Uncovering novel therapeutic targets in glucose, nucleotides and lipids metabolism during cancer and neurological diseases

Abstract

Background

Cell metabolism functions without a stop in normal and pathological cells. Different metabolic changes occur in the disease. Cell metabolism influences biochemical and metabolic processes, signaling pathways, and gene regulation. Knowledge regarding disease metabolism is limited.

Objective

The review examines the cell metabolism of glucose, nucleotides, and lipids during homeostatic and pathological conditions of neurotoxicity, neuroimmunological disease, Parkinson’s disease, thymoma in myasthenia gravis, and colorectal cancer.

Methods

Data collection includes electronic databases, the National Center for Biotechnology Information, and Google Scholar, with several inclusion criteria: cell metabolism, glucose metabolism, nucleotide metabolism, and lipid metabolism in health and disease patients suffering from neurotoxicity, neuroinflammation, Parkinson’s disease, thymoma in myasthenia gravis. The initial number of collected and analyzed papers is 250. The final analysis included 150 studies out of 94 selected papers. After the selection process, 62.67% remains useful.

Results and Conclusion

A literature search shows that signaling molecules are involved in metabolic changes in cells. Differences between cancer and neuroimmunological diseases are present in the result section. Our finding enables insight into novel therapeutic targets and the development of scientific approaches for cancer and neurological disease onset, outcome, progression, and treatment, highlighting the importance of metabolic dysregulation. Current understanding, emerging research technologies and potential therapeutic interventions in metabolic programming is disucussed and highlighted.

Background

The pathogenesis of neurodegenerative diseases related to disturbed metabolism is not clearly defined, although signalling molecules and pathways involved in the onset and progression of the disease are known. ¹ Metabolic reprogramming is a clear indicator of neurological disorders, so it is significant to be familiar with aetiology, altered cellular metabolism, genetics, metabolism, tumour environment and microbiome to achieve appropriate detection and treatment of the disease.^2,3 Association between the metabolic pathways of cellular pro-inflammatory and anti-inflammatory activity like glycolytic, oxidative, and lipid metabolism is beneficial or detrimental in various neurological conditions and potential therapy. ⁴ There is a connection between neuroinflammation and neurodegenerative diseases depending on leucocytes, aerobic glycolysis, macrophage dendritic cells, neutrophils, NK cells as a part of innate immunity and B lymphocytes as a part of adaptive immunity, cytokinin production, microglia and astrocytes.^4,5 Different diseases have distinct reasons for disease development, like mitochondrial function (PD), leucocytes (stroke), glycolytic metabolism (MS), Treg survival and Th17 suppression (experimental autoimmune encephalomyelitis).^6,7 The main characteristic of cancer is a disturbed glycolytic metabolism and a decrease in the pH of the microenvironment, which is associated with a worse prognosis and outcome of the disease. The plasticity of the energy mechanism in colorectal cancer cells assesses initiation, progression, tumour growth, metastasis and therapy. ⁸

Globally the incidence of cancer in 2020 year was 18.094.716 million cases. ⁹ The rate is higher in men, compared to women, 206.9 and 178.1 per 100.000 people. ⁹ In 2019, the incidence of neurological diseases was 7.5 million, among which 3.5 million in men and 3.9 million in women. Countries with the highest level of disease that are age-dependent (in a year per 100.000) are the United States of America, Uruguay, Canada, Suriname, Haiti, Cuba and Saint Lucia, making it 740 people with disability per 100.000 population. ¹⁰ In different percentages, people suffer from neuroimmunological disease, cancer, Myasthenia gravis, thymoma, neurotoxicity, and Parkinson’s disease in the population. This percentage will rise from 13.5 million in 2000 to 21.2 million in 2025 and 36.7 million in 2050. ¹¹ Lifestyle factors can contribute to the population’s rise in disease percentage. Age is one factor, as older individuals may be more susceptible to certain conditions. Lifestyle choices such as diet and physical activity can also play a role, as can water intake and social and cultural aspects.^11,12 It’s significant to take a holistic approach to health and consider all these factors to prevent or manage the disease.

The impact of disease treatment and interventions are discussed in diverse publications by country, disease, company and treatment regime that can be extended across multiple diseases.^13,14 Cancer treatment in the long term can develop long-term side effects, problems from surgery, increasing infections, physical and emotional stress, poor rehabilitation, swelling pain, problems with organs and system organs, causing problems with the heart, lungs, endocrine system, hormones, infertility, nervous and digestive system. ¹⁵ Neurological conditions remain a low priority for most countries despite health, social and economic consequences. ¹⁶ In 2020, the total cost of neurological disorders in Europe was $1.06tn, equivalent to the cost of heart diseases, cancer and diabetes combined.^17,18 Current challenges in disease treatment include hospitalization costs in patients with multiple comorbidities, insufficient awareness of relevant research evidence, medications, lack of personalized therapy, patients’ persistence of prescribed remedial treatment, improving clinical decision making and increasing complexity of information and communication technology systems. ¹⁹ Moreover, Informational technologies encounter difficulties defining ownership, the appliance of language, and implementing a new system into the old since systems are usually limited to one specific disease. ²⁰

The review provides the role of disturbed metabolism in neurodegenerative diseases and cancer. It emphasizes the importance of understanding the altered cellular metabolism, genetics, tumour environment and microbiome in disease detection and treatment. The paper provides a comprehensive overview of disease metabolism and potential therapeutic strategies. Include background information about prevalence, impact and current challenges in disease treatment. The review enables in-depth interpretation and analysis of research findings and compares them with existing scientific literature. The paper contains clear and logical organization, dividing the content into sections to make it easier for the reader to have a clear focus. The focus was to clearly outline the primary research question with a comprehensive review of the current understanding of cell metabolism in cancer and neurological diseases, emphasizing the gaps in knowledge, uncovering novel therapeutic targets in glucose, nucleotides and lipids metabolism, and revealing metabolic pathways leading to disease initiation and progression. Dysregulated metabolism of glucose, nucleotides, and lipids are cancer and neurological disease hallmarks, offering potential targets for intervention. However, the knowledge of specific alterations driving changes in initiation, progression, disease outcome, and therapeutic implications remains under investigation. The methodology is present in the literature with sample size, data collection methods and statistical analysis that enhance the reproducibility and scientific rigour of the study. Figures created by the author with instructions and legends are present. A comprehensive conclusion summaries the findings and their implications. Metabolic reprogramming is a disease hallmark, enabling cells to adapt to adapt to changing micro-environment. Disrupted lipid signaling, dysregulated glucose metabolis and altered nucleotide synthesis contribute to disease progression and therapeutic resistance. The purpose of the review was to unravel therapeutic targets in glucose, nucleotides and lipid metabolism during homeostasis and pathological conditions like neurotoxicity, neuroimmunological disease, Parkinson’s disease, thymoma in myasthenia gravis, and colorectal cancer and identify novel therapeutic targets for intervention.

Main text

Mehtods

Literature collection with database National Center for Biotechnology Information (NCBI) and Google Scholar contains several inclusion criteria: cell metabolism, glucose metabolism, nucleotide metabolism, and lipid metabolism in health and disease patients suffering from neurotoxicity, neuroinflammation, Parkinson’s disease, Thymoma in myasthenia gravis. The content relevance of published papers influences the data selection process. The total number of selected papers at the beginning of the study was 250. Fast skimming of the content and publication duplications striking out determined 150 papers (60%) for further analysis. After the data extraction in Microsoft Excel 2007, based on information relevance, studies were excluded. The final selection of articles contains a total number of 94 papers (62.67%) analyzed in this study. Using standardized data collection form and Microsoft Excel 2007, study characteristics like glucose metabolism and therapy, nucleotide metabolism and therapy, purine and pyrimidine nucleotides, the interplay between purine and pyrimidine pathway, lipid metabolism of neurodegenerative disease (neurotoxicity and neuroimmunological diseases like acute dissemination encephalomyelitis, multiple sclerosis, neuromyelitis optica, transverse myelitis, Parkinson disease) and Thymoma in myasthenia gravis, as well as Apoptosis, Migration, invasion and metastasis, Metabolic reprogramming and Mitophagy are included in the analysis.

