and clinical phenotypes.

The role of biotransformation and chemical structure of drugs in the diagnosis of drug allergies

The role of biotransformation and chemical structure of drugs in the diagnosis of drug allergies

Influence of pharmacotherapy on function of biotransformation of xenobiotics liver in patients with neuropsychiatric disorders

BACKGROUND: The mechanisms of drug interactions of psychotropic drugs are associated with the processes of drug biotransformation by enzymes of microsomal oxidation of cytochrome P-450 in the liver. Various drugs can increase or decrease the activity of enzymes of the cytochrome P450-dependent system. AIM: To evaluate the effect of pharmacotherapy with psychotropic drugs: alprazolam, bromazepam, lithium carbonate on the metabolic rate of the model substrate antipyrine in saliva in patients with neuropsychiatric disorders; the effect of the enzyme-inducing activity of the original anticonvulsant 1-[(3-chlorophenyl)(phenyl)methyl]urea on the pharmacokinetic parameters of antipyrine in healthy volunteers. MATERIALS AND METHODS: 34 male patients were divided into three groups according to the nosological forms of diseases according to ICD-10: Group 1 — heading F43.23 and F43.25; 2 — F06.61; 3 — F41.2. Patients in the group 1 were prescribed alprazolam, in the 2 — bromazepam, in the 3 — lithium carbonate, for a course of 21 days. The comparison group consisted of 10 healthy volunteers. The original anticonvulsant was prescribed to the volunteers. Determination of the pharmacokinetics of antipyrine parameters as a test witness of the processes of elimination from the body was carried out in saliva before and after the end of therapy at a dose of 10 mg/kg once. RESULTS: Alprazolam administration by patients of group 1 at a dose of 0.5–1.5 mg/day for 21 days did not significantly affect the pharmacokinetic parameters of antipyrine: T1/2, Clt, AUC. Alprazolam did not change the elimination of antipyrine from the saliva of patients. In patients of the group2, who received bromazepam at a dose of 6–12 mg / day,a background decrease in T1/2, an increase in Clt, a decrease in AUC due to concomitant therapy were noted. Comparison of the pharmacokinetic parameters of antipyrine under the influence of bromazepam with background values not reveal significant differences. Therapy with lithium carbonate at a dose of 500–1000 mg/day in patients of the group 3 did not change the parameters of antipyrine elimination. The obtained data indicate that the drugs do not affect the activity of liver microsomal oxidation in patients. The study of the effect of 1-[(3-chlorophenyl)(phenyl)methyl]urea on the pharmacokinetic parameters of antipyrine in volunteers revealed a diametrically opposite result: a significant decrease in T1/2 by 2 times, an increase in Clt and a decrease in AUC, which indicates accelerated elimination of antipyrine from the saliva of the subjects and indicates the induction of liver microsomal oxidation. CONCLUSIONS: Pharmacotherapy using the studied psychotropic drugs in patients is not associated with the induction or inhibition of liver enzymes, which indicates the absence of drug pharmacokinetic interference. The original anticonvulsant 1-[(3-chlorophenyl)(phenyl)methyl]urea stimulated the induction of liver microsomal oxidation in volunteers.

Liver CYP4A autophagic-lysosomal degradation (ALD): A major role for the autophagic receptor SQSTM1/p62 through an uncommon target interaction site.

The hepatic P450 hemoproteins CYPs 4A are typical N-terminally anchored Type I endoplasmic reticulum (ER)-proteins, that are inducible by hypolipidemic drugs and other "peroxisome proliferators". They are engaged in the ω-/ω-1-oxidation of various fatty acids including arachidonic acid, prostaglandins and leukotrienes and in the biotransformation of some therapeutic drugs. Herein we report that of the mammalian liver CYPs 4A, human CYP4A11 and mouse Cyp4a12a are preferential targets of the ER-lysosome-associated degradation (ERLAD). Consequently, these proteins are stabilized both as 1%Triton X100-soluble and -insoluble species in mouse hepatocytes and HepG2-cells deficient in the autophagic initiation ATG5-gene. Although these proteins exhibit surface LC3-interacting regions (LIRs) that would target them directly to the autophagosome, they nevertheless interact intimately with the autophagic receptor SQSTM1/p62. Through structural deletion analyses and site-directed mutagenesis, we have identified the Cyp4A-interacting p62 subdomain to lie between residues 170 and 233, which include its Traf6-binding and LIM-binding subdomains. Mice carrying a liver-specific genetic deletion of p62 residues 69-251 (p62Mut) that includes the CYP4A-interacting subdomain also exhibit Cyp4a-protein stabilization both as Triton X100-soluble and -insoluble species. Consistently, p62Mut mouse liver microsomes exhibit enhanced ω- and ω-1-hydroxylation of arachidonic acid to its physiologically active metabolites 19- and 20-HETEs relative to the corresponding wild-type mouse liver microsomes. Collectively, our findings suggest that any disruption of CYP4A ERLAD results in functionally active P450 protein and consequent production of proinflammatory metabolites on one hand, and insoluble aggregates on the other, which may contribute to pathological aggregates i.e. Mallory-Denk bodies/inclusions, hallmarks of many liver diseases.

