Sodium dichloroacetate 250mg/5ml oral solution

Pyruvate dehydrogenase complex deficiency (PDCD) is a heterogenous mitochondrial inborn error in carbohydrate oxidation manifesting as congenital lactic acidosis. PDCD presents diagnostic and therapeutic challenges. While no curative treatment exists for PDCD, certain therapeutic modalities may improve prognosis and ameliorate symptom severity. This article examines the effectiveness of treatments for PDCD and presents a case series of three patients with PDCD. A scoping literature review was conducted for treatments of PDCD. Patient data for case reports was extracted retrospectively from electronic medical records from a large tertiary hospital. We reviewed and summarized findings from seven preclinical studies and ten human studies, which showed that dichloroacetate and the ketogenic diet were the most frequently studied treatments. Therapeutic approaches observed select positive outcomes such as reduced lactate levels, improved neuropathological manifestations, and increased longevity. However, most interventions have yet to be rigorously investigated. Early diagnosis of PDCD is integral, as treatment methods may offer improved clinical and biochemical outcomes. Clinical trials of existing and novel treatments are necessary to improve management and further understand the prognostic potential of this metabolic disorder.

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The research presents data from a preclinical study on the anti-inflammatory effects of a sodium dichloroacetate and sodium valproate combination (DCA–VPA). The 2-week treatment with a DCA 100 mg/kg/day and VPA 150 mg/kg/day combination solution in drinking water’s effects on the thymus weight, its cortex/medulla ratio, Hassall’s corpuscles (HCs) number in the thymus medulla, and the expression of inflammatory and immune-response-related genes in thymocytes of male Balb/c mice were studied. Two groups of mice aged 6–7 weeks were investigated: a control (n = 12) and a DCA–VPA-treated group (n = 12). The treatment did not affect the body weight gain (p > 0.05), the thymus weight (p > 0.05), the cortical/medulla ratio (p > 0.05), or the number of HCs (p > 0.05). Treatment significantly increased the Slc5a8 gene expression by 2.1-fold (p < 0.05). Gene sequence analysis revealed a significant effect on the expression of inflammation-related genes in thymocytes by significantly altering the expression of several genes related to the cytokine activity pathway, the inflammatory response pathway, and the Il17 signaling pathway in thymocytes. Data suggest that DCA–VPA exerts an anti-inflammatory effect by inhibiting the inflammatory mechanisms in the mouse thymocytes.

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The study presents data on the anti-inflammatory effects of a combination of sodium dichloroacetate and sodium valproate (DCA-VPA) on the expression of inflammation- and immune response-related genes in T lymphocytes of SARS-CoV-2 patients. The study aimed to assess the effects of DCA-VPA on the genes of cytokine activity, chemokine-mediated signaling, neutrophil chemotaxis, lymphocyte chemotaxis, T-cell chemotaxis, and regulation of T-cell proliferation pathways. The study included 21 patients with SARS-CoV-2 infection and pneumonia: 9 male patients with a mean age of 68.44 ± 15.32 years and 12 female patients with a mean age of 65.42 ± 15.74 years. They were hospitalized between December 2022 and March 2023. At the time of testing, over 90% of sequences analyzed in Lithuania were found to be of the omicron variant of SARS-CoV-2. The T lymphocytes from patients were treated with 5 mmol DCA and 2 mmol VPA for 24 h in vitro. The effect of the DCA-VPA treatment on gene expression in T lymphocytes was analyzed via gene sequencing. The study shows that DCA-VPA has significant anti-inflammatory effects and apparent sex-related differences. The effect is more potent in T cells from male patients with SARS-CoV-2 infection and pneumonia than in females.

