The selective prolyl hydroxylase inhibitor IOX5 stabilizes HIF-1α and compromises development and progression of acute myeloid leukemia.

Acute myeloid leukemia (AML) is a largely incurable disease, for which new treatments are urgently needed. While leukemogenesis occurs in the hypoxic bone marrow, the therapeutic tractability of the hypoxia-inducible factor (HIF) system remains undefined. Given that inactivation of HIF-1α/HIF-2α promotes AML, a possible clinical strategy is to target the HIF-prolyl hydroxylases (PHDs), which promote HIF-1α/HIF-2α degradation. Here, we reveal that genetic inactivation of Phd1/Phd2 hinders AML initiation and progression, without impacting normal hematopoiesis. We investigated clinically used PHD inhibitors and a new selective PHD inhibitor (IOX5), to stabilize HIF-α in AML cells. PHD inhibition compromises AML in a HIF-1α-dependent manner to disable pro-leukemogenic pathways, re-program metabolism and induce apoptosis, in part via upregulation of BNIP3. Notably, concurrent inhibition of BCL-2 by venetoclax potentiates the anti-leukemic effect of PHD inhibition. Thus, PHD inhibition, with consequent HIF-1α stabilization, is a promising nontoxic strategy for AML, including in combination with venetoclax.

Aldehyde-mediated inhibition of asparagine biosynthesis has implications for diabetes and alcoholism.

Patients with alcoholism and type 2 diabetes manifest altered metabolism, including elevated aldehyde levels and unusually low asparagine levels. We show that asparagine synthetase B (ASNS), the only human asparagine-forming enzyme, is inhibited by disease-relevant reactive aldehydes, including formaldehyde and acetaldehyde. Cellular studies show non-cytotoxic amounts of reactive aldehydes induce a decrease in asparagine levels. Biochemical analyses reveal inhibition results from reaction of the aldehydes with the catalytically important N-terminal cysteine of ASNS. The combined cellular and biochemical results suggest a possible mechanism underlying the low asparagine levels in alcoholism and diabetes. The results will stimulate research on the biological consequences of the reactions of aldehydes with nucleophilic residues.

Flacourtia indica fruit extract modulated antioxidant gene expression, prevented oxidative stress and ameliorated kidney dysfunction in isoprenaline administered rats.

This study evaluated the effect of Flacourtia indica fruit extract against isoprenaline (ISO) induced renal damage in rats. This investigation showed that ISO administration in rats increased the level oxidative stress biomarkers such as malondialdehyde (MDA), nitric oxide (NO), advanced protein oxidation product (APOP) in kidneys followed by a decrease in antioxidant enzymes functions. Flacourtia indica fruit extract, which is rich in strong antioxidants, also reduced the MDA, NO and APOP level in kidney of ISO administered rats. Inflammation and necrosis was also visible in kidney section of ISO administered rats which was significantly prevented by atenolol and Flacourtia indica fruit extract. Moreover, atenolol and Flacourtia indica fruit extract also modulated the genes expressions related to inflammation and oxidative stress in kidneys. The beneficial effects could be attributed to the presence of a number of phenolic antioxidants. This study suggests that Flacourtia indica fruit extract may prevent kidney dysfunction in ISO administered rats, probably by preventing oxidative stress and inflammation.

Leaf powder supplementation of Senna alexandrina ameliorates oxidative stress, inflammation, and hepatic steatosis in high-fat diet-fed obese rats.