Systemic messenger RNA replacement therapy is effective in a novel clinically relevant model of acute intermittent porphyria developed in non-human primates

ObjectiveAcute intermittent porphyria (AIP) is a rare metabolic disorder caused by haploinsufficiency of hepatic porphobilinogen deaminase (PBGD), the third enzyme of the heme biosynthesis. Individuals with AIP experience neurovisceral attacks...

Emergence of community behaviors in the gut microbiota upon drug treatment

Pharmaceuticals can directly inhibit the growth of gut bacteria, but the degree to which such interactions manifest in complex community settings is an open question. Here, we compared the effects of 30 drugs on a 32-species synthetic community with their effects on each community member in isolation. While most individual drug-species interactions remained the same in the community context, communal behaviors emerged in 26% of all tested cases. Cross-protection during which drug-sensitive species were protected in community was 6 times more frequent than cross-sensitization, the converse phenomenon. Cross-protection decreased and cross-sensitization increased at higher drug concentrations, suggesting that the resilience of microbial communities can collapse when perturbations get stronger. By metabolically profiling drug-treated communities, we showed that both drug biotransformation and bioaccumulation contribute mechanistically to communal protection. As a proof of principle, we molecularly dissected a prominent case: species expressing specific nitroreductases degraded niclosamide, thereby protecting both themselves and sensitive community members.

Advanced Liver-on-a-Chip Model for Evaluating Drug Metabolism and Hepatotoxicity.

The liver has many important functions, including the biotransformation of drugs and detoxification of the human organism. As such, it is also exposed to many harmful substances, which leads to disorders and diseases such as cirrhosis. For these reasons, it seems important to consider liver metabolism and the direct effects on the liver when evaluating the efficacy of new drugs. Accordingly, we have developed an advanced in vitro liver model using an organ-on-a-chip approach that replicates many of the morphological and functional features of the liver in vivo. The model we created can metabolize drugs, which we demonstrated using two widely used anticancer drugs, 5-fluorouracil (5FU) and capecitabine (CAP). In addition, to the best of our knowledge, we are the first who evaluate the direct effects of these drugs not only on the viability of liver model-building cells but on their functions, such as cytochrome P450 activity and albumin production. Our study brings new hope to properly evaluating drug efficacy at the in vitro level.

Concentration-dependent effects of the nerve agents cyclosarin and VX on cytochrome P450 in a HepaRG cell-based liver model.

The exposure to highly toxic organophosphorus (OP) compounds, including pesticides and nerve agents, is an ongoing medical challenge. OP can induce the uncontrolled overstimulation of the cholinergic system through inhibition of the enzyme acetylcholinesterase (AChE). The cytochrome P450 (CYP) enzymes in the liver play a predominant role in the metabolism of xenobiotics and are involved in the oxidative biotransformation of most clinical drugs. Previous research concerning the interactions between OP and CYP has usually focused on organothiophosphate pesticides that require CYP-mediated bioactivation to their active oxon metabolites to act as inhibitors of AChE. Since there has been little data available concerning the effect of nerve agents on CYP, we performed a study with cyclosarin (GF) and O-ethyl-S-[2-(diisopropylamino)-ethyl]-methylphosphonothioate (VX) by using a well-established, metabolically competent in vitro liver model (HepaRG cells). The inhibitory effect of the nerve agents GF and VX on the CYP3A4 enzyme was investigated showing a low CYP3A4 inhibitory potency. Changes on the transcription level of CYP and associated oxygenases were evaluated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) using the two nerve agent concentrations 250 nM and 250 μM. In conclusion, the results demonstrated various effects on oxygenase-associated genes in dependence of the concentration and the structure of the nerve agent. Such information might be of relevance for potential interactions between nerve agents, antidotes or other clinically administered drugs, which are metabolized by the affected CYP, for example, for the therapy with benzodiazepines, that are used for the symptomatic treatment of OP poisoning and that require CYP-mediated biotransformation.

