Tumor necrosis factor-induced lethal hepatitis: pharmacological intervention with verapamil, tannic acid, picotamide and K76COOH.

AbstractTumor necrosis factor (TNF) induces hepatitis when injected in human beings or in rodents. The molecular mechanism by which TNF induces hepatic distress remains largely unknown, although induction of apoptosis of hepatocytes appears to be an essential step. In order to increase the therapeutic value of TNF, we have studied the protective activity of several molecules and found that four chemically totally different substances confer significant protection in the model of TNF-induced lethal hepatitis in mice sensitized with D-(+)-galactosamine (GalN), but not in mice sensitized with actinomycin-D (ActD) or against anti-Fas-induced lethal hepatitis. Verapamil, a calcium-channel blocker, tannic acid, picotamide, a thromboxane A2 receptor antagonist, and K76COOH, an inhibitor, amongst others, of complement, protected significantly against induction of lethality, release of the liver-specific enzyme alanine aminotransferase (ALT) and induction of apoptosis in the liver after TNF/GalN, except for K76COOH, which paradoxically increased ALT values after challenge, and which also protected against TNF/GalN in complement-deficient mice. The data suggest that activation of platelets and neutrophils, as well as induction of inflammation occur in the TNF/GalN model, but not in the TNF/ActD or anti-Fas models, in which direct induction of apoptosis of hepatocytes may be more relevant. The protective activity of the drugs may lead to an increase in therapeutic value of TNF

Application of computational fluid dynamics modelling to an ozone contactor

Computational fluid dynamics (CFD) modelling has been applied to examine the operation of the pre-ozonation system at Wiggins Waterworks, operated by Umgeni Water in Durban, South Africa. A hydraulic model has been satisfactorily verified by experimental tracer tests. The turbulence effect induced by the gas injection was modelled by increasing the level of turbulence intensity at the ozone contactor inlet. The simulated tracer response corresponded closely to the experimental results. The framework of ozone reaction modelling was subsequently investigated using values of rate constants from the literature. The predicted profile of residual ozone concentration suggests the current operating strategy can be improved to optimise the ozone utilisation. The wide range of values found in the literature suggests that the ozone reactions are strongly dependent on site-specific characteristics of the water. Further experimental work is required to determine rate constants which are applicable to water from the Inanda Dam. Water SA Vol.30(1): 51-5

Nitric oxide regulates skeletal muscle fatigue, fiber type, microtubule organization, and mitochondrial ATP synthesis efficiency through cGMP-dependent mechanisms

Aim: Skeletal muscle nitric oxide–cyclic guanosine monophosphate (NO-cGMP) pathways are impaired in Duchenne and Becker muscular dystrophy partly because of reduced nNOSμ and soluble guanylate cyclase (GC) activity. However, GC function and the consequences of reduced GC activity in skeletal muscle are unknown. In this study, we explore the functions of GC and NO-cGMP signaling in skeletal muscle. Results: GC1, but not GC2, expression was higher in oxidative than glycolytic muscles. GC1 was found in a complex with nNOSμ and targeted to nNOS compartments at the Golgi complex and neuromuscular junction. Baseline GC activity and GC agonist responsiveness was reduced in the absence of nNOS. Structural analyses revealed aberrant microtubule directionality in GC1−/− muscle. Functional analyses of GC1−/− muscles revealed reduced fatigue resistance and postexercise force recovery that were not due to shifts in type IIA–IIX fiber balance. Force deficits in GC1−/− muscles were also not driven by defects in resting mitochondrial adenosine triphosphate (ATP) synthesis. However, increasing muscle cGMP with sildenafil decreased ATP synthesis efficiency and capacity, without impacting mitochondrial content or ultrastructure. Innovation: GC may represent a new target for alleviating muscle fatigue and that NO-cGMP signaling may play important roles in muscle structure, contractility, and bioenergetics. Conclusions: These findings suggest that GC activity is nNOS dependent and that muscle-specific control of GC expression and differential GC targeting may facilitate NO-cGMP signaling diversity. They suggest that nNOS regulates muscle fiber type, microtubule organization, fatigability, and postexercise force recovery partly through GC1 and suggest that NO-cGMP pathways may modulate mitochondrial ATP synthesis efficiency

