Comprehensive Ecotoxicity Studies on Quaternary Ammonium Salts Synthesized from Vitamin B3 Supported by QSAR Calculations.

Lately, ionic forms (namely, quaternary ammonium salts, QASs) of nicotinamide, widely known as vitamin B3, are gaining popularity in the sectors developing novel pharmaceuticals and agrochemicals. However, the direct influence of these unique QASs on the development of various terrestrial plants, as well as other organisms, remains unknown. Therefore, three compounds comprising short, medium, and long alkyl chains in N-alkylnicotinamide were selected for phytotoxicity analyses, which were conducted on representative dicotyledonous (white mustard) and monocotyledonous (sorghum) plants. The study allowed the determination of the impact of compounds on the germination capacity as well as on the development of roots and stems of the tested plants. Interestingly, independently of the length of the alkyl chain or plant species, all QASs were established as non-phytotoxic. In addition, QSAR simulations, performed using the EPI Suite™ program pack, allowed the determination of the products' potential toxicity toward fish, green algae, and daphnids along with the susceptibility to biodegradation. The obtained nicotinamide derivative with the shortest chain (butyl) can be considered practically non-toxic according to GHS criteria, whereas salts with medium (decyl) and longest (hexadecyl) substituent were included in the 'acute II' toxicity class. These findings were supported by the results of the toxicity tests performed on the model aquatic plant Lemna minor. It should be stressed that all synthesized salts exhibit not only a lack of potential for bioaccumulation but also lower toxicity than their fully synthetic analogs.

Pulmonary artery targeted therapy in treatment of COVID-19 related ARDS. Literature review.

INTRODUCTION: The most grievous complication of the COVID-19 is the acute respiratory distress syndrome. A specific, rescue treatment for rapidly deteriorating patients should emerge to improve respiratory function and help patients to survive the most challenging period. Drugs used in targeted therapy of pulmonary arterial hypertension (PAH) appears to be suitable for this task and this article describes their potential for treatment of severe cases of COVID-19. METHODS: The authors reviewed the following databases for randomized controlled trials, reviews and meta-analyses published up to July 2020: Pubmed, Scopus, Google Scholar, Cochrane Database and ClinicalKey. The authors included every study contributory to the assessment of the potential of drugs used in targeted PAH therapy in treatment of COVID-19. RESULTS: Endothelin receptor antagonists, phosphodiesterase 5 inhibitors, riociguat and prostacyclin have proven ani-inflammatory effect and reduce pulmonary artery blood pressure, lung oedema and remodelling. Bosentan shows antiviral properties and sildenafil, as well as epoprostenol, inhibits apoptosis of lung epithelial cells. Among patients with lung lesions the decrease of pulmonary blood pressure can lead to increase of ventilation/perfusion mismatch and decrease of blood oxygenation. CONCLUSIONS: Among all assessed drugs bosentan, sildenafil and epoprostenol appear to be most promising and a combination of these drugs should be considered due to synergism. The targeted PAH therapy in treatment of COVID-19 associated ARDS could be a useful tool saving lives of patients with severe SARS-CoV-2 infection, however, its introduction should be investigated and monitored very carefully as it can lead to transient deterioration of patient condition.

Potential of herbal products in prevention and treatment of COVID-19. Literature review.

The COVID-19 epidemic is the greatest pandemic that human kind experienced for decades, with high morbidity and mortality. Despite recent development of vaccines there is still many severe cases of COVID-19. Unfortunately there is still no standardized therapies and treatment of severe cases is very challenging. The aim of this study is to indicate if herbs administered alone or as a complementary therapy could be used as prophylaxis or treatment of SARS-CoV-2 infection. Over 85% of patients with COVID-19 in China used Traditional Chinese Medicine (TCM), and a most common herb is Glycyrrhiza glabra, which in vitro inhibits replication of different enveloped viruses, including coronaviruses. Glycyrrhizin in vitro connects and changes conformation of ACE2 receptors, which are vital for SARS-CoV-2 penetration into host cells. Pelargonium sidoides show immunomodulatory and antiviral properties in clinical and in vitro studies, and it inhibits replication of HCo-229E coronavirus. Glycyrrhiza glabra in combination with standard therapies significantly reduces the hospitalization rate and occurrence of COVID-19 symptoms. As complementary therapies lianhuaqingwen capsules and jinhua qinggan granules reduces hospitalization rates, time to symptoms recovery and improve patient psychological comfort. In view of SARS-CoV-2 other herbs are not effective, e.g. maxingshigan-yinqiaosan, or therapeutic concentration would be impossible to achieve, e.g. ephedra herb, or there is simply no proper data. Therefore, Liquorice and Pelargonium sidoides are effective against coronaviruses and could be possibly used as prophylaxis and treatment of COVID-19, while lianhuaqingwen capsules and jinhua qinggan granules can be useful as a complementary therapy to conventional treatment.