Biotransformation of rifampicin by Aspergillus niger and antimicrobial activity of proposed metabolites.

Drug biotransformation studies emerges as an alternative to pharmacological investigations of metabolites, development of new drug candidates with reduced investment and most efficient production. The present study aims to evaluate the capacity of biotransformation of rifampicin by the filamentous fungus Aspergillus niger ATCC 9029. After incubation for 312 h, the drug was metabolized to two molecules: an isomer (m/z 455) and the rifampicin quinone (m/z 821). The monitoring of metabolite formation was performed by high-performance liquid chromatography, followed by their identification through ultra-high-performance liquid chromatography coupled to tandem mass spectrometer. In vitro antimicrobial activity of the proposed metabolites was evaluated against Staphylococus aureus microorganism, resulting in the loss of inhibitory activity when compared with the standards, with minimum inhibitory concentration of 7.5μg/ml. The significant biotransformation power of the ATCC 9029 strain of A. niger was confirmed in this study, making this strain a candidate for pilot studies in fermentation tanks for the enzymatic metabolization of the antimicrobial rifampicin. The unprecedented result allows us to conclude that the prospect of new biotransforming strains in species of anemophilic fungi is a promising choice.

Miniaturized Extraction Techniques in Drug Biotransformation Studies by using Endophytic Fungi Cunninghamella elegans

In addition to predicting biotransformation in humans, drug biotransformation studies are important because they can generate active metabolites or new intermediates with possible use by the pharmaceutical industry. Endophytic fungi of the genus Cunninghamella can metabolize many drugs in a similar way to humans. The analysis of these metabolites requires prior treatment of the samples in order to obtain compatibility with the detection system and the separation technique. This work aimed to study the biotransformation of the drugs duloxetine (DLX), citalopram (CIT) and amlodipine (ANL) by endophytic fungi Cunninghamella elegans ATCC 9245, the development of micro extraction methods in the context of green chemistry, and the validation of the analytical methods for drugs and their respective metabolites. Bioanalytical method by HPLC was successfully developed and validated for both drugs (DLX, CIT and ANL). The metabolites of DLX and CIT obtained by biotransformation studies were not detected in the conditions of this study, but it was possible to visualize one additional peak in the chromatogram analysis of ANL indicate that this drug has been metabolized by Cunninghamella elegans. Furthermore, it has been developed two liquid-liquid micro extraction methods achieving success by removing drugs in both techniques, with recovery greater than 90%. The use of Quality by Design (QbD) through the experimental design provided the best conditions for carrying out biotransformation and micro extraction studies of drugs from the fungal matrix.

Alternative therapeutics to control antimicrobial resistance: a general perspective

Antimicrobial Resistance (AMR) is a critical global health challenge, and in this review article, we examine the limitations of traditional therapeutic methods and the emerging role of alternative therapies. By examining the reasons behind the failure of conventional treatments, including the inadequacy of one-drug-one-enzyme approaches, the complex evolution of AMR, and the impact of drug biotransformation, we better understand why conventional treatments failed. Moreover, the review discusses several alternative therapies, including RNA-based treatments, aptamers, peptide-based therapies, phage therapy, and probiotics, discussing their applications, advantages, and limitations. Additionally, we discuss the obstacles to develop these therapies, including funding shortages, regulatory barriers, and public perception. This comprehensive analysis aims to provide insight into the future of AMR, emphasizing the need for innovative strategies and practical approaches.

