The objective of this study was to elucidate if chronic and acute ammonia intoxication in mudskippers, Periophthalmodon schlosseri and Boleophthalmus boddaerti, were associated with high levels of ammonia and/or glutamine in their brains, and if acute ammonia intoxication could be prevented by the administration of methionine sulfoximine [MSO; an inhibitor of glutamine synthetase (GS)] or MK801 [an antagonist of N-methyl D-aspartate type glutamate (NMDA) receptors]. For P. schlosseri and B. boddaerti exposed to sublethal concentrations (100 and 8 mmol l(-1) NH4Cl, respectively, at pH 7.0) of environmental ammonia for 4 days, brain ammonia contents increased drastically during the first 24 h, and they reached 18 and 14.5 micromol g(-1), respectively, at hour 96. Simultaneously, there were increases in brain glutamine contents, but brain glutamate contents were unchanged. Because glutamine accumulated to exceptionally high levels in brains of P. schlosseri (29.8 micromol g(-1)) and B. boddaerti (12.1 micromol g(-1)) without causing death, it can be concluded that these two mudskippers could ameliorate those problems associated with glutamine synthesis and accumulation as observed in patients suffering from hyperammonemia. P. schlosseri and B. boddaerti could tolerate high doses of ammonium acetate (CH3COONH4) injected into their peritoneal cavities, with 24 h LC50 of 15.6 and 12.3 micromol g(-1) fish, respectively. After the injection with a sublethal dose of CH3COONH4 (8 micromol g(-1) fish), there were significant increases in ammonia (5.11 and 8.36 micromol g(-1), respectively) and glutamine (4.22 and 3.54 micromol g(-1), respectively) levels in their brains at hour 0.5, but these levels returned to normal at hour 24. By contrast, for P. schlosseri and B. boddaerti that succumbed within 15-50 min to a dose of CH3COONH4 (15 and 12 micromol g(-1) fish, respectively) close to the LC50 values, the ammonia contents in the brains reached much higher levels (12.8 and 14.9 micromol g(-1), respectively), while the glutamine level remained relatively low (3.93 and 2.67 micromol g(-1), respectively). Thus, glutamine synthesis and accumulation in the brain was not the major cause of death in these two mudskippers confronted with acute ammonia toxicity. Indeed, MSO, at a dosage (100 microg g(-1) fish) protective for rats, did not protect B. boddaerti against acute ammonia toxicity, although it was an inhibitor of GS activities from the brains of both mudskippers. In the case of P. schlosseri, MSO only prolonged the time to death but did not reduce the mortality rate (100%). In addition, MK801 (2 microg g(-1) fish) had no protective effect on P. schlosseri and B. boddaerti injected with a lethal dose of CH3COONH4, indicating that activation of NMDA receptors was not the major cause of death during acute ammonia intoxication. Thus, it can be concluded that there are major differences in mechanisms of chronic and acute ammonia toxicity between brains of these two mudskippers and mammalian brains.
We explored the severity and risk factors for cardiac and liver iron overload (IOL) in 69 thalassemia patients who underwent T2* magnetic resonance imaging (T2* MRI) in a Malaysian tertiary hospital from 2011 to 2015. Fifty-three patients (76.8%) had transfusion-dependent thalassemia (TDT) and 16 (23.2%) had non transfusion-dependent thalassemia (NTDT). Median serum ferritin prior to T2* MRI was 3848.0 μg/L (TDT) and 3971.0 μg/L (NTDT). Cardiac IOL was present in 16 (30.2%) TDT patients and two (12.5%) NTDT patients, in whom severe cardiac IOL defined as T2* <10 ms affected six (11.3%) TDT patients. Liver IOL was present in 51 (96.2%) TDT and 16 (100%) NTDT patients, 37 (69.8%) TDT and 13 (81.3%) NTDT patients were in the most severe category (>15 mgFe/gm dry weight). Serum ferritin showed a significantly strong negative correlation with liver T2* in both TDT (rs = -0.507, p = 0.001) and NTDT (r = -0.762, p = 0.002) but no correlation to cardiac T2* in TDT (r = -0.252, p = 0.099) as well as NTDT (r = -0.457, p = 0.100). For the TDT group, regression analysis showed that cardiac IOL was more severe in males (p = 0.022) and liver IOL was more severe in the Malay ethnic group (p = 0.028) and those with higher serum ferritin levels (p = 0.030). The high prevalence of IOL in our study and the poor correlation between serum ferritin and cardiac T2* underline the need to routinely screen thalassemia patients using T2* MRI to enable the early detection of cardiac IOL.
Isosteviol sodium (STVNa) is a beyerane diterpene synthesized via acid hydrolysis of stevioside, which can improve glucose and lipid metabolism in animals with diabetes. However, it remains unknown whether STVNa can exhibit a therapeutic effect on nonalcoholic fatty liver disease (NAFLD) and its underlying mechanism. We hypothesize that autophagic initiation may play a key role in mediating the development of NAFLD. Herein, we assessed the effects of STVNa on NAFLD and its underlying mechanisms. The results demonstrated that STVNa treatment effectively ameliorated NAFLD in rats fed high-fat diet (HFD). Moreover, STVNa decreased the expression of inflammation-related genes and maintained a balance of pro-inflammatory cytokines in NAFLD rats. STVNa also reduced lipid accumulation in free fatty acid (FFA)-exposed LO2 cells. In addition, STVNa attenuated hepatic oxidative stress and fibrosis in NAFLD rats. Furthermore, STVNa enhanced autophagy and activated Sirtuin 1/adenosine monophosphate-activated protein kinase (Sirt1/AMPK) pathway both in vivo and in vitro, thus attenuating intracellular lipid accumulation. In summary, STVNa could improve lipid metabolism in NAFLD by initiating autophagy via Sirt1/AMPK pathway. Therefore, STVNa may be an alternative therapeutic agent for treatment of NAFLD.
An effective drought monitoring tool is essential for the development of timely drought early warning system. This study evaluates Evaporative Demand Drought Index (EDDI) as a drought indicator in measuring spatiotemporal evolution of droughts over Peninsular Malaysia during 1989-2018. The modified Mann-Kendall and Sen's slope tests were performed to detect the presence of monotonic trends in EDDI, Standardized Precipitation Index (SPI), Standardized Precipitation Evapotranspiration Index (SPEI) and their related climate variables. The performance of EDDI in capturing the drought onset, evolutions and demise of historical severe droughts was also compared with SPI and SPEI at multiple timescales. EDDI demonstrates strong spatiotemporal correlations with SPI and SPEI and comparable performance in historical drought events identification. At sub-monthly timescale, 2-week EDDI displays equivalent drought severities and durations for all historical severe droughts corresponding to the monthly EDDI. In the case when rainfall deficits are normalized in an otherwise warm and dry month, EDDI may serve as a great alternative to SPI and SPEI due to it being sensitive to the changes in prevalent atmospheric conditions. Collectively, the results fill in the knowledge gaps on drought evolutions from the evaporative perspective and highlight the efficacy of EDDI as a valuable drought early warning tool for Peninsular Malaysia. Future study should explore the physical mechanisms behind the development of flash drought and the role of evaporation in the drought propagation processes.