Aflatoxin and Disruption of Energy Metabolism

Aflatoxins constitute a cluster of mycotoxins that are derived from fungal metabolites and are produced from diverse fungi species, especially Aspergillus. They are a collection of closely linked heterocyclic compounds produced predominantly by two filamentous fungi, Aspergillus flavus and Aspergillus parasiticus. They are also known to cause severe health threats to humans and animals, thereby resulting to several complications like immunotoxicity, teratogenicity hepatotoxicity. Aflatoxins interfere with normal metabolic processes. This interference encompasses the regulatory processes that occur throughout the progression of energy metabolism. Thus, the effects of aflatoxins are seen in the inhibition of ATP generation, carbohydrate and lipid metabolism, mitochondrial structure and proteins synthesis. This chapter will focus on the mechanisms of aflatoxin-induced disruption of lipids, carbohydrates, and proteins metabolism, and how they affect the bioenergetic systems.

Targeting Mitochondrial Oncometabolites: A New Approach to Overcome Drug Resistance in Cancer

Drug resistance is the main obstacle for a successful cancer therapy. There are many mechanisms by which cancers avoid drug-mediated death, including alterations in cellular metabolism and apoptotic programs. Mitochondria represent the cell’s powerhouse and the connection between carbohydrate, lipid and proteins metabolism, as well as crucial controllers of apoptosis, playing an important role not only in tumor growth and progression, but also in drug response. Alterations in tricarboxylic acid cycle (TCA) caused by mutations in three TCA enzymes—isocitrate dehydrogenase, succinate dehydrogenase and fumarate hydratase—lead to the accumulation of 2-hydroxyglutarate, succinate and fumarate respectively, collectively known as oncometabolites. Oncometabolites have pleiotropic effects on cancer biology. For instance, they generate a pseudohypoxic phenotype and induce epigenetic changes, two factors that may promote cancer drug resistance leading to disease progression and poor therapy outcome. This review sums up the most recent findings about the role of TCA-derived oncometabolites in cancer aggressiveness and drug resistance, highlighting possible pharmacological strategies targeting oncometabolites production in order to improve the efficacy of cancer treatment.

Tazemetostat– A Drug review

Epithelioid sarcoma affects three in 10 million people, usually teenagers and young adults. Tumours grow under the skin of the extremities or they can affect the trunk, head, or neck. It grows slowly, but can infiltrate surrounding tissues, later on, it frequently metastasis to lymph nodes. For advanced case, doxorubicin-based chemotherapy regimen is recommended. In January 2020, FDA approved the first-in-class, small molecule enhancer of zeste homolog 2 (EZH2) inhibitor, tazemetostat (Tazverik) to treat adults and paediatric patients aged 16 years and older with locally advanced or metastatic epithelioid sarcoma not suitable for complete resection. The recommended dosage is 800 mg twice daily until disease progression or unacceptable toxicity. The first-in-human study of tazemetostat was a phase 1 open-label multi-centered dose-escalation study. Tazemetostat is having an oral bioavailability of approximately 33%. Apparent volume of distribution at steady-state (Vss/F) is 1230 L (46%) with 88% bound to human plasma proteins. Metabolism takes place via CYP3A. 15% and 79% of radioactivity is excreted through urine and feces respectively. ≥20% of the adverse reactions and above was fatigue, pain, constipation, nausea, anorexia and vomiting. This article summarizes the history, chemistry, physical properties, mechanism of action, indications, and drug–drug interactions of tazemetostat and we also discuss briefly the results of various clinical trials.

Recent Progress in Mitochondria-Targeted Drug and Drug-Free Agents for Cancer Therapy

The mitochondrion is a dynamic eukaryotic organelle that controls lethal and vital functions of the cell. Being a critical center of metabolic activities and involved in many diseases, mitochondria have been attracting attention as a potential target for therapeutics, especially for cancer treatment. Structural and functional differences between healthy and cancerous mitochondria, such as membrane potential, respiratory rate, energy production pathway, and gene mutations, could be employed for the design of selective targeting systems for cancer mitochondria. A number of mitochondria-targeting compounds, including mitochondria-directed conventional drugs, mitochondrial proteins/metabolism-inhibiting agents, and mitochondria-targeted photosensitizers, have been discussed. Recently, certain drug-free approaches have been introduced as an alternative to induce selective cancer mitochondria dysfunction, such as intramitochondrial aggregation, self-assembly, and biomineralization. In this review, we discuss the recent progress in mitochondria-targeted cancer therapy from the conventional approach of drug/cytotoxic agent conjugates to advanced drug-free approaches.