Phylogenetic and transcriptomic study of aldo-keto reductases in Haemonchus contortus and their inducibility by flubendazole

Aldo-keto reductases (AKRs), a superfamily of NADP(H)-dependent oxidoreductases, catalyze the oxidoreduction of a wide variety of eobiotic and xenobiotic aldehydes and ketones. In mammals, AKRs play essential roles in hormone and xenobiotic metabolism, oxidative stress, and drug resistance, but little is known about these enzymes in the parasitic nematode Haemonchus contortus. In the present study, 22 AKR genes existing in the H. contortus genome were investigated and a phylogenetic analysis with comparison to AKRs in Caenorhabditis elegans, sheep and humans was conducted. The constitutive transcription levels of all AKRs were measured in eggs, larvae, and adults of H. contortus, and their expression was compared in a drug-sensitive strain (ISE) and a benzimidazole-resistant strain (IRE) previously derived from the sensitive strain by imposing benzimidazole selection pressure. In addition, the inducibility of AKRs by exposure of H. contortus adults to benzimidazole anthelmintic flubendazole in vitro was tested. Phylogenetic analysis demonstrated that the majority of AKR genes in H. contortus lack orthologues in the sheep genome, which is a favorable finding for considering AKRs as potential drug targets. Large differences in the expression levels of individual AKRs were observed, with AKR1, AKR3, AKR8, and AKR10 being the most highly expressed at most developmental stages. Significant changes in the expression of AKRs during the life cycle and pronounced sex differences were found. Comparing the IRE and ISE strains, three AKRs were upregulated, and seven AKRs were downregulated in adults. In addition, the expression of three AKRs was induced by flubendazole exposure in adults of the ISE strain. Based on these results, AKR1, AKR2, AKR3, AKR5, AKR10 and AKR19 in particular merit further investigation and functional characterization with respect to their potential involvement in drug biotransformation and anthelmintic resistance in H. contortus.

A review on drug interaction

Drug interaction occur when the response of one drug is altered by the simultaneous or closely time administration of another drug. Polypharmacy involving the simultaneous use of multiple drugs, raise concern due to unpredictable and potential severe internation. While some drug interactions are intentionally utilized in therapeutics strategies, their severity can vary making prediction challenging. Prescribing multiple medications increases the risk of drug interactions, which can occur with other drugs, foods, beverages, and herbs, both inside and outside the body. Understanding in vitro interactions is crucial to prevent drug activity loss before administration. While not all theoretical drug interactions may occur in practice, they remain a significant cause of adverse events associated with drug administration. Drug-drug interactions (DDIs) represent a significant source of medication errors in developed nations, especially among the elderly who often take multiple medications simultaneously, leading to a prevalence of 20-40%. The complexity of managing therapy increases with poly-therapy, elevating the risk of clinically significant DDIs that can either trigger adverse drug reactions or diminish clinical efficacy. DDIs are typically categorized into two groups: pharmacokinetic and pharmacodynamic. In vivo interactions at pharmacokinetic level affect absorption, distribution, biotransformation or excretion of drugs. Induction or inhibition of cytochrome P450 (CYP450) enzymes forms a major basis of drug interactions. Induction of metabolism of a substrate drug leads to treatment failure.

Central Nervous System Medications: Pharmacokinetic and Pharmacodynamic Considerations for Older Adults.

Most drugs have not been evaluated in the older population. Recognizing physiological alterations associated with changes in drug disposition and with the ultimate effect, especially in central nervous system-acting drugs, is fundamental. While considering pharmacokinetics, it should be noted that the absorption of most drugs from the gastrointestinal tract does not change in advanced age. There are only few data about the effect of age on the transdermal absorption of medications such as fentanyl. Absorption from an intramuscular injection may be similar in older adults as in younger patients. The distribution of lipophilic drugs (such as diazepam) is increased owing to a relative increase in the percentage of body fat, causing drug accumulation and prolonged drug elimination following cessation. Phase I drug biotransformation is variably decreased in aging, impacting elimination, and hepatic drug clearance has been shown to decrease in older individuals by 10-40% for most drugs studied. Lower doses of phenothiazines, butyrophenones, atypical antipsychotics, antidepressants (citalopram, mirtazapine, and tricyclic antidepressants), and benzodiazepines (such as diazepam) achieve the same extent of exposure. For renally cleared drugs with no prior metabolism (such as gabapentin), the glomerular filtration rate appropriately estimates drug clearance. Important pharmacodynamic changes in older adults include an increased sedative effect of benzodiazepines at a given drug exposure, and a higher sensitivity to mu opiate receptor agonists and to opioid adverse effects. Artificial intelligence, physiologically based pharmacokinetic modeling and simulation, and concentration-effect modeling enabling a differentiation between the pharmacokinetic and the pharmacodynamic effects of aging might help to close some of the gaps in knowledge.