Statistical analysis

Data analysis analysis includes IBM SPSS software version 23.0 with percentages (%), counts and graphs presentation.

Results

Results are present in 3 main areas: (1) study characteristics; (2) metabolic pathways in cancer (3) metabolic pathways in neurodegenerative diseases;

Study characteristics

Figure 1 shows information about the paper selection process as a flow chart. The most prevalent number of papers before the intensive selection contains information regarding metabolic pathways in cancer (67 publications, 71.27%) with topics of glucose metabolism and therapy (23 publications, 24.47%) and Nucleotide Metabolism and Therapy (19 publications, 20.21%). Metabolic pathways in neurodegenerative diseases in this paper contains (27 publications, 28.73%). Publication information in the literature is missing for transverse myelitis (0 publications, 0%). The detailed information regarding number of papers per selected topic is present in Supplemental file 1.

Figure 1.

Flow chart of article selection criteria for analysis.

The market share decreased after the selection process (40%). This study shows a 37.33% decrease in the data quality after selection. It was noticeable that the market share of the interplay between purine and pyrimidine pathway reached a high (6.39%) after the final article selection. The lipid metabolism parameters decreased in publications after the selection process from 15.34% to 13.83% retrospectively as well as publications in purine and pyrimidine nucleotides (12.76% and 10.64%). After the selection process, the market share of articles published regarding neurotoxicity and multiple sclerosis and mitophagy rose to the same level (5.32%). Information regarding purine nucleotides contains a 2.13% higher amount of data when compared to pyrimidine nucleotides, multiple sclerosis and PD (1.14%). In papers, data regarding acute disseminated encephalomyelitis, neuromyelitis optica and metabolic reprogramming is present in 1.06% and 3.19%. However, a minority of totally selected papers with topics regarding transverse myelitis and thymoma in myastenia gravis after the selection process were not present at all in the publications (0%). In total, 94 publications remain in Microsoft Excel.

The most common publications were in Journals Cancer with 6.38% (6 publications), Int J Mol Sci 4.25% (4 publication), Mol Neurodegeneration, J Neurochem, Biomed Rep, Cells, BR J Cancer, Nat Rev Drug Disco and Curr Issues Mol Biol with 2 publications and 2.13%, where all the reset are present with 1 publications in other journals. Detailed list about the numbers is seen in Supplemental file 1.

The most common publisher is MDPI, with an incidence of 20.21% (19 publications). The second most common publishers are Springer nature and Elsevier 9.57% (9 publications). The market share of Science direct and Wiley publishers reached a high of 8.51% (8 publications) during this period. Nature and Springer Link publisher decrease in number of 5 publications (5.31%). Figure 2 summarizes percentages of published papers by year from 2002 to 2023 year. The most prevalent year of publication is 2023 (20 publications, 21.27%), whose number rose dramatically from 2002 to 2023 year, with a rate of 20.21%. Other prevalent years of published papers are 2021 (18 publications, 19.15%) and 2022 (14 publications, 14.89%).

Figure 2.

Number of selected published articles in journals per year from 2002 to 2023 year.

The number of published papers hit a percentage-wise low in the 2002, 2005, 2008, 2010, 2015 and 2016 years (1.06%) and remains erratically stable in the 2018 year (5.32%). It was noticeable that the article publication share started accumulating from the 2017 year (3.2%), with a rise to the maximum in 2021 (19.15%) and a sudden fall in 2022 (14.89%) and then leveled off to the 2023 year (21.28%) and is still rising. The number of publications fluctuated from 2002 to 2018 year. The trend of academic paper publications increases with time and is still rising in 2024. During the 2017–2021 year, the proportion of papers had a 15.96% increase (2.13%, 4.26%, 0%, 9.57%) retrospectively from year to year. Published articles fall into observational, clinical, review, mixed study, and not stated publications.

Based on the proposed data, consistency and differences between these findings and other studies in the field are discussed, along with possible future directions and mechanisms. As for limitations, the documents did not mention any specific restrictions, but it’s always important to keep in mind the potential for bias and incomplete data in any study. Notable trends or patterns in the types of publications, the document mentions that most of the publications were observational studies. There were also a significant number of clinical trials and review articles.

Metabolic pathways in cancer

Glucose metabolism and therapy

In normal cells, the glycolytic mechanism follows a fixed pathway presented in Figure 3. Numerous mechanisms involve glucose metabolism and miRNA regulation. ²¹ Glucose degrades into pyruvate and activates the tricarboxylic acid cycle (TCA-tricarboxylic acid cycle) for energy production in normal cells. ²¹ Cancer cells start the Warburg effect through anaerobic glycolysis, overexpression of glucose transporters such as glucose transporter (Glut), glycolytic enzymes such as hexokinase (HK), lactate dehydrogenase (LDH) and pyruvate kinase (PK).^21,22 Numerous proto-oncogenes (Ras, c-Myc) and tumour suppressors (p53) affect metabolism.^8,21,22 Upstream mutations in these genes regulate glucose intake and promote a metabolic phenotype to tumour growth and progression through PI3K, HIFs, p53, and v-myc, controlling cell proliferation and energy metabolism.^7,22 Hypoxia-inducible transcriptional factor (HIF) in normal physiological conditions regulates hypoxic stress by regulating angiogenesis, glucose metabolism and resistance to oxidative stress.^8,21,22 Disturbance in HIF metabolism is associated with clinical outcomes, poorer prognosis, and drug resistance through the PI3K/Akt signalling pathway and represents a molecule for future drug discovery studies.^21,22 Heat shock protein 78 regulates glucose (GRP78), where glucose regulates the chaperone of the endoplasmic reticulum.^7,22 GRP78 protein therapy inhibits tumour growth through the HIF-1 A/vascular growth factor/VEGRF2 pathway.^7,21,22 Glut1 glucose transporter interacts with HIF1 and colocalizes in peri-necrotic regions of human colorectal carcinoma.^21,22 A downstream effector of the Hippo signalling pathway promotes glycolysis by interacting with the AMPK protein.^21,22 Prion protein molecules regulate Glut1 expression through the Fyn-HIF2A signalling pathway. ²² AEG-1 protein promotes anaerobic glycolysis, where the AEG1/AMPK/phosphofructokinase-2 interaction of the glycolytic process represents a therapeutic target site for cancer treatment. ²³ AMPK promote the adaptation of metabolism to the tumour environment by increasing the glucose and oxygen utilization in cancer cells, reducing mitophagy and increasing cell death. ²³ AREG is responsible for the 3D structure of tumour formation. A decrease in the level of estrogen receptor ERRα leads to glucose uptake and lipogenesis decrease mediated by glucose decreasing the expression of genes involved in glycolysis, TCA cycle and lipid synthesis, hexokinase 1, glucose-6-phosphatase catalytic subunit, 6-phosphofructo -2-kinase/fructose-2,6-biphosphatase (PFKFB) 1, PFKFB2, aldolase C, fructose-bisphosphate, glutamic-pyruvic transaminase 2, and phosphoglucomutase 2, likely reducing pyruvate production. ²⁴ The Wnt signalling pathway and PDK1 influence mitochondrial respiration and Warburg’s metabolism in the tumour environment.^22,23 The activation of the Wnt signalling pathway is a consequence of the inactivation of the APC tumour suppressor gene and the activation of beta-catenin, which is associated with TCF/LEF transcription factors that influence the control of cell fate, stem cell function, proliferation and migration, as well as interaction with PDK1, PDH, acetyl Co-A, MCT1 and TCF4 genes, MYC, CTNNB1.^25,26

Figure 3.

Biochemical pathways (glycolitic) including oxygen and epigenetic mechanism in the cell.

