Acid Ceramidase Inhibitor LCL-805 Antagonizes Akt Signaling and Promotes Iron-Dependent Cell Death in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy requiring urgent treatment advancements. Ceramide is a cell-death-promoting signaling lipid that plays a central role in therapy-induced cell death. We previously determined that acid ceramidase (AC), a ceramide-depleting enzyme, is overexpressed in AML and promotes leukemic survival and drug resistance. The ceramidase inhibitor B-13 and next-generation lysosomal-localizing derivatives termed dimethylglycine (DMG)-B-13 prodrugs have been developed but remain untested in AML. Here, we report the in vitro anti-leukemic efficacy and mechanism of DMG-B-13 prodrug LCL-805 across AML cell lines and primary patient samples. LCL-805 inhibited AC enzymatic activity, increased total ceramides, and reduced sphingosine levels. A median EC50 value of 11.7 µM was achieved for LCL-805 in cell viability assays across 32 human AML cell lines. As a single agent tested across a panel of 71 primary AML patient samples, a median EC50 value of 15.8 µM was achieved. Exogenous ceramide supplementation with C6-ceramide nanoliposomes, which is entering phase I/II clinical trial for relapsed/refractory AML, significantly enhanced LCL-805 killing. Mechanistically, LCL-805 antagonized Akt signaling and led to iron-dependent cell death distinct from canonical ferroptosis. These findings elucidated key factors involved in LCL-805 cytotoxicity and demonstrated the potency of combining AC inhibition with exogenous ceramide.

Acid Ceramidase Inhibitor LCL-805 Antagonizes Akt Signaling and Promotes Iron-Dependent Cell Death in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy requiring urgent treatment advancements. Ceramide is a cell death-promoting signaling lipid that plays a central role in therapy-induced cell death. Acid ceramidase (AC), a ceramide-depleting enzyme, is overexpressed in AML and promotes leukemic survival and drug resistance. The ceramidase inhibitor B-13 and next-generation lysosomal-localizing derivatives termed dimethylglycine (DMG)-B-13 prodrugs have been developed but remain untested in AML. Here, we report the in vitro anti-leukemic efficacy and mechanism of DMG-B-13 prodrug, LCL-805, across AML cell lines and primary patient samples. LCL-805 inhibited AC enzymatic activity, increased total ceramides, and reduced sphingosine levels. A median EC50 value of 11.7 µM was achieved for LCL-805 in cell viability assays across 32 human AML cell lines. As a single agent tested across a panel of 71 primary AML patient samples, a median EC50 value of 15.8 µM was achieved. Exogenous ceramide supplementation with C6-ceramide nanoliposomes, which is entering phase I/II clinical trial for relapsed/refractory AML, significantly enhanced LCL-805 killing. Mechanistically, LCL-805 antagonized Akt signaling and led to iron-dependent cell death distinct from canonical ferroptosis. These findings elucidated key factors involved in LCL-805 cytotoxicity and demonstrated the potency of combining AC inhibition with exogenous ceramide.

Therapeutic Benefits of Selenium in Hematological Malignancies.

Supplementing chemotherapy and radiotherapy with selenium has been shown to have benefits against various cancers. This approach has also been shown to alleviate the side effects associated with standard cancer therapies and improve the quality of life in patients. In addition, selenium levels in patients have been correlated with various cancers and have served as a diagnostic marker to track the efficiency of treatments or to determine whether these selenium levels cause or are a result of the disease. This concise review presents a survey of the selenium-based literature, with a focus on hematological malignancies, to demonstrate the significant impact of selenium in different cancers. The anti-cancer mechanisms and signaling pathways regulated by selenium, which impart its efficacious properties, are discussed. An outlook into the relationship between selenium and cancer is highlighted to guide future cancer therapy development.

Engineered Probiotic and Prebiotic Nutraceutical Supplementations in Combating Non-communicable Disorders: A Review.