Multiple UDP glycosyltransferases modulate benzimidazole drug sensitivity in the nematode Caenorhabditis elegans in an additive manner

Xenobiotic biotransformation is an important modulator of anthelmintic drug potency and a potential mechanism of anthelmintic resistance. Both the free-living nematode Caenorhabditis elegans and the ruminant parasite Haemonchus contortus biotransform benzimidazole drugs by glucose conjugation, likely catalysed by UDP-glycosyltransferase (UGT) enzymes. To identify C. elegans genes involved in benzimidazole drug detoxification, we first used a comparative phylogenetic analysis of UGTs from humans, C. elegans and H. contortus, combined with available RNAseq datasets to identify which of the 63 C. elegans ugt genes are most likely to be involved in benzimidazole drug biotransformation. RNA interference knockdown of 15 prioritized C. elegans genes identified those that sensitized animals to the benzimidazole derivative albendazole (ABZ). Genetic mutations subsequently revealed that loss of ugt-9 and ugt-11 had the strongest effects. The “ugt-9 cluster” includes these genes, together with six other closely related ugts. A CRISPR-Cas-9 deletion that removed seven of the eight ugt-9 cluster genes had greater ABZ sensitivity than the single largest-effect mutation. Furthermore, a double mutant of ugt-22 (which is not a member of the ugt-9 cluster) with the ugt-9 cluster deletion further increased ABZ sensitivity. This additivity of mutant phenotypes suggest that ugt genes act in parallel, which could have several, not mutually exclusive, explanations. ugt mutations have different effects with different benzimidazole derivatives, suggesting that enzymes with different specificities could together more efficiently detoxify drugs. Expression patterns of ugt-9, ugt-11 and ugt-22 gfp reporters differ and so likely act in different tissues which may, at least in part, explain their additive effects on drug potency. Overexpression of ugt-9 alone was sufficient to confer partial ABZ resistance, indicating increasing total UGT activity protects animals. In summary, our results suggest that the multiple UGT enzymes have overlapping but not completely redundant functions in benzimidazole drug detoxification and may represent “druggable” targets to improve benzimidazole drug potency.

Acute exposure and biomarkers assessment in rainbow trout exposed to selected pharmaceuticals

Pharmaceuticals released from municipal effluents discharges pose a risk to aquatic organisms. The toxicity of 5 pharmaceuticals with distinct therapeutic actions were assessed in rainbow trout: olanzapine (antipsychotic), erythromycin (antibiotic), mycophenoate (immunosuppression), pinaverium (anti-inflammatory) and trazodone (sedative). Juveniles were exposed to these drugs for 96 h at concentrations between 64 µg/L up to 40 mg/L to reach lethality. Survival was determined and a suite of biomarkers was analyzed for drug biotransformation, oxidative stress/damage and metabolic activity at sublethal concentrations. The data revealed the following toxicity: olanzapine >trazodone>mycophenolate>pinaverium∼erythromycin based on mortality. The data also revealed that toxicity was associated to mass, pKa and hydrophobicity and the following sublethal effects: GST, LPO and DNA strand breaks. Pharmaceuticals with lower molecular weight, physiological pKa, moderate hydrophobicity, low biotransformation and DNA strand breaks were generally more toxic to fish. However, this should be considered as a general guide in identifying toxic pharmaceuticals in non-target organisms.

Роль полиморфных вариантов генов цитохромов Р450, а также генов GSTP1 и MDR1 в развитии токсических осложнений при проведении программной противоопухолевой лекарственной терапии у пациентов с классической лимфомой Ходжкина

