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Mitochondrial Pathologies and Their Neuromuscular Manifestations
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Carlos Ortez, Andrés Nascimento
In a family affected by an X-linked dominant form of CMT (CMTX6) a missense mutation c.473G>A (p.R158H) has recently been identified in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene119. PDK3 is a nuclear-coded protein regulating the pyruvate dehydrogenase complex in the mitochondrial matrix, which is a key enzyme linking glycolysis to the energy-producing Krebs cycle and lipogenic pathways. Combined effects of R158H PDK3 are likely to lock PDC in a predominantly phosphorylated inactive state leading to impaired ATP production and or lactate accumulation. The clinical phenotype is milder than that seen in PDC deficiency, and is limited to the peripheral nerves. Reduced PDC activity has previously been detected in fibroblast lines from several unrelated and genetically undefined CMT patients120. The cellular energy depletion is likely the underlying cause of the peripheral neuropathy, although lactate accumulation may also contribute. X-linked CMT with AIF mutation.
The commensal bacterium Lactiplantibacillus plantarum imprints innate memory-like responses in mononuclear phagocytes
Published in Gut Microbes, 2021
Aize Pellon, Diego Barriales, Ainize Peña-Cearra, Janire Castelo-Careaga, Ainhoa Palacios, Nerea Lopez, Estibaliz Atondo, Miguel Angel Pascual-Itoiz, Itziar Martín-Ruiz, Leticia Sampedro, Monika Gonzalez-Lopez, Laura Bárcena, Teresa Martín-Mateos, Jose María Landete, Rafael Prados-Rosales, Laura Plaza-Vinuesa, Rosario Muñoz, Blanca de las Rivas, Juan Miguel Rodríguez, Edurne Berra, Ana M. Aransay, Leticia Abecia, Jose Luis Lavín, Hector Rodríguez, Juan Anguita
Transcriptomic analyses of primed human monocytes further confirmed the prominent decrease in the expression of pro-inflammatory mediators and effectors, including an array of cytokines, chemokines and antimicrobial peptides. Moreover, we observed a differential regulation of genes and pathways involved in metabolism, especially in the transport and use of carbohydrates, amino acids and fatty acids, which could be linked to the decreased metabolic rates and ROS production observed in primed cells. Cellular metabolism is intimately linked to the regulation of immune responses, with metabolic rewiring being described in both acutely stimulated 44 and innate memory cells 45. Notably, priming with live bacteria increased the expression of pyruvate dehydrogenase kinase genes PDK2, PDK3, PDK4. These proteins are involved in cellular metabolism regulation through the inactivation of components of pyruvate dehydrogenase, the enzyme complex converting pyruvate to acetyl-CoA, leading to decreased glucose and lipid metabolism, and aerobic respiration. 46 In addition, ACO1 and ACOD1, coding for aconitase and aconitate decarboxylase, were found downregulated. Itaconate, a metabolite with anti-microbial and immunomodulatory properties, 47 has been associated with the modulation of β-glucan-induced trained immunity, and ACOD1 expression showed decreased levels in memory monocytes compared to acutely stimulated cells. 48 Thus, the observed differential gene expression suggests a reduction in the integrity of the tricarboxylic acid (TCA) cycle and the itaconate pathway that might be relevant for the L. plantarum-induced long-term memory phenotype in monocytes.
Therapeutic challenges at the preclinical level for targeted drug development for Opisthorchis viverrini-associated cholangiocarcinoma
Published in Expert Opinion on Investigational Drugs, 2021
Watcharin Loilome, Hasaya Dokduang, Manida Suksawat, Sureerat Padthaisong
In CCA, the result from DNA sequencing revealed that there are many mutated genes, including TP53, KRAS, SMAD4, NF1, ARID1A, PBRM1, ATR [224], IDH, KRAS and TP53 [225]. In addition, unique oncogenic mutations have different pharmacological responses [225]. In 2019, Duangkumpha et al. identified potential protein biomarkers for CCA diagnosis using serum/urine-proteomics and found 6 candidate proteins which included 3 proteins (S100A9, thioredoxin and cadherin-related family member 2 (CDHR2)) from serum and 3 proteins (lysosome associated membrane glycoprotein 1 (LAMP1), LAMP2 and CDHR2) from urine as promising biomarkers for CCA diagnosis [226,227]. In addition, several studies have also reported the potential biomarkers for CCA identified using omics approaches. By using proteomics, Proungvitaya et al. demonstrated that the overexpression of the coiled-coil domain containing 25 (CCDC25) was found in CCA cells, and this was associated with cell migration [228]. In 2019, Tummanatsakun et al. showed that the serum apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1) level was high in CCA compared with benign biliary diseases and healthy groups. Moreover, the level of APEX1 was higher in patients having metastases compared with those without metastases, and a high level of serum APEX1 also correlated with low survival of CCA patients, suggesting that the serum APEX1 level might be a biomarker for CCA diagnosis and progression [229]. Pyruvate dehydrogenase kinase (PDK), Ser/Thr kinase, was also reported as a potential biomarker for CCA using proteomic analysis, especially PDK3 which was found at a higher level in CCA than benign biliary diseases and healthy groups. Moreover, a high level of serum PDK3 was associated with a low survival for CCA [230]. This information suggests that these protein biomarkers may be used as drug targets in CCA prevention and treatment. Moreover, metabolomics, the latest-omics technology, has also been applied to identify the anticancer activity-related bioactive compounds from Thai medicinal herb-treated CCA using the in vitro model [100].
Revision of potential prognostic markers of cholangiocarcinoma for clinical practice
Published in Expert Review of Anticancer Therapy, 2023
Charupong Saengboonmee, Sumalee Obchoei, Kanlayanee Sawanyawisuth, Sopit Wongkham
Secreted proteins with known pro-tumorigenic functions and detectable in patients’ serum are also correlated with the poor prognosis of patients. These proteins play roles in tumor progression and have crucial activities in cancer cells, and thus high levels of these serum proteins reflect the aggressive phenotypes at the primary tumors. The high levels of these serum proteins are usually associated with poor prognosis in patients. For example, pyruvate dehydrogenase kinase 3 (PDK3), a Ser/Thr kinase inactivating mitochondrial pyruvate dehydrogenase to promote aerobic glycolysis, was found overexpressed in patient-CCA tissues. High serum PDK3 is significantly associated with shorter overall survival of CCA patients which might be resulted from the aggressiveness of the primary tumor [67]. The CXC chemokine family is a group of important chemokines in cell–cell communications. Elevated CXCL13 levels in CCA before and after tumor resection suggested a subgroup of patients at risk of impaired clinical outcomes following the operation. Multivariate analysis confirmed that CXCL13 could be used as an independent prognostic marker in CCA patients [60]. Urokinase plasminogen activator receptor (uPAR) is a known protein that promotes the invasiveness of many types of cancers. High expression of uPAR in CCA tissues is associated with poor clinical outcomes of patients. Soluble uPAR could be detectable in serum and was elevated in CCA patients compared with healthy control. Elevated preoperative soluble uPAR is also an independent prognostic marker for CCA patients which is associated with shorter overall survival [69]. Yoh et al. reported that Nardilysin (NRDC), a metalloendopeptidase of the M16 family, has several roles in CCA cells, namely proliferation, migration, invasion, and tumor growth in xenografted mice. The expression of NRDC was correlated with the epithelial-mesenchymal transition (EMT) genes and thus was used as a surrogate marker for EMT. High serum NRDC levels were associated with a shorter overall survival and disease-free survival that are suspected to involve the EMT and metastasis process of CCA cells [64].