PI3K, RTK-RAS, and p53 signalling influence glucose metabolism. PI3K interacts with PDGF, EGF, IGF and insulin. ²⁷ When these growth factors bind to the RTK and G protein-coupled receptor, PI3Kalda phosphorylates PIP2 to PIP3, which activates the secondary signalling molecules Ser/Thr kinase AKT and mTOR, which alters cell cycle progression and activates a metabolic program necessary for growth and synthesis of new cells.^26,27 The signalling molecule mTOR is multiplying phosphorylated affecting catabolism and anabolism. ²⁸ mTOR pathway activates SREB, leading to induced transcription of genes necessary for lipid synthesis and increases mitochondrial flux via PPP, which increases the level of HIF-1alpha, leading to angiogenesis and expression of genes essential for glycolysis, including GLUT1 and phosphofructokinase. ²⁸ Also, changes in the PI3K pathway include mutation in IGF2 and IRS2 and inactivation of PTEN and PIK3R that inhibit the PI3K pathway, with PI3K also affecting GLUT, whereby AKT increases glucose by phosphorylating HKN2, PFKFB2 and mTOR affecting GPT2 which converts glutamate to Alpha-ketoglutarate (a-KG) which acts on the TCA cycle, generating ATP and intermediates for the synthesis of lipids and amino acids. ²⁹ The step involves the RTK-RAS-MAPK pathway and can activate the mTOR signalling pathway by binding the RTK-RAS to RTKs that activate RAS that activates MEK/ERK leading to the activation of transcription factors that lead to survival and proliferation cells. ²⁹ KRAS combined with G13D KRAS increase the level of GLUT1 and the Warburg phenotype, leading to significant changes in glycolysis, the non-oxidative form of PPP, glutamine metabolism and the phosphoserine biosynthetic pathway, increased glucose uptake and lactate production in compared to individuals without mutations. ³⁰ Mutations like Caco-2-KRAS G12V and Caco-2-BRAF-V600E lead to gene up-regulation by glucose, activating the mTOR signalling pathway. ³¹ p53 signalling pathway mediates the cellular arrest cycle, apoptosis and ageing of cells in response to stress. In colorectal cancer, it leads to inactivation with TP53, glycolysis, hypermutations, inactivation of glycolysis by repression of GLUT transcription, PDK2 that negatively regulates PDH that leads to an increase in pyruvate acetyl CoA, activation of PARK2 expression that affects the PDHA1 subunit, induces the expression of cytochrome c oxidase and genes that are necessary for the synthesis that ultimately prevents oxidative phosphorylation. ³² p53 induces interaction with the pentose phosphate pathway by activating PFK1, which generates GSH and reduces ROS production. ³² Transketolase-like 1 (TKTL1) regulation contributes to glucose degradation through the anaerobic mechanism and in the presence of oxygen. ³³ The aggressiveness of colorectal cancer depends on phosphoglucose isomerase (PGI), where solute carrier family-2 member 3/Glut3 transcription enhances aerobic glycolysis with Caveolin 1 (CAV1). ³⁴ Reduced CAV1 contributes to reduced glucose uptake, intracellular ATP levels, and lactate accumulation. ³⁴ Autophagy is promoted by activating the AMPK-TP53/P53 signalling pathway. ³⁴ The transcription factor glucose depends on anabolic pathways and suppression of p53 activity. ³⁴ Mutation in signalling molecules contributes to increased glucose intake and glycolysis, affecting mitochondrial metabolisms like KRAS, BRAF, GLUT1, TNFalpha, and IL-17. ³⁴ Other signalling molecules participate in miRNA regulation, the mutation of which contributes to the onset, progression, worsening or therapeutic outcome of the disease. The most frequent and significant analyzed miRNAs are miR-26a, miR-34, miR-122, miR-124, miR-137, miR-143, miR-340, miR-369-3p, miR-374a, miR-676-3p and miR-718, miR-1181, miR-4524a/b.^35,36 These miRs indicate disease outcome, therapy efficacy, survival, disease progression, energy metabolism, and respiration, through interaction with PKM, hnRNAP, HK-2, and PTBP1.^35,36

Alteration of glucose metabolism affects signalling pathways of glucose metabolism. The pentose phosphate pathway (PPP) is under control by transketolase (TKT) which can be altered in cancer by ubiquitination and interaction with the mTOR-PPP axis as a potential therapeutic molecule of the disease.^35–37 A deficiency of protein kinase Cζ (PKCζ) leads to increased utilization of glutamine in the absence of glucose by inhibiting PHGDH and phosphoserine aminotransferase 1, which inhibits enzyme activity.^36,37 Loss of PKCζ leads to an increase in two metabolic enzymes and a worse prognosis in patients with colorectal cancer. ³⁷ Signalling pathways b-F1-ATPase/GAPDH in mitochondria indicate the level of glucose metabolism in tumour tissue. ³⁴ One of the most common methodologies used for diagnosis and therapy related to glucose metabolism is the detection of carcinoembryonic antigen in blood and tissue samples of affected individuals, FDG (Fluorodeoxyglucose), PET (positron emission tomography), MRI, therapeutics, use of diet, molecules that reduce the amount of sugar in the blood, inhibitors that affect the inactivation of signalling pathways. ³⁴ Cancer cells affect glucose metabolism differently depending on the process, like glycolysis, oxidative phosphorylation, and pentose phosphate pathways, whereas glutamine, serine, and fatty acid oxidation together with 5-lipoxygenase are the main pathways that attract attention for therapy. ³⁷

Glycolysis is a promising pathway target for therapy in preclinical and clinical studies from phases 0-III. ³⁹ Breast and lung cancer treatment includes inhibitors like silibinin, 2-DG, 3-BP, lonidamine, AR-C155858, enzymes and transporters to target hexokinase II, GLUT, and Complex II causing ATP depletion, chemoresistance overcoming and apoptosis. ⁴⁰ For leukaemia and lymphoma, cell line inhibitor ST1326 targets CPT1 to inhibit growth and stimulate cytotoxicity and for skin tumours, Docebenone targets 5-LOX and blocks proliferation, metastasis-inducing apoptosis and reduces cancer growth. Dicholoacetate and its derivate inhibit pyruvate dehydrogenase kinase inhibiting pyruvate dehydrogenase complex. ⁴⁰ Polydatin DHEA and 6-AN inhibit G6PD during the conversion of G-6-P to 6PG and R-5-P. ⁴¹ When glutamine enters the cancer cells, mitochondria inhibitors of glutaminase apply, like BPTES, CB-839, Azaserine, Acivicin, 1-DON, hormone and chemotherapy therapy applies. ⁴¹

The glycolytic mechanism and the molecular pathway are presented graphically and discussed throughout the segment. We can conclude that the glucose metabolism involving glycolysis and the pentose phosphate pathway supports cell proliferation and survival of cancer cells by upregulation. Protooncogenes and tumour suppressors, mutation and signalling pathways are so far known. Cell organelles and the following proteins are present in colorectal carcinoma, as well as the interaction of signalling molecules and pathways that alter the cell cycle, catabolism and anabolism, leading to cell apoptosis and ageing of the cell, regulating miRNA. Several signalling pathways are involved in colorectal carcinoma. These include PI3K/Akt, HIF-1A/vascular growth factor/VEGRF2, Hippo, Fyn-HIF2A, Wnt, PI3K, RTK-RAS, and p53, as well as the Ser/Thr kinase AKT and mTOR, RTK-RAS-MAPK, and AMPK-TP53/P53 pathways. Each of these pathways plays a unique role in the development and progression of colorectal carcinoma. Moreover, the diagnosis and therapy of glucose metabolism are present and their application in preclinical and clinical studies. Healthcare professionals need to understand these pathways and how they contribute to the disease to develop effective treatments and therapies. The research publication contains all relevant segments for providing quality knowledge information.

Nucleotide metabolism and therapy

Nucleotides are the main building blocks of genetic material, which can be purines (adenine and guanine) or pyrimidines (thymine, uracil and cytosine).^40,42 Nucleotides are necessary for the biosynthesis of DNA, RNA, cell signalling, enzyme regulation and metabolism.^38,40 De novo synthesis of nucleotides contributes to cell proliferation so that nucleotide metabolites represent target molecules in diseases.^39,42 Nucleotide biosynthesis uses negative feedback from substrates (Pi, purine, pyrimidine).^42,43 The AMP, GMP and Pi inhibit purine biosynthesis, acting on PRPP synthetase, adenosine and Guo mono, di or triphosphates (AKSP and GKSP) at two sites on PRPP amidotransferase.^42,43 The CAD molecule uses a negative feedback loop and activates by PRPP of UTP binding to the CPSII domain of CAD.^42,43 The nucleotide mechanism is presented in Figure 4.

Figure 4.

Nucleotide metabolism map.

