Author: Koopmans, Guido ; Hasse, Birgit ; Rohbeck, Elisabeth ; Romacho, Tania ; Belgardt, Bengt‐Frederik ; Eckel, Jürgen ; Roden, Michael ; Romero, Alejandra

AbstractAimTo determine if a novel positive allosteric modulator of the γ‐aminobutyric acid type A (GABAA) receptor, the thioacrylamide‐derivative HK4, which does not penetrate the blood–brain barrier, protects human hepatocytes against lipotoxicity‐induced injury.Materials and MethodsAllosteric modulation of the GABAAreceptor by HK4 was determined by patch clamp in HEK‐293 cells, calcium influx in INS‐1E cells and by using the specific GABAAchannel blockers picrotoxin and tert‐butylbicyclophosphorothionate (TBPS) in HepG2 cells. Apoptosis was analysed using caspase 3/7, terminal deoxynucleotidyl transferase‐dUTP nick end labelling (TUNEL) and array assays in HepG2 cells and/or human primary hepatocytes. Phosphorylation of STAT3 and the NF‐κB subunit p65, protein disulphide isomerase (PDI) and poly‐ADP‐ribose polymerase‐1 (PARP‐1) was detected by Western blotting.ResultsPatch clamping, calcium influx measurements and apoptosis assays with the non‐competitive GABAAchannel blockers picrotoxin and TBPS proved HK4 as a selective positive allosteric modulator of the GABAAreceptor. In HepG2 cells, which expressed the main GABAAreceptor subunits, HK4 prevented palmitate‐induced apoptosis. This protective effect was mediated by downregulation of caspase 3/7 activity and was additionally verified by TUNEL assay. HK4 effectively prevented palmitate‐induced apoptosis in human primary hepatocytes. HK4 reduced STAT3 and NF‐κB phosphorylation, reduced cleaved PARP‐1 expression and upregulated the endoplasmic reticulum (ER) chaperone PDI.ConclusionsHK4 reduced lipotoxic‐induced apoptosis by preventing inflammation, DNA damage and ER stress. We propose that the effect of HK4 is mediated by STAT3 and NF‐κB. It is suggested that thioacrylamide compounds represent an innovative pharmacological tool to treat or prevent non‐alcoholic steatohepatitis as first‐in‐class drugs.

01 Jul 2021·Microbiological ResearchQ2 · BIOLOGY

Genomics assisted functional characterization of Paenibacillus polymyxa HK4 as a biocontrol and plant growth promoting bacterium

Q2 · BIOLOGY

Article

Author: Soni, Riteshri ; Rawal, Khushboo ; Keharia, Hareshkumar

The diseases caused by phytopathogens account for huge economic losses in the agricultural sector. Paenibacillus polymyxa is one of the agriculturally important biocontrol agents and plant growth promoting bacterium. This study describes the antifungal potential of P. polymyxa HK4 against an array of fungal phytopathogens and its ability to stimulate seed germination of cumin and groundnut under in vitro conditions. The cumin and groundnut seeds bacterized with HK4 exhibited enhanced germination efficiency in comparison to controls. The use of HK4 as a soil inoculant significantly promoted the shoot length and fresh weight of groundnut plants in pot studies. The draft genome analysis of HK4 revealed the genetic attributes for motility, root colonization, antagonism, phosphate solubilization, siderophore production and production of volatile organic compounds. The bacterium HK4 harnessed several hydrolytic enzymes that may assist its competence in the rhizosphere. The PCR amplification and sequence analysis of the conserved region of the fusA gene amplicon revealed the ability of HK4 to produce fusaricidin. Furthermore, the LC-ESI-MS/MS of crude cell pellet extract of HK4 confirmed the presence of fusaricidin as a major antifungal metabolite. This study demonstrated the potential of HK4 as a biocontrol agent and a plant growth promoter.

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetes Mellitus	Preclinical	DE	Heinrich-Heine-Universität Düsseldorf	-

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