Nutritional supplementations are a form of nutrition sources that may help in improving the health complexities of a person throughout his or her life span. Being also categorized as food supplementations, nutraceuticals are products that are extracted from edible sources with medical benefits as well as primary nutritional values. Nutraceuticals can be considered as functional foods. There are evidences that nutraceutical supplementations can alter the commensal gut microbiota and help to prevent or fight against chronic non-communicable degenerative diseases in adults, including neurological disorders (Autism Spectrum Disorder [ASD], Parkinson's disease [PD], Multiple sclerosis [MS]) and metabolic disorders (Type-II diabetes, obesity and non-alcoholic fatty liver disease). They can even lessen the complexities of preterm babies like extra-uterine growth restriction, necrotizing enterocolitis, infant eczema and allergy (during pregnancy) as well as bronchopulmonary dysplasia. Molecular perception of inflammatory and apoptotic modulators regulating the pathogenesis of these health risks, their control and management by probiotics and prebiotics could further emphasize the scientific overview of their utility. In this study, the pivotal role of nutraceutical supplementations in regulating or modulating molecular pathways in the above non-communicable diseases is briefly described. This work also gives an overall introduction of the sophisticated genome-editing techniques and advanced delivery systems in therapeutic activities applicable under these health risks.

Sen1, the homolog of human Senataxin, is critical for cell survival through regulation of redox homeostasis, mitochondrial function, and the TOR pathway in Saccharomyces cerevisiae.

Mutations in the Senataxin gene, SETX are known to cause the neurodegenerative disorders, ataxia with oculomotor apraxia type 2 (AOA2), and amyotrophic lateral sclerosis 4 (ALS4). However, the mechanism underlying disease pathogenesis is still unclear. The Senataxin N-terminal protein-interaction and C-terminal RNA/DNA helicase domains are conserved in the Saccharomyces cerevisiae homolog, Sen1p. Using genome-wide expression analysis, we first show alterations in key cellular pathways such as: redox, unfolded protein response, and TOR in the yeast sen1 ΔN mutant (N-terminal truncation). This mutant exhibited growth defects on nonfermentable carbon sources, was sensitive to oxidative stress, and showed severe loss of mitochondrial DNA. The growth defect could be partially rescued upon supplementation with reducing agents and antioxidants. Furthermore, the mutant showed higher levels of reactive oxygen species, lower UPR activity, and alterations in mitochondrial membrane potential, increase in vacuole acidity, free calcium ions in the cytosol, and resistance to rapamycin treatment. Notably, the sen1 ∆N mutant showed increased cell death and shortened chronological life span. Given the strong similarity of the yeast and human Sen1 proteins, our study thus provides a mechanism for the progressive neurological disorders associated with mutations in human senataxin.

Evaluation of diuretic and laxative activity of hydro-alcoholic extract of Desmostachya bipinnata (L.) Stapf in rats.

OBJECTIVE: In continuation to the growing evidence for therapeutical potential of Desmostachya bipinnata (Linn) Stapf, the current pharmacological study was carried out to evaluate the diuretic and laxative activity of its hydro-alcoholic extract in rats. METHODS: The hydro-alcoholic extract of D. bipinnata whole plant was prepared by using Soxhlet extractor and subjected to analysis by standard preliminary phytochemical tests. Evaluation of both diuretic and laxative activity was carried out using standard methods as reported earlier. Frusemide (20 mg/kg) was served as positive control for diuretic activity and sennosides (10 mg/kg) served as negative control for laxative activity. RESULTS: The hydro-alcoholic extract showed significant diuretic activity and was found to be the most potent in increasing the urinary output at 500 mg/kg when the effect was compared with that of the standard frusemide (P<0.01). Moreover, this extract was found to be most effective in increasing urinary electrolyte concentration (Na(+), K(+), and Cl(-)) at both doses tested. Whereas the results for laxative activity showed minimal increase of feces output at the dose of 500 mg/kg and the increase was negligible when compared with that of the standard drug sennosides. CONCLUSION: Altogether, the above significant findings validate and support its folkloric diuretic use and lend pharmacological credence to the ethno-medical use of this plant in traditional system of medicine, which demands further studies to investigate its active constituents, as well as its use and safety.