Multiple metabolic processes alter during tumorigenesis and cancer progression, like nitrogen increase and insufficient nucleotides for complex molecules, enhancing cell proliferation and progression that lead to genomic instability. ⁴⁴ An oncogene C-myc regulates the expression of metabolic enzymes (CAD, TS, IMPDH). ⁴⁴ In cancer cells, CAD upregulates and indicates a poor prognosis. Mutations in p53 influence tumour onset and metastasis, mediating the stability of GMPS with USP7. ⁴⁴ IMPDH and GMPS facilitate activating mTOR complex 1 (mTORC1), promoting de novo synthesis of pyrimidines and purines with CAD enzymes. ⁴⁴ Nucleotide metabolism is regulated at the transcriptional level by tumour suppressor genes and oncogenes, while tumour cells show a great diversity of nucleotides and an active nucleotide anabolic pathway. ⁴⁵ Cells in proliferation require nutrients (glucose, glutamine and CO2) to generate energy that drives the anabolism of nucleic acids. ⁴⁶ The de novo biosynthetic pathway remains the main pathway through which the cellular synthesis of nucleotides and their metabolites is carried out, although nucleotides participate in the salvage pathway. ⁴⁶ Changed nucleotide metabolism accelerates cancer development and inhibits the normal immune response in the tumour microenvironment.^43,45 Few studies on altered nucleotide metabolism exist. Increasing knowledge is a potential strategy for disease treatment, prevention and understanding of cancer development and metastasis.^42,45 Nucleotide metabolism exhibits a non-proliferative effect on immune progression.^39,41,45 Targeting the nucleotide mechanism increases the anti-tumour immune response.^41,45 The immune system activates by maintaining the concentration of several essential metabolites, such as ATP. ⁴⁵ Promoting immunogenicity increases mutability and genomic instability by disrupting the purine and pyrimidine pool.^37,42,45 Releasing nucleoside analogues through microbes regulates the immune response. ⁴⁵ Combining immunotherapy and nucleotide metabolism represents success in the treatment of animal models.^39,42,45 In nucleotide metabolism, metabolic genes NTSE (CD73), ENTPD1 (CD39), and PNP use phosphate ribonucleoside to gain ribonucleoside or phosphate ribonucleoside involved in purine nucleobase metabolism, pyrimidine nucleobase metabolism, adenosine biosynthesis, AMP and DNA catabolic process and purine nucleotide biosynthesis.^45,47 Therapeutic agents that apply are oleclumab, AB680, APCP, TTX-030, IPH5201 and Forodesine.^42,44 Chemotherapeutic agents (5-FU, Gemcitabine) interfere with nucleotide metabolism to suppress cancer.^42,43 Over 20 nucleotides and nucleotide analogues apply in cancer chemotherapy, accounting for nearly 20% of all cancer FDA-approved drugs.^42,45 They include Mercaptopurine, Methotrexate, Fluorouracil, Thioguanin, Cytarabine, Floxuridine, Cisplatin, Carboplatin, Fludarabine, Cladribine, Pentostatin, Fludarabine, Cladribine, Pentostatin along with others.^42,43 These drugs usually inhibit hypoxanthine, IMP, thymine synthase, DNA and RNA molecules in cancer.^42–45 First-generation FDA-approved drugs include chemotherapy and enhanced immunotherapy like mercaptopurine, methotrexate 5FU and cytarabine from 1953 to 1974.^42,44 Second-generation drugs include Gemcitabine, enhanced 5-FU, Anti-CD73, Fludarabine, A2AR and microbiome as a part of enhanced immunotherapy.^42,43 Some enzyme blockers have not received FDA approval and remain in phase I/II clinical trials.^42–44 Nucleotide metabolism enzyme blockers include purine, pyrimidine and general inhibitors like mizoribine, merimepodib and mycophenolate mofetil.^42,46 Pemetrexed inhibits folate-dependent enzymes such as TS and GART. ⁴² MLN4924m, a structural analogue of AMP, inhibits carcinogenesis by blocking the proteasomal degradation pathway.^42,47 Dihydroorotate dehydrogenase (DHODH) is the target of several drugs, such as teriflunomide and leflunomide.^42,45 Although these therapeutic agents achieve antiproliferative effects on cancers such as multiple myeloma, NSCLC, and neuroblastomas, didn’t receive FDA approval for cancer treatment.^42,46 Gimeracil plays an antineoplastic role by blocking DPID to prevent the degradation of 5-FU. ⁴⁸ Oleclumab, AB680 and APCP represent Anti-CD73 inhibitors. ⁴⁸ Oleclumab and other anti-CD73 monoclonal antibodies (mAbs) are currently in phase I/II clinical trial studies. ⁴⁸ Pharmacological inhibitors of CD39, including sodium polyoxotungstate (POM-1), antisense oligonucleotides (ASOs), and TTKS-030, have been evaluated as monotherapies and in combination with chemotherapy/immunotherapy in ongoing clinical trials. ⁴⁹ Dual blockers have a potential synergistic antitumor effect in several preclinical studies. ⁵⁰ Resistance to chemotherapeutics, including gene mutations, chromosomal instability, and DNA repair, led scientists to consider other systemic therapies. ⁵⁰

Purine analogues (ATP, adenosine) activate immune cell receptors to promote/inhibit the immune response. ⁵¹ Adenosine acts on several receptors, including A1R, A2AR, A2BR, and A3R, and mediates its regulatory role. A1R, A2AR and A3R bind to accumulate adenosine, while A2BR when it encounters high adenosine concentrations. ⁵² The high concentration of adenosine activates A2BR. ⁵² Blockade of A2BR contributes to tumour growth inhibition in vivo. ⁵² Extracellular adenosines act on A2AR in Treg cells and effector T cells, inducing the activation of CD39, CD73, programmed cell death protein 1 (PD-1), and cytotoxic T lymphocyte antigen 4 (CTLA-4) on Treg cells and inhibiting the secretion of IL- 2 and other cytokines. ⁵² The inhibitory mechanism of adenosine is through the inhibition of Ca2+ influx and nuclear factor stimulating activated T cells (NFAT). ⁵³ Adenosine inhibits the proliferation of effector T lymphocytes and the secretion of inflammatory cytokines and is critical for innate and adaptive immune responses. ⁵⁴ High levels of ATP activate P2Xs on Treg cells to trigger apoptosis and bind to P2Xs and P2I receptors on effector T cells to facilitate proliferation. ⁵⁵ In cancer cells, there is an increase in purine metabolism.^42,45 Cells undergo regulation through adenosine, purinergic receptors and disrupted nucleotide pool, raising tumour immunogenicity and microbes releasing nucleoside analogues to regulate immunity. ⁴² Purinergic receptors and adenosine activate Neutrophils, dendritic cells co-stimulation, effector and regulator T cells, monocytes and NK cells.^42,44,47,51 Tumour immunogenicity arises with the imbalance of the purine/pyrimidine ratio releasing PTMB in cancer cells, raising immunogenicity and sensitivity to ICB drugs.^42,45,48 When microbes release nucleosides, they activate effector T cells, monocytes, macrophages, NK cells and dendritic cells leading to immune activation.^42,46,52

Recent advantages of therapeutic agents of nucleotide metabolism include target purine and pyrimidine pathways that block DNA synthesis, adenosine pathways and microbial transplantation separately.^42,47,52,53 Drugs that target purine and pyrimidine pathways include specific FDA, which causes CAD and IMPDH blockade by increasing CD8+ T cell promotion and Immuno proteasome.^42,49,53 Capecitabine, 5-azacytidine decitabine and Gemcitabine inhibit DNA and induce immunity, leading to a decrease in MIDSCs proliferation and an increase in type I interferon signal, causing immune infiltration.^42,44,50 Inhibition of adenosine pathway with drugs Oleclumab, ASOs, POM-1, DPCPX and AZD4635 block CD73, CD39, and A2AR decrease PD-L1 and adenosine, where ATP increase.^42,45,52,56 Faecal microbiota transplantation releases inosine and c-di-AMP molecules, increasing response to immunotherapy.^{42,44,47,51,54} Targeting purine and pyrimidine metabolism improves immunotherapy.^{42,45,48,50,52} Information on ongoing and completed immunotherapy clinical trials with its metabolic targets is available at ClinicalTrials.gov. ⁵⁶