Biochemical effects of Cigarettes Smoking on Liver functions of Sudanese diabetics smokers

The present study was conducted in Khartoum state (Sudan) as a cross-sectional study in 200 participants (100 smokers and 100 non-smokers), to investigate the effects of Cigarettes Smoking on Liver functions of Sudanese smokers. The smokers were categorized into either current smokers (70 participants) or past smokers (30 Participants). Parameters were analyzed by using spectrophotometer. From the results, the levels of liver function tests (TB, Albumin and globulin) were significantly higher in non-smokers (6.0, 3.6 and 2.43 g/dl) as compared to current smokers (4.4, 2.4 and 1.98 g/dl) and past smokers (4.7, 2.7 and 1.93 g/dl). Meanwhile, ALT was significantly increased in current and past smokers as compared to non-smokers, where as AST was significantly higher in current smokers as compared to non-smokers, while there was no significant difference between current and past smokers as well as between past and non-smokers for this parameter. In addition, heavy and long duration of smoking were both associated with low total protein, albumin and AST levels .Also liver function tests were not significantly differing in current smoker's non-diabetics and non-smokers diabetics except total protein. From the results when, liver enzymes raised that may lead to increase proteins metabolism and increase blood glucose. These signs may place cigarettes smoking one of the top causes of hepatitis, pancreatitis, insulin resistance and finally diabetes mellitus type II. On the other hand, smoking cessation in diabetics lead to decrease the risk of hepatitis, Also regular physical activity and using medication regularly in diabetics lead to the same actions above; in addition diabetes complications were decreased.

Genomewide Expression and Functional Interactions of Genes under Drought Stress in Maize

A genomewide transcriptome assay of two subtropical genotypes of maize was used to observe the expression of genes at seedling stage of drought stress. The number of genes expressed differentially was greater in HKI1532 (a drought tolerant genotype) than in PC3 (a drought sensitive genotype), indicating primary differences at the transcriptional level in stress tolerance. The global coexpression networks of the two genotypes differed significantly with respect to the number of modules and the coexpression pattern within the modules. A total of 174 drought-responsive genes were selected from HKI1532, and their coexpression network revealed key correlations between different adaptive pathways, each cluster of the network representing a specific biological function. Transcription factors related to ABA-dependent stomatal closure, signalling, and phosphoprotein cascades work in concert to compensate for reduced photosynthesis. Under stress, water balance was maintained by coexpression of the genes involved in osmotic adjustments and transporter proteins. Metabolism was maintained by the coexpression of genes involved in cell wall modification and protein and lipid metabolism. The interaction of genes involved in crucial biological functions during stress was identified and the results will be useful in targeting important gene interactions to understand drought tolerance in greater detail.

Metabolic frailty in malnourished heart failure patients

Muscular wasting (MW) and cardiac cachexia (CC) are often present in patients with chronic heart failure (HF). Aim: To identify whether MW and CC are due to malnutrition or impairment of protein metabolism in HF patients. Material and Method: In 78 clinically stable HF patients (NYHA class II-III), aged from 32 to 89 years, we measured anthropometrical parameters and nutritional habits. In the identified 35 malnourished patients, we also measured: insulin resistance, gluconeogenetic amino acids blood concentration and nitrogen balance. Results: Seventy-five patients had eating-related symptoms. However we found significant nutritional impairment in 35 patients only. In addition, these 35 patients had: 1) significant increase of blood Alanine independently from both presence of insulin resistance or food intake reduction and 2) positive nitrogen balance. Conclusion: Food intake is not impaired in CHF patients. In spite of normal food intake, 35 of 78 patients had nutritional impairment with reduced anthropometric parameters and increased blood Alanine. These findings show alteration of proteins metabolism with proteolysis. We believe that specific physical training with nutritional supplement can be an additional therapy able to prevent protein disarrangement in CHF patients.

Pathogenesis, modulation, and therapy of Alzheimer’s disease: A perspective on roles of liver-X receptors

The pathogenesis of Alzheimer’s disease (AD) has been mostly linked to aberrant amyloid beta (Aβ) and tau proteins metabolism, disturbed lipid/cholesterol homeostasis, and progressive neuroinflammation. Liver X receptors (LXR) are ligand-activated transcription factors, best known as the key regulators of cholesterol metabolism and transport. In addition, LXR signaling has been shown to have significant anti-inflammatory properties. In this brief review, we focus on the outcome of studies implicating LXR in the pathogenesis, modulation, and therapy of AD.