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

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

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

Effect of arsenic on paracetamol binding to bovine serum albumin using site specific probes

Arsenic contamination in groundwater is a global health challenge. A large number of people worldwide are affected by arsenic poisoning. Paracetamol is a widely used analgesic-antipyretic drug. Effect of arsenic on paracetamol binding to protein has been investigated using two site specific probes and equilibrium dialysis method was used for the experiment. In absence of any site specific probes free concentration of paracetamol bound to bovine serum albumin increased from 3.95 ± 1.164% to 25.36 ± 1.164%. In presence of site-I specific probe warfarin sodium the % release of drug was steady at around 14%. But in presence of site-II specific probe an increment of free drug concentration was observed from 14.38 ± 1.164% to 54.72 ± 1.552%. Thus it can be assumed that the free concentration of paracetamol was increased to a greater extent in presence of arsenic and probably arsenic bound to site-II of BSA. Thus arsenic may displace paracetamol by binding with high affinity binding site, site-II in the BSA and probably arsenic has little effect to site-I

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 of 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 dealt 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

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