Remarks regarding nucleotide mechanism, therapy with current FDA and non-FDA drugs, key molecules and molecular interactions with the potential effect on the level of cells and organisms are present in this section. Specific FDA drugs are oleclumab, AB680, APCP, TTX-030, IPH5201, Forodesine, Chemotherapeutic agents (5-FU, Gemcitabine), Mercaptopurine, Methotrexate, Fluorouracil, Thioguanin, Cytarabine, Floxuridine, Cisplatin, Carboplatin, Fludarabine, Cladribine, Pentostatin, Fludarabine, Cladribine, Pentostatin, Gemcitabine, enhanced 5-FU, Anti-CD73, Fludarabine, A2AR and microbiome, Purine analogues (ATP, adenosine). Non-FDA drugs are teriflunomide and leflunomide. Negative feedback, biosynthesis pathways, metabolic processes in cancer, oncogene regulation of molecules, activation of molecular complexes at the transcriptional level and changes in nucleotide metabolism and immunotherapy are present. Interaction of genes and interaction with ribonucleosides, potential effect, therapeutic agents, and enzyme blockers of purine and pyrimidine pathways elucidates the inhibition of specific molecules. Cancer cells lead to changes in nucleotide metabolism, affect immune cells, block DNA synthesis, and activate immune cells leading to immune response. Deviating DNA regulation and repair, with immune cell dysfunction, leads to cancer with aberrant purine and pyrimidine synthesis. This section represents good scientific literature combined on one spot and enables keeping alongside all available publications.

Purine nucleotides

De novo nucleotide metabolism depends on several metabolic genes and encoded enzymes. Purine metabolism contains significant metabolic genes like ADSS, ADA, XDH, PPAT, PRPS, GART and IMPDH, which uses IMP, adenosine, hypoxanthine, xanthine, PRPP and Ribose SP as substrates to gain ADP, ATP, Inosine, Xantine, uric acid, 5-phosphoribosylamine and pyrophosphate, PRPP, IMP, GDP and GTP as a product. ⁵⁷ Therapeutic agents applied in purine metabolism are Elapegademase, pentostatin, allopurinol, amflutizole, D-pantetheine 4-phosphate, lometrexol sodium, pelitrexol, pemetrexed, merimepodib, mizoribine and mycophenolic acid. ⁵⁷ Genes and encoded enzymes play a significant role in maintaining nucleotide biosynthesis. Purine nucleotides are synthesized directly by adding a pyrophosphate to the C-1 sugar of ribose and differ from pyrimidine nucleotides in several ways. Purine biosynthesis begins with ribose-5-phosphate that converts into phosphoribosyl pyrophosphate (eng. phosphoribosyl pyrophosphate PRPP), and several ATP molecules are equivalent to active PRPP.^42,43,48,54 Step dictates the catalysis of PRPP by PPAT, which binds glutamine and leads to the formation of 5-phosphoribosyl amine, during which pyrophosphate is set free.^42,44,49,51 The next step is ATP-dependent and includes several reactions in which IMP converts from 5 phosphoribosylamine and glycin amine ribonucleotide transformylase (eng. glycinamide ribonucleotide transformylase), which plays a role in maintaining biosynthesis. ³ IMP serves as a precursor for AMP and GMP synthesis. ⁴² During the synthesis process of AMP and GMP from IMP, ADSS and IMPDH convert IMP into sAMP and XMP via several kinetic intermediates. ⁴²

The most significant substances are CO2 and glutamine, PRPP, PRA, PRS and GPRATase. IMPDH and adenylosuccinate synthetase ADSS degrade IMP to CMP and AMP.^42,47 The purine nucleotide pathway is straightforward and consumes less energy than de novo synthesis.^42,47 In mammalian cells, enzymes CPSII and DHODH are regulated by the UMP negative feedback mechanism. ⁴⁵ In breast cancer, thymidylate synthase (TS) Gene knockout is characterised by the inhibition of epithelial-mesenchymal transformation in tumour cells contributing to metastasis. ⁵⁸ Rapidly proliferating colorectal cancer cells express glycoprotein MHC class I polypeptide-related sequence A (MICA) by NK cell type 2D (NKG2D) that enables the identification by immune cells and the removal of potential pathogenic cells. ⁵⁹ The antitumor immune response is under inhibition by the release of IL-2 by TLR, which stimulates tumour growth. Purine nucleotide metabolism targets MICA, A1, A2A, A2B, and A3 and relates to NK, Monocytes, Macrophages, and Dendritic and T immune cells. ⁶⁰ Genes with substrates and applied therapeutics in disease eradication are present. Further studies are needed to understand the purine nucleotide metabolism.

Pyrimidine nucleotides

During the De novo pyrimidine pathway, the pyrimidine ring forms in 6 steps with L-glutamine and L-aspartate is a precursor that transforms into dihydroorotate at the beginning.^42,61 Carbamoyl phosphate synthetase, aspartate transcarbamylase, and dihydroorotase (CAD) proteins are associated with enzymatic activities during the first three reactions. The limiting factor of pyrimidine biosynthesis is the enzyme DHODH (eng. dihydroorotate dehydrogenase), which catalyzes dihydroorotate into orotate and derivatives of mitochondrial electron transport and oxygen consumers.^42,61,62 Two steps of de novo pyrimidine biosynthesis catalyze uridine monophosphate synthetase (UMPS).^42,45,57,61 A bifunctional enzyme UMPS includes orotate phosphoribosyltransferase and orotidine monophosphate (OMP) decarboxylase.^42,54,56,61 During the first reaction, orotidine 5p forms from orotate and converts into uridine-5-phosphate.^{42,47,50,55,61} Uridine-5-phosphate builds reaction blocks of pyrimidine biosynthesis.^42,48,54,61 In Pyrimidine metabolism, metabolic genes CAD, DHODH, UMPS, DPYD, and CDD use Glutamine, Dihydroorotate, Glutamine, Uracil, thymine, cytidine and deoxycytidine as a substrate to produce UMP, Orotate, UMP, Beta-alanine, 3-aminoisob-utanoate, uridine and deoxyuridine.^42,61,62 Therapeutics in pyrimidine metabolism include brequinar sodium, leflunomide and teriflunomide.^42,61,62 Enzymes, reaction catalizators with significant genes and applied therapeutics in disease eradication are a part of pyrimidine nucleotides.

Interplay between purine and pyrimidine pathway

The common pathway of purine and pyrimidine nucleotide biosynthesis involves several reactions. Homeostasis and transformation of nucleoside triphosphates and monophosphates are under control by the side of ENTPD1 (ecto-nucleoside triphosphate diphosphohydrolase-1, synonym CD39). ENTPD1 and ecto-5-nucleotidases (NT5E, CD73) are critical mediators of the regulator.^42,61,62 CD73 converts AMP to adenosine, whereas CD39 hydrolyzes nucleoside-5-triphosphate to nucleoside-5-monophosphate. CD39 and CD73 maintain nucleotide metabolism while regulating the immune response at the extracellular ATP and adenosine substrates with tumour-promoting and tumour-suppressing effects. ⁶³ Ribose 5-monophosphate and deoxyribose-5-monophosphate catalyze to form a nucleoside and a deoxynucleoside mediated by CD73 and CD39. ⁶³ PNP catalyzes the reversible phosphorylation of nucleosides generating the corresponding purine and pyrimidine bases and ribose-1-phosphate, which converts to purines and pyrimidines.^46,61 The salvage pathway with free nucleotides derived endogenously from nucleic acid turnover or exogenously from dietary intake generates purines and pyrimidines.^42,64,65 The exact steps involved in recycling are known only for purine bases. The end products of the purine salvage pathway are AMP, IMP, and GMP.^42,64,65 During the salvage pathway, ubiquitous PNPs play a role in catalyzing hypoxanthine-guanine phosphoribosyltransferase (HGPRT) to synthesize inosine (Ino) and guanosine (Guo) monophosphates (MPs).^42,64,65 Ribo and deoxyribonucleosides with adenosine deaminase (ADA) form ribonucleotides in the PNP pathway.^42,64,65 Uridine-cytidine kinases (UCK1 and UCK2) are involved in the salvage pathway of pyrimidine-nucleotides and convert uridine and cytidine to their respective MPs.^42,64,65

Nucleotide degradation is another step in maintaining nucleotide homeostasis. Purine nucleotides undergo degradation processes in which nucleotides are converted into nucleosides with nucleotidase catalysis in the first step.^42,64,65 Adenosine initiates deamination and catalyzes Ino and Guo, which convert to hypoxanthine and guanine.^42,64,65 In the last two steps, hypoxanthine degrades into uric acid mediated by xanthine dehydrogenase (XDH), and the uric acid exits the body.^42,64,65 Open-chain amino acids arise from pyrimidine catabolism.^42,64,65 Dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme encoded by DPID, not only initiates the pyrimidine catabolic pathway but is also involved in the catabolism of fluorouracil (5-FU).^42,64,65 Uridine and thymidine are cleaved and metabolized via amino acids to NH3 and CO2 mediated by uridine phosphorylase (UPP1) and thymidine phosphorylase (TIMP), respectively.^42,64,65

Literature shows that homeostasis of nucleotide metabolism depends on a few molecules like ENTPD1 that control nucleotide transformation and degradation. Key molecules and enzymes in the salvage pathway are within the interplay between the purine and pyrimidine pathways.