Obesity is an enduring medical issue that has raised concerns around the world. Natural plant extracts have shown therapeutic potential in preventing oxidative stress and inflammation related to obesity complications. In this study, Senna alexandrina Mill. leaves were utilized to treat high-fat diet-related metabolic disorders and non-alcoholic fatty liver diseases. Plasma biochemical assays were conducted to determine the lipid profiles and oxidative stress parameters, and the gene expression of antioxidant enzymes and inflammatory mediators was measured. Histological stained livers of high-fat diet-fed rats were observed. S. alexandrina leaf powder supplementation prevented the increase in cholesterol and triglyceride levels in high-fat diet-fed rats. Moreover, S. alexandrina leaves also reduced lipid peroxidation and nitric oxide production in these rats. Prevention of oxidative stress by S. alexandrina leaf supplementation in high-fat diet-fed rats is regulated by enhancing the antioxidant enzyme activity, followed by the restoration of corresponding gene expressions, such as NRF-2, HO-1, SOD, and CAT. Histological staining provides further evidence that S. alexandrina leaf supplementation prevents inflammatory cell infiltration, lipid droplet deposition, and fibrosis in the liver of high-fat diet-fed rats. Furthermore, this investigation revealed that S. alexandrina leaf supplementation controlled non-alcoholic fatty liver disease by modulating the expression of fat metabolizing enzymes in high-fat diet-fed rats. Therefore, S. alexandrina leaf supplementation inhibits fatty liver inflammation and fibrosis, suggesting its usefulness in treating non-alcoholic steatohepatitis. Thus, this natural leaf extract has potential in treatment of obesity related liver dysfunction.

Insights on Melatonin as an Active Pharmacological Molecule in Cancer Prevention: What's New?

Along with playing an important role in circadian rhythm, melatonin is thought to play a significant role in preventing cells from damage, as well as in the inhibition of growth and in triggering apoptosis in malignant cells. Its relationship with circadian rhythms, energetic homeostasis, diet, and metabolism, is fundamental to achieve a better comprehension of how melatonin has been considered a chemopreventive molecule, though very few papers dealing with this issue. In this article, we tried to review the most recent evidence regarding the protective as well as the antitumoral mechanisms of melatonin, as related to diet and metabolic balance. From different studies, it was evident that an intracellular antioxidant defense mechanism is activated by upregulating an antioxidant gene battery in the presence of high-dose melatonin in malignant cells. Like other broad-spectrum antioxidant molecules, melatonin plays a vital role in killing tumor cells, preventing metastasis, and simultaneously keeping normal cells protected from oxidative stress and other types of tissue damage.

Self-medication among medical and pharmacy students in Bangladesh.

BACKGROUND: This cross-sectional survey examined the pattern of self-medication and factors associated with this practice among medical and pharmacy students in context to Bangladesh. METHODS: The study used a self-administered questionnaire. A total of 500; 250 medical and 250 pharmacy, students participated in the study. As it is a comparative analysis between the medical and pharmacy students, we used independent t test and Chi square test. RESULTS: The findings indicated that the impact of self-medication is almost similar in medical and pharmacy students. It was found that medical students were more careful about getting advice from a physician or seeking professional help from some healthcare personnel. About the safety of self-medication pharmacy students were more aware than medical students were. The study also showed that female and younger medical or pharmacy students were more aware about self-medication. CONCLUSIONS: The current study presents a comprehensive picture of self-medication in medical and pharmacy students in Bangladesh. It is clear from the findings that practice of self-medication is highly prevalent in medical and pharmacy students in the country. This may potentially increase misuse or irrational use of medicines.

In vitro Anti-oxidant Activity and HPLC-DAD System Based Phenolic Content Analysis of Codiaeum variegatum Found in Bangladesh.

PURPOSE: This study evaluated the in vitro antioxidant potential of two varieties of Codiaeum variegatum leaves (spiral (CP) and royal like (BP)) extracts. METHODS: The different antioxidant assays, including DPPH free radical scavenging, nitric oxide scavenging, hydrogen peroxide, reducing power, total antioxidant activity, protection of lipid peroxidation and RBC membrane stabilization activity, were studied. Moreover, high-performance liquid chromatography (HPLC) coupled with diode-array detection was used to identify and quantify the phenolic compounds in the royal like (BP) leaves extract. RESULTS: Codiaeum variegatum extracts showed effective DPPH free radical scavenging, hydrogen peroxide radical scavenging and nitric oxide scavenging activity. However, reducing power of ferric ion was not significant compared to the standard antioxidant activity. In addition, Codiaeum variegatum extracts exhibited protection against lipid peroxidation. The total antioxidant activity was increased dose dependently when compared with standard drug ascorbic acid. (-)-Epicatechin, p-coumaric acid, rutin hydrate and ellagic acid were identified in the extract. Among the phenolic compounds, ellagic acid was abundantly present in the extract. CONCLUSION: Our investigation suggests that Codiaeum variegatum leaves contain high amount of phenolic compounds which may responsible for its biological activities in folkloric medicine.