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To date, there is no effective treatment for glioblastoma (GBM). This study aimed to compare the effectiveness of sodium dichloroacetate (NaDCA), a valproic acid and NaDCA combination (VPA–NaDCA), or temozolomide (TMZ) on U87 and T98G cell tumors on the chick embryo chorioallantoic membrane (CAM), and on the expression of proliferating cell nuclear antigen (PCNA), polycomb inhibitory complex catalytic subunit 2 (EZH2), and TP53 gene-encoded p53 protein (p53) in tumors on the CAM, and SLC12A2 (gene encoding Na+-K+-2Cl− (NKCC1) co-tarnsporter), SLC12A5 (gene encoding K+-Cl− (KCC2) co-transporter), SLC5A8 (gene encoding Na+-dependent monocarboxylate transporter) and CDH1 (gene encoding the E-cadherin protein) and CDH2 (gene encoding the N-cadherin protein) in cells. VPA–NaDCA and TMZ reduced the invasion of U87 and T98G tumors, as well as the expression of PCNA and EZH2 in the tumor. TMZ reduced p53 expression in tumors from both cell lines, whereas VPA–NaDCA did not affect the expression of this marker. VPA–NaDCA, but not TMZ, reduced SLC12A2 expression in T98G cells. However, VPA–NaDCA and TMZ did not affect SLC12A2 expression in U87 cells. VPA–NaDCA increased SLC5A8 expression only in U87 cells, and TMZ did not affect gene expression in either cell line. Only VPA–NaDCA increased CDH1 expression and decreased CDH2 expression in T98G cells, whereas TMZ had no effect on gene expression in the study cells. This study demonstrated that VPA–NaDCA exhibits a more effective anticancer effect than NaDCA. The data suggest that VPA–NaDCA has a more effective impact than TMZ; however, the effect of investigational medicines on carcinogenesis varies depending on the cell line. The study of the efficacy of drugs used to treat tumors on the CAM and cells demonstrates that it is essential to assess the effectiveness of treatment, which should be personalized, before administering chemotherapy.

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T-cell acute lymphoblastic leukemia (T-ALL) is a challenging childhood cancer to treat, with limited therapeutic options and high relapse rates. This study explores deamidated triosephosphate isomerase (dTPI) as a novel therapeutic target. We hypothesized that selectively inhibiting dTPI could reduce T-ALL cell viability without affecting normal T lymphocytes. Computational modeling and recombinant enzyme assays revealed that disulfiram (DS) and curcumin (CU) selectively bind and inhibit dTPI activity without affecting the non-deamidated enzyme. At the cellular level, treatment with DS and CU significantly reduced Jurkat T-ALL cell viability and endogenous TPI enzymatic activity, with no effect on normal T lymphocytes, whereas the combination of sodium dichloroacetate (DCA) with DS or CU showed synergistic effects. Furthermore, we demonstrated that dTPI was present and accumulated only in Jurkat cells, confirming our hypothesis. Finally, flow cytometry confirmed apoptosis in Jurkat cells after treatment with DS and CU or their combination with DCA. These findings strongly suggest that targeting dTPI represents a promising and selective target for T-ALL therapy.

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Objectives: Inadequate cytotrophoblast migration and invasion are speculated to result in preeclampsia, which is a pro-inflammatory condition. Sodium dichloroacetate (DCA) exerts anti-inflammatory actions. Thus,we sought to investigate the effect of DCA on the migration function of the lipopolysaccharide (LPS)-stimulated human-trophoblast-derived cell line (HTR-8/SVneo). Materials and Methods: HTR-8/SVneo cells were treated with LPS to suppress cell migration. Cell migration was examined by both scratch wound healing assay and transwell migration assay. Western blotting was used to analyze the expression levels of toll-like receptor-4 (TLR4), nuclear factor-κB (NF-κB), TNF-α, IL-1β, and IL-6 in the cells. Results: DCA reversed LPS-induced inhibition of migration in HTR-8/SVneo cells. Furthermore, DCA significantly suppressed LPS-induced activation of TLR4, phosphorylation of NF-κB (p65), translocation of p65 into the nucleus, and the production of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6). Treatment with inhibitors of TLR4 signal transduction (CLI095 or MD2-TLR-4-IN-1) reduced LPS-induced overexpression of pro-inflammatory cytokines, and a synergistic effect was found between TLR4 inhibitors and DCA in HTR-8/SVneo cells. Conclusion: DCA improved trophoblast cell migration function by suppressing LPS-induced inflammation, at least in part, via the TLR4/NF-κB signaling pathway. This result indicates that DCA might be a potential therapeutic candidate for human pregnancy-related complications associated with trophoblast disorder.