Lipid metabolism

Cell membrane composition, signaling pathways, and energy storage are under the effect of lipid metabolism, where lipid metabolism can contribute to the pathogenesis and progression of disease. Changes in lipid metabolism are associated with changes in glucose metabolism. Omega-3 EPA and arachidonic acid mediate the activation of inflammatory pathways for colorectal cancer.^66,67 Modulating lipid metabolism with drugs or diet represents a potential strategy for disease control.^66,67

Lipids are significant for energy metabolism, structure and fluidity of cell membranes, energy substrates, signal transduction, intracellular trafficking, cell secretion, and migration. ⁶⁸ Affected lipid metabolism in cancer cells leads to poor disease prognosis and shorter survival in CRC.^66,68 Fatty acid synthase (FASN) is an enzyme of lipid biosynthesis.^66,68 It catalyzes the synthesis of palmitoyl-CoA from acetyl-CoA, malonyl-CoA and NADPH. In CRC cells, FASN upregulates via oncogenic pathways such as Wnt, HER2, PI3K/Akt, AMPK/mTOR, cMET and β-oxidation which enhances the saturation of membrane lipids in CRC cells.^66,68 KRAS and p53 mutation is present in 75% of cancer cells. In CRC cells, lipidome changes cause additional metabolic syndrome, obesity, non-alcoholic fatty liver disease, diabetes and cardiovascular diseases.^66,68 The endoplasmatic reticulum contains several molecules like DGAT, PAP, AGPAT and GPAT that communicate through CPT1 in mitochondria, the same or similar molecules on the surface of lipid droplets through a subset of biochemical molecules in the cytoplasm activate lipid signalling and membrane synthesis. ⁶⁹ Some biochemical molecules activated in the cytoplasm include citrate, acetyl CoA and glycerol. Diverse biological samples contain CRC-related lipid changes. The most common biological samples in the studies are cancer tissue, serum, plasma, erythrocytes and adipose tissue. ⁶⁹ The lipid fractions are increased or decreased depending on lipid content and selected samples. The most common lipid change in cancer tissue includes diverse lipid species ranging from 140, 160, 180, 200, 220, 240, 260, 22-1. 24-1, 204-n6, 205-n3, PA-31:0 as a total lipid, ceramide, free fatty acid, and sphingomyelin lipid fractions.^66–70 The most common lipid changes in serum include diverse lipid species ranging from 140, 150, 180, 220, 240, 260, 280, 300, and 26.1 as lipid fractions. The most common lipid changes in plasma include diverse lipid species ranging from 160, 180, 240, 16.1 n-7, 201, 183 n-3, lpc-18.2, PE-18.1/202, SM-38.8 contained as a total lipid, free fatty acids lipid fractions.^66–70 The most common lipid changes in erythrocytes include diverse lipid species ranging from 18:0, 20:0, 18:1 n-9, 24:1, and 20:4 n-6 containing total lipid fraction.^66–70 The most common lipid changes in adipose tissue include diverse lipid species ranging from 16:1 n-9, 20:1, 18:3 n-6, and 22:4 n-6 contained as a total lipid fraction.^66–70

Reducing nucleotide metabolism is an effective strategy for killing changed cells. Inhibition of CLK3 and UHMK1 blocks further cancer progression, while Gemcitabine inhibits breast and ovarian cancer. ⁷¹ In specific tumour/cell types, specific kinase and signalling axis activates enzymes. ⁴⁵ In Gastric cancer, kinase UHMK1 activates the NCOA3/ATF4 signalling pathway, including ATIC and IMPDH enzymes.^45,72 In Cholangiocarcinoma, kinase CLK3 activates USP13/Fbxl14/c-Myc signalling pathway, including ATIC enzymes.^45,73 In hepatocellular carcinoma, kinase Dyrk3 activates the NCOA3/ATF4 signalling pathway, including the PPAT enzyme.^45,74 In Glioblastoma-initiating cells, kinase UHMK1 activates the DHODH signalling pathway.^45,75 In pancreatic ductal carcinoma, kinase KRAS/MAPK activates, increasing the expression of the MYC oncogene by upstream regulation and increasing the transcriptional activity of RPIA.^45,76 Due to insufficient research knowledge of signalling molecules that participate in nucleotide metabolism, understanding complex interactions and processes involving multiple enzymes allows more precise and effective treatment of patients. ⁷⁷ The publication suggests that changes in lipid metabolism are connected to sugar metabolism, activating the immune system and are necessary for maintaining energy. The poor prognosis of cancer correlates to changes in lipid metabolism and signalling pathways. The endoplasmic reticulum and mitochondria affect lipid signalling and membrane synthesis. Repeatable changes in cancer tissue are detailed researched regarding lipid species, and the most common types are present along with appropriate therapeutics. However, insufficient knowledge of signalling molecules involved in lipid metabolism exists, making it a good starting point for further scientific research.

Metabolic pathways in neurodegenerative diseases

In this paper, we will discuss neurological diseases starting from neurotoxicity and neuroimmunological diseases like acute disseminated encephalomyelitis (ADEM), multiple sclerosis (MS), neuromyelitis optica (NMO), transverse myelitis (TM), Parkinson’s disease (PD) and thymoma in myasthenia gravis (TMG).

Neurotoxicity

During neurotoxicity, Quinolinic acid shows a neuroprotective effect on brain inflammation and metabolism in a rat. ⁷⁸ Metabolism of Catecholamine Neurotransmitters isdisturbed during neurotoxicity induced by Nanoscale Zinc–metal–organic molecules. Malondialdehyde (MDA) and superoxide dismutase (SOD) are the parameters of oxidative stress, whereas human toxicity risks of nanoscale low-toxicity metal-based MOF provide valuable insight into the rational and safe use of MOF nanomaterials. ⁷⁹ Fluorosis-induced neurotoxicity links to the PI3K/AKT/HIF-1α pathway and ameliorates by Sodium Butyrate Regulating Hippocampal Glycolysis InVivo. ⁸⁰ The microbe-gut-brain axis shows neurotoxicity during exposure to imidacloprid. ⁸¹ Glycogen mediates metabolic switching in ischemic astrocytes during neurotoxicity. ⁸²

Based on the available studies Quinolinic acid, SOD and nanomaterials represent promising therapy against neurotoxicity in human and animal studies. Further studies need to explore the possible molecular mechanism of additional drugs that can be more efficient, easier to produce, use and retain within the cell to give better results.

Neuroimmunological diseases

Acute dissemination encephalomyelitis

There is an altered fatty acid oxidation in lymphocyte populations of myalgic encephalomyelitis/chronic fatigue syndrome dependent on T and NK cell effector function, which may shed light on the disease mechanism of action. ⁸³

In acute dissemination of encephalomyelitis, there are few publications on molecule involvement in metabolism. Additional studies within this area of expertise are necessary.