The potential of decentralised wastewater treatment in urban and rural sanitation in South Africa: lessons learnt from a demonstration-scale DEWATS within the eThekwini Municipality

The design principles of decentralised wastewater treatment systems (DEWATS) make them a practical sanitation option for municipalities to adopt in fast-growing cities in South Africa. Since 2014, a demonstration scale DEWATS with a modular design consisting of a settler, anaerobic baffled reactor (ABR), anaerobic filter (AF), vertical down-flow constructed wetland (VFCW) and horizontal flow constructed wetland (HFCW) has been in operation in eThekwini. A performance evaluation after the long-term operation was undertaken in 2019 by comparing the final effluent with national regulatory requirements. Despite limitations in characterising the raw wastewater, a comparison of the settler and final effluent quality indicated high (≥ 85%) removal efficiencies of total chemical oxygen demand (CODt), ammonium-N (NH4-N) and orthophosphate-P (PO4-P), 75% removal of total suspended solids (TSS) and 83.3% log10 removal of Escherichia coli. Lack of exogenous and endogenous carbon and high dissolved oxygen (DO) concentrations (> 0.5 mg·L−1) inhibited denitrification in the HFCW, resulting in 12.5% of the effluent samples achieving compliance for nitrate-N (NO3-N). Moreover, mixed aggregate media and low residence times in the HFCW may have also contributed to poor NO3-N removal. During the COVID-19 lockdown, an unexpected shutdown and subsequent resumption of flow to the DEWATS indicated a 16-week recovery time based on achieving full nitrification in the HFCW. Although design modifications are necessary for the HFCW, the installation of urine diversion flushing toilets at the household level will reduce the nutrient loading to the DEWATS and potentially achieve fully compliant effluent. Alternatively, the application of two-stage vertical flow constructed wetlands to improve denitrification should also be explored in the South African context. With an improved design, DEWATS has the potential to fill the gap in both urban and rural sanitation in South Africa, where waterborne sanitation is still desired but connections to conventional wastewater treatment works (WWTWs) are not possible.&nbsp

Ferulic acid-4-O-sulfate rather than ferulic acid relaxes arteries and lowers blood pressure in mice

Consumption of foods rich in ferulic acid (FA) such as wholegrain cereals, or FA precursors such as chlorogenic acids in coffee, is inversely correlated with risk of cardiovascular disease and type 2 diabetes. As a result of digestion and phase II metabolism in the gut and liver, FA is converted predominantly into ferulic acid-4-O-sulfate (FA-sul), an abundant plasma metabolite. Although FA-sul may be the main metabolite, very little has been reported regarding its bioactivities. We have therefore compared the ex vivo vasorelaxing effect of FA and FA-sul (10−7 - 3.10−5 M) on isolated mouse arteries mounted in tissue myographs. FA-sul, but not FA, elicited a concentration-dependent vasorelaxation of saphenous and femoral arteries and aortae. The FA-sul mediated vasorelaxation was blunted by 1H- [1, 2, 4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a soluble guanylate cyclase (sGC) inhibitor. The role of sGC was confirmed in femoral arteries isolated from sGCα1(−/−) knockout mice. Furthermore, 4-aminopyridine, a specific inhibitor of voltage-dependent potassium channels, significantly decreased FA-sul mediated effects. In anesthetized mice, intravenous injection of FA-sul decreased mean arterial pressure, whereas FA had no effect, confirming the results obtained ex vivo. FA-sul is probably one of the major metabolites accounting for the blood pressure-lowering effects associated with FA consumption

SAFE: A Framework for Assessing Sustainability Levels in Agricultural Systems

Evaluating the sustainability of agricultural systems is a major challenge for scientists, policy makers and farmers. Numerous sets of indicators have recently been designed, both at national and international levels. However, most of these initiatives focus only on environmental aspects of sustainability, indicators are often selected arbitrarily and usually do not fit in a consistent, comprehensive and universally applicable framework. This paper presents an original framework for integrating the information contained by indicators into a single quantitative measure of agricultural sustainability in order to facilitate comparison and diagnosis