Background. Although considerable progress has been achieved in the treatment of classical Hodgkin lymphoma (cHL), toxic complications of program drug chemotherapy remain an issue. Standard cytostatic agents used in cHL therapy are metabolized in liver by the enzymes with Р450 cytochrome and GSTP1 gene-controlled synthesis. At the same time, the excretion of active metabolites of antitumor drugs is mediated by MDR1 coded P-glycoprotein. Polymorphisms[1] of these genes may change the processes of antitumor drug biotransformation and their metabolite excretion. Additionally, they may result in organo-toxic complications, disablement of patients, and even death.
 Aim. To assess the role of polymorphisms in cytochrome genes Р450 as well as genes GSTP1 and MDR1 in organ toxicity dynamics during program chemotherapy (CT) in cHL patients.
 Materials & Methods. The study enrolled 122 cHL patients treated with first-line regimens (ABVD, BEACOPP) of program drug chemotherapy. The patients were aged 18–78 years (median 35 years); there were 67 (54.9 %) women and 55 (45.1 %) men. In compliance with the NCCN CTC (2003) criteria of hepatotoxicity and practical recommendations for correcting cardiovascular toxicity of chemotherapy (2021), the signs of toxic liver and heart damage were assessed in all patients. PCR was used to analyze polymorphisms in cytochrome genes Р450 as well as genes GSTP1 and MDR1, their association with toxic complications of CT was analyzed.
 Results. Drug-induced liver damage on program CT was identified in 80 % of cHL patients. The toxicity was increasing from CT cycle 1 to cycle 6 both on ABVD and BEACOPP. Complications grade 3/4 were observed only in BEACOPP recipients. Significant (p < 0.05) associations were found between hepatotoxic complications with increased cytolytic (AST, ALT) and cholestatic (ALP) values and polymorphic variants of MDR1. Significant (p < 0.05) reduction of left ventricle myocardium contractility in cHL patients was associated with Т-allele presence in genotypes CYP2D6*10 (rs1065852), CYP2C9*2 (rs1799853) and A-allele deletion in genotype CYP2D6_3 (rs4986774).
 Conclusion. The identification of genetic predictors for toxic effects of program CT in cHL patients at the baseline examination can minimize the risks of drug chemotherapy-related adverse events and allow these patients to maintain a satisfactory quality of life.
 
 [1] Gene polymorphism is a structural difference between alternative variants of a gene. Alternative variants of genes result from mutations.

Targeting nicotinamide N-methyltransferase decreased aggressiveness of osteosarcoma cells.

Osteosarcoma (OS) is a primary bone malignancy that mostly affects young people, characterized by high metastatic potential, and a marked chemoresistance that is responsible for disease relapse in most patients. Therefore, it is necessary to identify novel molecules to setup targeted strategies to improve the clinical outcome. The enzyme nicotinamide N-methyltransferase (NNMT) catalyses the N-methylation of nicotinamide and other analogs, playing a crucial role in the biotransformation of drugs and xenobiotics. NNMT overexpression was reported in a wide variety of cancers, and several studies demonstrated that is able to promote cell proliferation, migration and resistance to chemotherapy. The aim of this study was to explore the potential involvement of NNMT in OS. Immunohistochemical analyses have been performed to evaluate NNMT expression in selected OS and healthy bone tissue samples. Subsequently, OS cell lines have been transfected with vectors targeting NNMT mRNA (shRNAs) and the impact of this downregulation on migration, cell proliferation, and response to chemotherapeutic treatment was also analysed by wound healing, MTT, SRB and Trypan blue assays, respectively. Results showed that OS samples display a significantly higher NNMT expression compared with healthy tissue. Preliminary results suggest that NNMT silencing in OS cell lines is associated to a decrease of cell proliferation and migration, as well as to enhanced sensitivity to chemotherapy. Data obtained showed that NNMT may represent an interesting marker for OS detection and a promising target for effective anti-cancer therapy.

Metabolic Rewiring of Mycobacterium tuberculosis upon Drug Treatment and Antibiotics Resistance.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a significant global health challenge, further compounded by the issue of antimicrobial resistance (AMR). AMR is a result of several system-level molecular rearrangements enabling bacteria to evolve with better survival capacities: metabolic rewiring is one of them. In this review, we present a detailed analysis of the metabolic rewiring of Mtb in response to anti-TB drugs and elucidate the dynamic mechanisms of bacterial metabolism contributing to drug efficacy and resistance. We have discussed the current state of AMR, its role in the prevalence of the disease, and the limitations of current anti-TB drug regimens. Further, the concept of metabolic rewiring is defined, underscoring its relevance in understanding drug resistance and the biotransformation of drugs by Mtb. The review proceeds to discuss the metabolic adaptations of Mtb to drug treatment, and the pleiotropic effects of anti-TB drugs on Mtb metabolism. Next, the association between metabolic changes and antimycobacterial resistance, including intrinsic and acquired drug resistance, is discussed. The review concludes by summarizing the challenges of anti-TB treatment from a metabolic viewpoint, justifying the need for this discussion in the context of novel drug discovery, repositioning, and repurposing to control AMR in TB.