Multiple sclerosis

Lipid metabolism, cholesterol efflux, retinoid-X-receptor α dependent pathways, phagocytosis, and epigenetic regulation are potential therapeutic targets of MS. Oxygen–glucose deprivation leads to decreased ATP production, promotes sodium accumulation and calcium entry from the extracellular space and regulates cell death. mTOR signalling shifts metabolism towards aerobic glycolysis in activated microglia and has a protective therapeutic effect. ⁸⁴

There is a seasonal change in serum metabolites in MS relapse. In the spring, two groups of metabolites are present. ⁸⁵ One contains two pathways (phosphatidylethanolamine biosynthesis and phosphatidylcholine biosynthesis), and the other six pathways (beta-alanine, histidine, ammonia recycling, methionine, glutamate, purine). ⁸⁵ During summer, the first group was identical, and the second one had six metabolites (gluconeogenesis, pyruvate, urea cycle, glutamate, aspartate, and purine) different. ⁸⁵ Histidine, beta-alanine and methyl histidine metabolism are active in spring and fall in MS, where histidine and beta-alanine metabolism, methyl histidine metabolism the pathway was the most affected in MS. ⁸⁵ Lower levels of metabolites of the glucose metabolism pathway in MS explain reports of lower glucose levels in MS. ⁸⁵ Warburg effect in fall and winter MS serum refers to increased glycolysis and fermentation of pyruvate to lactate as an alternative to oxidation in the mitochondria. ⁸⁶ 1,2-13C2-Glucose tracing assesses metabolic alterations of human monocytes under neuroinflammatory conditions. ⁸⁷ There is in silico drug repurposing in MS by using scRNA-Seq Data. ⁸⁸ The current publication indicates fair knowledge of cell metabolism’s effect on disease initiation, progression and eradication.

Neuromyelitis optica

MS and NMO disorders characterize but with the further elucidation of metabolism changes. ⁸⁹ Based on the proposed publication, further studies in this area are necessary to get functional and applicable knowledge in clinical practice.

Transverse myelitis

Metabolic changes are not present in the literature for TM disease. Further completer studies are needed.

Parkinson’s disease

Neurological diseases like Parkinson’s have impaired mitochondrial function and glucose utilization. PINK1 I368 N mutation in PD causes global metabolic changes for therapeutic intervention.^78,79 PD-associated protein Parkin influences the cell cycle, cell proliferation, apoptosis, metastasis, mitophagy and metabolic reprogramming of tumorigenesis and mitochondrial homeostasis, anti-oxidative stress and mitophagy during PD.^90,91 PARK2 translates a protein with an N-terminal ubiquitin-like domain (Ubl), a cysteine-rich RING0 domain, and two C-terminal RING domains (RING1, RING2) separated by RING (IBR) domain. PARK2 localizes to human chromosome 6q25-27, where the loss of heterozygosity and copy number is present in breast, lung, colorectal, and ovarian cancers. Post-translational modifications of Parkin modulate its activity.^90,91 Parkin inhibits cell cycle progression by ubiquitination and degradation of cyclin E, which binds to CDK2 to promote the transition from the G1 to the S phase of the cell cycle.^90,91 Parkin ubiquitinates, degrades cyclin D, induces G1/S cell cycle arrest and inhibits cell proliferation. Parkin deficiency results in the overexpression of cyclin B1, Aurora A/B and other mitotic regulators, which leads to mitotic defects, genomic instability and tumorigenesis.^90,91

Gene mutations are accountable for PD initiation and progression along with known metabolism changes presented in the literature.

Apoptosis

Apoptosis arises by Parkin, causing mitochondrial depolarization, ubiquitination and degradation of the Bcl-2 family member Mcl-1, opening the Bax/Bak channel. Restoration of Parkin expression in cervical cancer HeLa cells reduces levels of apoptosis inhibitor sensitizing the cells to TNF-α-induced apoptosis, breast cancer MCF7 cells by microtubule-stabilizing drugs such as paclitaxel. Other therapeutic agents can cause apoptosis, like the downregulation of follistatin, chemotherapeutic agents, cisplatin, doxorubicin and etoposide.^90,91 Parkin promotes apoptosis in cancer by inhibiting Mcl-1, Bax/Bak; surviving, cleavage of caspase 8/9/3/7; follistatin, activin and activating microtubule stabilization leading to apoptosis.^90,91

Apoptosis is present in diverse studies after metabolic changes in healthy and cancer cells. The applicable approved therapeutics apply in clinical trials. Further studies could include analysis of gene mutations in DNA and RNA molecules among molecules.

Migration, invasion and metastasis

Parkin expression is lower in tumours with lymph node metastases. Metastasis sublimation is done by Parkin ubiquitinating HIF-1α and triggering its degradation in breast cancer cells.^90,91 Parkin inhibits cancer metastasis by ubiquitinating HIF-1α leading to proteasomal degradation.^90,91 Research studies should focus more on signalling molecules compared to current knowledge.

Metabolic reprogramming

Metabolic reprogramming contains the inactivation of tumour suppressors p53 and PTEN or the activation of oncoproteins such as HIF-1α, Myc and PI3K in cancer. p53 suppresses glycolysis, and Parkin expression activates by binding to the p53-responsive elements in PARK2.^90,91 Parkin-mediated ubiquitination and degradation of HIF-1α prevents HIF-1α from transcriptionally activating the proteins involved in glycolysis.^90,91 In cancer cells, Parkin inhibits glycolysis, and Parkin deficiency causes S-nitrosylation and ubiquitination, inactivates PTEN and activates PI3K/AKT signalling in cancer cells.^90,91 PI3K/AKT signalling drives metabolic reprogramming in cancer cells, including glycolysis promotion.^90,91 Parkin interacts with PKM2, catalyzing ubiquitin conjugation to PKM2. PKM2 enzymatic activity promotes glycolysis.^90,91 Metabolic reprogramming causes the inactivation of mitochondrial pyruvate carriers and promotes the activation and development of NLRP3 inflammasome and gout. ⁹²

Tumour suppressors, oncoproteins, signalling pathways, and lipid metabolism changes in mitochondria are present in cancer onset and progression. Further studies could include changes in other cell organelles and receptors.

Mitophagy

PINK1 and Parkin prevent PD by eliminating the accumulation of damaged mitochondria, ROS and mitochondrial DNA mutations. BNIP3 and Nix (also named BNIP3L) induce mitophagy independently of Parkin and suppress the growth of tumours.^90,91

There is an association between PD and reduced risk of cancer (prostate, lung, bladder, stomach, uterine, and colorectal cancers) and increased risk of melanoma and brain and breast cancers.^90,91 PKM2-mediated neuronal hyperglycolysis enhances the risk of Parkinson’s disease in diabetic rats. ⁹³ High blood and brain blood barrier (BBB) glucose level enters the PC12 neuron cells leading to glycolysis associated with mitochondrial fusion and apoptosis where glycose, MFN2, Pyr, Lac, and mitochondrial fusion upregulates. PDHB and TCA downregulate and lead to 6-OHDA vulnerability and movement disorders. ⁹³ Id the PC12 cells are treated with shikonin, PKM2, MFN2, abnormal mitochondrial fusion, apoptosis, glycolysis, LDHA and lac are downregulated, and Glucose, Pyr, PDHB, and TCA upregulates leading to 6-OHDA tolerance and movement improvement. ⁹³ In the PD file model, there is increased cysteine metabolism in PINK1. ⁹⁴

Mitochondria and lipid metabolic changes are identified and connected to mitophagy and specific diseases. Further studies could focus more on presented polymorphisms included in specific metabolic changes.

Thymoma in myasthenia gravis

Disease metabolism has not been mentioned in the literature so far for TMG. Similar data analysis could be employed from the topics mentioned above for thymoma in myasthenia gravis.