Evaluation of antioxidant and DNA damage protection activity of the hydroalcoholic extract of Desmostachya bipinnata L. Stapf.

Desmostachya bipinnata Stapf (Poaceae/Gramineae) is an official drug of ayurvedic pharmacopoeia. Various parts of this plant were used extensively in traditional and folklore medicine to cure various human ailments. The present study was aimed to evaluate the antioxidant and DNA damage protection activity of hydroalcoholic extract of Desmostachya bipinnata both in vitro and in vivo, to provide scientific basis for traditional usage of this plant. The extract showed significant antioxidant activity in a dose-dependent manner with an IC50 value of 264.18±3.47 µg/mL in H2O2 scavenging assay and prevented the oxidative damage to DNA in presence of DNA damaging agent (Fenton's reagent) at a concentration of 50 µg/mL. Also, the presence of extract protected yeast cells in a dose-dependent manner against DNA damaging agent (Hydroxyurea) in spot assay. Moreover, the presence of extract exhibited significant antioxidant activity in vivo by protecting yeast cells against oxidative stressing agent (H2O2). Altogether, the results of current study revealed that Desmostachya bipinnata is a potential source of antioxidants and lends pharmacological credence to the ethnomedical use of this plant in traditional system of medicine, justifying its therapeutic application for free-radical-induced diseases.

Evaluation of diuretic and laxative activity of hydro-alcoholic extract of Desmostachya bipinnata (L.) Stapf in rats / 中西医结合学报

<p><b>OBJECTIVE</b>In continuation to the growing evidence for therapeutical potential of Desmostachya bipinnata (Linn) Stapf, the current pharmacological study was carried out to evaluate the diuretic and laxative activity of its hydro-alcoholic extract in rats.</p><p><b>METHODS</b>The hydro-alcoholic extract of D. bipinnata whole plant was prepared by using Soxhlet extractor and subjected to analysis by standard preliminary phytochemical tests. Evaluation of both diuretic and laxative activity was carried out using standard methods as reported earlier. Frusemide (20 mg/kg) was served as positive control for diuretic activity and sennosides (10 mg/kg) served as negative control for laxative activity.</p><p><b>RESULTS</b>The hydro-alcoholic extract showed significant diuretic activity and was found to be the most potent in increasing the urinary output at 500 mg/kg when the effect was compared with that of the standard frusemide (P<0.01). Moreover, this extract was found to be most effective in increasing urinary electrolyte concentration (Na(+), K(+), and Cl(-)) at both doses tested. Whereas the results for laxative activity showed minimal increase of feces output at the dose of 500 mg/kg and the increase was negligible when compared with that of the standard drug sennosides.</p><p><b>CONCLUSION</b>Altogether, the above significant findings validate and support its folkloric diuretic use and lend pharmacological credence to the ethno-medical use of this plant in traditional system of medicine, which demands further studies to investigate its active constituents, as well as its use and safety.</p>

Depletion of cellular iron by curcumin leads to alteration in histone acetylation and degradation of Sml1p in Saccharomyces cerevisiae.

Curcumin, a naturally occurring polyphenolic compound, is known to possess diverse pharmacological properties. There is a scarcity of literature documenting the exact mechanism by which curcumin modulates its biological effects. In the present study, we have used yeast as a model organism to dissect the mechanism underlying the action of curcumin. We found that the yeast mutants of histone proteins and chromatin modifying enzymes were sensitive to curcumin and further supplementation of iron resulted in reversal of the changes induced by curcumin. Additionally, treatment of curcumin caused the iron starvation induced expression of FET3, FRE1 genes. We also demonstrated that curcumin induces degradation of Sml1p, a ribonucleotide reductase inhibitor involved in regulating dNTPs production. The degradation of Sml1p was mediated through proteasome and vacuole dependent protein degradation pathways. Furthermore, curcumin exerts biological effect by altering global proteome profile without affecting chromatin architecture. These findings suggest that the medicinal properties of curcumin are largely contributed by its cumulative effect of iron starvation and epigenetic modifications.