Transcriptional and preliminary functional analysis of the six genes located in divergence of phoR/phoP in Streptomyces lividans.

Streptomyces lividans senses and adjusts to a situation of Pi limitation via the expression of genes of the pho regulon controlled by the two-component system PhoR/PhoP. Interestingly, an in silico analysis of the proteins encoded by the six genes located in divergence of phoR/phoP revealed that the latter bear features often found in metalloproteins involved in the sensing/resistance to oxidative stress. We determined whether genes of this region were belonging to the pho regulon and whether the encoded proteins do play a role in the resistance to oxidative stress. For this purpose, a transcriptional analysis of these genes was carried out on the carbon and nitrogen rich medium R2YE and on a minimal medium (MM). On R2YE, the expression of the genes phoU to sco4225 was much higher than on MM and constant throughout growth. On this medium, the expression of phoU was totally PhoP-dependent whereas the expression of sco4227 and sco4226 was partially PhoP-dependent, taking place from the phoU promoter region. In contrast, on MM, the expression of sco4227 and sco4226 was PhoP-independent whereas that of phoU remained PhoP-dependent and showed, as phoR/phoP, a peak of expression at 48 h. sco4225, sco4224, and sco4223 were transcribed from their own promoter independently of PhoP in both media. The mutants of five out of six genes of the region (Δsco4226 mutant could not be obtained) grew poorly in the presence of exogenous oxidants, suggesting a role of the encoded proteins in the resistance to oxidative stress, especially on the rich medium R2YE.

Mutations in the C-terminus of the conserved NDR kinase, Cbk1p of Saccharomyces cerevisiae, make the protein independent of upstream activators.

In Saccharomyces cerevisiae, the RAM network is involved in cell separation after cytokinesis, cell integrity and cell polarity. The key function of this network is the regulation of the activity of the protein kinase Cbk1p, which is a member of the conserved NDR kinase family. Cbk1p function is controlled by its sub-cellular localization and at least two phosphorylation events: an auto phosphorylation in the kinase domain (S570) and the phosphorylation of a C-terminal hydrophobic motif by an upstream kinase (T743). After a UV mutagenesis, we have isolated 115 independent extragenic suppressors of four ram mutations: tao3, hym1, kic1 and sog2. Over 50% of the suppressors affect a single residue in Cbk1p (S745F), which is close to the phosphorylation site in the hydrophobic motif. Our results show that the CBK1-S745F allele leads to a constitutively active form of Cbk1p that is independent of the upstream RAM network. We hypothesize that the mutant Cbk1-S745Fp mimics the effect of the phosphorylation of T743.

Mutations in the Saccharomyces cerevisiae kinase Cbk1p lead to a fertility defect that can be suppressed by the absence of Brr1p or Mpt5p (Puf5p), proteins involved in RNA metabolism.

In Saccharomyces cerevisiae the protein kinase Cbk1p is a member of the regulation of Ace2p and cellular morphogenesis (RAM) network that is involved in cell separation after cytokinesis, cell integrity, and cell polarity. In cell separation, the RAM network promotes the daughter cell-specific localization of the transcription factor Ace2p, resulting in the asymmetric transcription of genes whose products are necessary to digest the septum joining the mother and the daughter cell. RAM and SSD1 play a role in the maintenance of cell integrity. In the presence of a wild-type SSD1 gene, deletion of any RAM component causes cell lysis. We show here that some mutations of CBK1 also lead to a reduced fertility and a reduced expression of some of the mating type-specific genes. As polarized growth is an integral part of the mating process, we have isolated suppressors of the fertility defect. Among these, mutations in BRR1 or MPT5 lead to a restoration of fertility and a more-or-less pronounced restoration of polarity; they also show genetic interactions with SSD1. Our experiments reveal a multilayered system controlling aspects of cell separation, cell integrity, mating, and polarized growth.