Discussion

Literature data quality is present and provides notions regarding miRNA molecules, therapeutic agents and metabolic, nucleotide and lipid metabolism. Published article content is missing to keep brief, and practical discussion is present. Papers summarize concise information, arguments, and ideas and systematically investigate and test new research knowledge. The lower number of publications lacks idea clarity and uniformity. Other articles suggest good communication of data. The research paper aims to convey the information and give significance to the presented data by providing novel information regarding disease metabolism. A flow chart and graph improve data quality and interpretation. Available information allows us to validate and create novel solutions to the ongoing research question. The most common topic of the selected papers is signalling pathways and molecules within cancer and neurodegenerative disease metabolism and therapy. The most common publication articles are Cancer and Int J Mol Sci, while the publishersare MDPI, Springer and Whiley. The most intense year of publishing good and quality research data is 2021. The most prevalent study in the papers is observational studies. The differences among the data are cost, identification of predictors and the outcome, exposure to environmental and genetic factors and reliability of data, statistical analysis and interpretation. The strength of this study is its applicability in clinical and research practice and analysis speed. Differences regarding therapeutical agents and procedures enable monitoring of disease onset, progression and eradication; and provide preliminary data to justify the treatment efficacy. More than 40% of selected papers contain participant age, health status, diseased and healthy participants ranging from cancer to neurodegenerative diseases and participant general information like life habits and genetics. The most common sample types were tissue and blood. Blood analysis includes haematology, genetic and biochemical parameters. The number of participants varies from one to a few thousand depending on the wanted results, standard ethical rules and precision. Software like NCBI, Google Scholar, SPSS, and STATA exist in publications. Selected information includes signalling molecules in a metabolic pathway, nucleotide and lipid metabolism, therapeutic agents in health and disease, discussing potential biomarkers relation and validation. Compare distinctions and connections between mechanisms in cancer and neurodegenerations. The purpose of the research enable a grasp of the latest discoveries in the field, contributing to intellectual creativity and healthcare, and leaving room for suggestions. The review identifies genetic background, risk factors and molecules of metabolism, methodological analysis and therapy. Results indicate the information and similarities between cancer and neurodegenerative disease, creating new data in science. Limitations of the study do not involve polymorphism information and molecule reference range of key molecules as well as the absence of selected information due to data quality selection. This manuscript provides data information control and implementation of new information by critical thinking, deduction and reasoning, justifying knowledge. Data collection is significant. This review enables readers to gain a comprehensive overview of the topic under investigation, key terms, concepts, and theories related to the cancer and neurology disease field. Readers should be able to synthesize the historical development of the topic, milestone studies, significant findings, and changes in the research ideas in the specific period. Enable current understanding of the findings, theories, and methodological approaches up to date. Gaps and controversies are under discussion in critical aspects of the literature, identifying inconsistencies in the published results and being aware of the unanswered questions, debates, and future research areas. The study enables finding synthesis from common literature trends in addressing the topic. Strengths and limitations of the studies are present throughout the text, including findings warranting the credibility and reliability of the current manuscript. This research can apply to decision-making processes, enabling further research direction in disease detection and treatment. A particular topic elaborates on future research opportunities, raising potential research questions. Current cancer and neurological disease therapeutic approaches include a metabolic vulnerability that disrupts tumor growth and degeneration of nervous tissue. Therapeutic agents like 5-fluorouracil and methotrexate influence nucleotide synthesis pathways inhibition, and statins and fatty acid synthase inhibitors affect lipid metabolism. Resistance mechanisms, off-target effects, and systemic toxicity are under restriction of treatment efficacy. Based on the literature review, novel therapeutics should lessen limitations and improve patients’ disease outcomes by overcoming troubleshooting issues connected to the scientific question.

Identifying novel therapeutic targets within metabolic pathways is enabled by advancements in system biology, metabolomics, and computational modeling. Functional characterization and target validation usually apply with High-throughput screening assays and CRISPR-Cas9 gene editing technology. Disease-specific metabolic alterations with metabolic flux analysis and metabolite profiling enable improvement and development of target therapies. Using multi-omic data sets empowers understanding complex metabolic network and signaling cascades by data integration. Further studies on glucose, nucleotides and lipids metabolism during cancer disease should focus on regulatory roles of signalling molecules (Wnt/beta-catenin pathway in lipid metabolism, the Notch signalling pathways, etc) and rewriting in disease initiation, differentiation and progression. Investigate additional molecular pathways and mechanisms that can interfere with glucose, nucleotide and lipid metabolism. Since RNA mediates cancer metabolic reprogramming, it is significant to investigate an additional role in modelling the disease metabolism, influence of microenvironment and immune antigene presentations. Metabolomics is a significant methodology for cancer screening. Drug targeting on immune cells that affect these three types of metabolism should be further studied to see its therapeutic effect and side effects. Discovering new therapeutic targets could lead to therapy improvement. Investigate mutations to determine the efficacy of specific metabolic therapy. Selecting and advancing appropriate molecular methodology for disease detection and interactions between signalling molecules on different levels should influence the therapy efficacy and precise metabolic alterations, improving patients’ health. Since the investigation focused more on acid signalling, further studies are needed. Antidisease drugs should be considered better along with different developmental strategies. With the progress of modern technologies, increasing the precision of experimental and bioinformatics methodology could lead to more accurate signalling molecule detection and disease eradication by utilizing larger sample sizes and various analytical methods. Understanding metabolic reprogramming will enable effective therapy. A better understanding of metabolic networks, regulation processes and molecules will increase disease therapy and eradication. Cell cycle checkpoints in normal and diseased cells will enable a better understanding of the metabolic processes and effective monitoring approaches. Moreover, further metabolic substrates can affect identity and behaviour through changes in genetic and epigenetic modifications, and because of that, we need a more comprehensive understanding of the effect. Potential therapeutic interventions enable emerging targets with metabolism pathways in cancer and neurological diseases. For example, targeting enzymes in glycolysis like hexokinase and pyruvate kinase express antitumor activity in preclinical model systems. Gemcitabine and cytarabine influence DNA synthesis and repair processes in cancer cells like nucleotide analogs, while peroxisome proliferator-activated receptor agonists and acetyl-CoA carboxylase inhibitors influence lipid homeostasis and tumor microenvironment as lipid metabolism regulators.

This paper opens the new research question of whether targeting novel metabolic pathways enables effective therapy for cancer and neurological disease, whether alterations in metabolism contribute to disease progression, and what mechanisms are involved. Understanding the interplay between metabolic pathways and disease by uncovering specific metabolic pathways in disease initiation and progression will enable the developing of target therapeutic interventions to address the root cause of the disease development. Glucose, nucleotides, and lipid metabolism pathways are pivotal in cancer and neurodegenerative disorders. Metabolic alterations include glucose uptake, glycolysis, dysregulated nucleotide synthesis, and aberrant signaling pathways and molecules on the way. Knowledge about disease progression is crucial to develop proper therapeutic targets. For example, aberrant glucose, nucleotide, and lipid metabolism provide energy, enabling fast cell proliferation in cancer that affects cell composition and signaling pathways in cancer and neurodegenerative disorders. The elucidating function of specific enzymes, signaling pathways, and transcription regulators enables the modulation of metabolic pathways and molecule mechanisms that promote cell survival and growth. Identifying novel therapeutic targets in this interconnected metabolism interplay holds promise for personalized medicine, minimizing disease progression and off-target effects on healthy tissue, enabling efficient treatment targeting a specific metabolic hot spot in dysregulated pathways. Investigating the interplay between metabolism and disease initiation, development, and progression expands creativity in the therapeutic industry for curing the disease.

Conclusion

The study focuses on information, molecules, signalling pathways in cancer and neurodegenerative diseases, metabolism and therapeutic agents. Utilize quantitative and qualitative looks at research problems. Researchers have information on the question of debate in a concise, systematic critical way. Detailed information regarding methodologies in the study includes sample size, the protocol of data collection and statistical analysis that increase the reproducibility and scientific rigour of the study. Saves time for data mining and connects information on one spot understanding evidence of knowledge in scientific and clinical practice and exploring the possible mechanism and future directions for research. Understanding the cell metabolism during health and disease will enable better scientific and medical practice, enabling disease eradication and homeostasis maintenance. Biochemical and metabolic molecules involved in disease initiation, progression and metastasis warrant the development of efficient therapy for patients. Gathering information on significant processes, pathways, genes, and interactions will ease the burden of researchers in future generations. Developing effective therapeutic interventions is dependable on our understanding of the interplay between metabolic pathways and disease pathogenesis in cancer and neurological diseases. The effectiveness of therapy depends on personalized medicine by identification of novel therapeutic targets within glucose, nucleotides, and lipid metabolism. Translating preclinical findings into clinical practice and addressing the challenges associated with therapy toxicity and resistance represent a potential place for future research.

ORCID iD

Snežana M Jovičić https://orcid.org/0000-0001-6087-0620