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The search for an effective treatment for adult high-grade glioblastoma (GBM) remains urgent. Background/Objectives: The study aimed to determine the expression of carcinogenesis-related genes, such as SLC12A2, SLC12A5, CDH1, CDH2, EZH2, and GFAP, in primary glioblastoma (WHO Grade IV; IDH-wild-type) cells from three adult women: GBM5-1, GBM5-2F, and GBM5-3F. Methods: The impact of the combination of sodium valproate and sodium dichloroacetate (2 mM NaVPA–3 mM NaDCA) on the expression of these genes was determined and compared with the effects of 50 µM temozolomide after 24 h of treatment. Results: 2 mM NaVPA–3 mM NaDCA, as well as temozolomide, had individual impacts on the SLC12A2, SLC12A5, CDH1, CDH2, EZH2, and GFAP expressions of tested GBM5-1, GBM5-2F, and GBM5-3F primary cells of female GBM patients. Conclusions: The combination of 2 mM NaVPA–3 mM NaDCA may have an advantage in antitumor activity and may be more effective than TMZ; however, the effect is individual.

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Oral mucosal melanoma (OMM) is a common neoplasm in canines, although it is rare in humans. Cancer cells present alterations in energetic metabolism, and the Warburg effect states that most cancer cells undergo aerobic glycolysis. This can be reversed by certain drugs, resulting in decreased cell viability and cell death. We sought to evaluate the effects of sodium dichloroacetate (DCA) and omeprazole (OMP) alone or in combination on canine OMM and human melanoma cells. CMGD5 and SK-MEL-28 cell lines were treated with DCA and OMP alone or in combination, and cell viability was assessed using the crystal violet assay. Cell death (apoptosis and necrosis) was assessed by Annexin V and propidium iodide (PI) staining assays using flow cytometry. In addition, the oxygen consumption rate (OCR) was evaluated using a SeaHorse XF assay. Treatment with DCA or OMP alone resulted in a significant, but not dose-dependent, reduction in cell viability in both cell lines; however, the combination of DCA and OMP resulted in a significant and dose-dependent decrease in viability in both cell lines. DCA and OMP, alone or in combination, did not alter OCR at the concentrations tested in either cell line. Since the combination of DCA and OMP potentialized the inhibition of viability and increased cell death in a synergistic manner in melanoma cells, this approach may represent a new repurposing strategy to treat cancer.

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BACKGRUOUND: Reactive oxygen species (ROS) and inflammation are reported to have a fundamental role in the pathogenesis of ischemia-reperfusion (IR) injury, a leading cause of acute kidney injury. The present study investigated the role of pyruvate dehydrogenase kinase 4 (PDK4) in ROS production and inflammation following IR injury. METHODS: We used a streptozotocin-induced diabetic C57BL6/J mouse model, which was subjected to IR by clamping both renal pedicles. Cellular apoptosis and inflammatory markers were evaluated in NRK-52E cells and mouse primary tubular cells after hypoxia and reoxygenation using a hypoxia work station. RESULTS: Following IR injury in diabetic mice, the expression of PDK4, rather than the other PDK isoforms, was induced with a marked increase in pyruvate dehydrogenase E1α (PDHE1α) phosphorylation. This was accompanied by a pronounced ROS activation, as well as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), and monocyte chemoattractant protein-1 (MCP-1) production. Notably, sodium dichloroacetate (DCA) attenuated renal IR injury-induced apoptosis which can be attributed to reducing PDK4 expression and PDHE1α phosphorylation levels. DCA or shPdk4 treatment reduced oxidative stress and decreased TNF-α, IL-6, IL-1β, and MCP-1 production after IR or hypoxia-reoxygenation injury. CONCLUSION: PDK4 inhibition alleviated renal injury with decreased ROS production and inflammation, supporting a critical role for PDK4 in IR mediated damage. This result indicates another potential target for reno-protection during IR injury; accordingly, the role of PDK4 inhibition needs to be comprehensively elucidated in terms of mitochondrial function during renal IR injury.

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