Nicotinamide riboside (NR) has recently become one of the most studied nicotinamide adenine dinucleotide (NAD+) precursors, due to its numerous potential health benefits mediated via elevated NAD+ content in the body. NAD+ is an essential coenzyme that plays important roles in various metabolic pathways and increasing its overall content has been confirmed as a valuable strategy for treating a wide variety of pathophysiological conditions. Accumulating evidence on NRs’ health benefits has validated its efficiency across numerous animal and human studies for the treatment of a number of cardiovascular, neurodegenerative, and metabolic disorders. As the prevalence and morbidity of these conditions increases in modern society, the great necessity has arisen for a rapid translation of NR to therapeutic use and further establishment of its availability as a nutritional supplement. Here, we summarize currently available data on NR effects on metabolism, and several neurodegenerative and cardiovascular disorders, through to its application as a treatment for specific pathophysiological conditions. In addition, we have reviewed newly published research on the application of NR as a potential therapy against infections with several pathogens, including SARS-CoV-2. Additionally, to support rapid NR translation to therapeutics, the challenges related to its bioavailability and safety are addressed, together with the advantages of NR to other NAD+ precursors.

K ؉ channels operate in the plasma membrane and in membranes of organelles including mitochondria. The mechanisms and topogenic information for their differential synthesis and targeting is unknown. This article describes 2 similar viral K ؉ channels that are differentially sorted; one protein (Kesv) is imported by the Tom complex into the mitochondria, the other (Kcv) to the plasma membrane. By creating chimeras we discovered that mitochondrial sorting of Kesv depends on a hierarchical combination of N-and C-terminal signals. Crucial is the length of the second transmembrane domain; extending its C terminus by >2 hydrophobic amino acids redirects Kesv from the mitochondrial to the plasma membrane. Activity of Kesv in the plasma membrane is detected electrically or by yeast rescue assays only after this shift in sorting. Hence only minor structural alterations in a transmembrane domain are sufficient to switch sorting of a K ؉ channel between the plasma membrane and mitochondria.algal viruses ͉ dual targeting ͉ Kϩ channel sorting ͉ PBCV-1 ͉ Esv-1

Previous studies have established that chlorella viruses encode K؉ channels with different structural and functional properties. In the current study, we exploit the different sensitivities of these channels to Cs ؉ to determine if the membrane depolarization observed during virus infection is caused by the activities of these channels. Infection of Chlorella NC64A with four viruses caused rapid membrane depolarization of similar amplitudes, but with different kinetics. Depolarization was fastest after infection with virus SC-1A (half time [t 1/2 ], about 9 min) and slowest with virus NY-2A (t 1/2 , about 12 min). Cs ؉ inhibited membrane depolarization only in viruses that encode a Cs ؉ -sensitive K ؉ channel. Collectively, the results indicate that membrane depolarization is an early event in chlorella virus-host interactions and that it is correlated with viral-channel activity. This suggestion was supported by investigations of thin sections of Chlorella cells, which show that channel blockers inhibit virus DNA release into the host cell. Together, the data indicate that the channel is probably packaged in the virion, presumably in its internal membrane. We hypothesize that fusion of the virus internal membrane with the host plasma membrane results in an increase in K ؉ conductance and membrane depolarization; this depolarization lowers the energy barrier for DNA release into the host.

The K + channel Kcv is encoded by the chlorella virus PBCV-1. There is evidence that this channel plays an essential role in the replication of the virus, because both PBCV-1 plaque formation and Kcv channel activity in Xenopus oocytes have similar sensitivities to inhibitors. Here we report circumstantial evidence that the Kcv channel is important during virus infection. Recordings of membrane voltage in the host cells Chlorella NC64A reveal a membrane depolarization within the ¢rst few minutes of infection. This depolarization displays the same sensitivity to cations as Kcv conductance; depolarization also requires the intact membrane of the virion. Together these data are consistent with the idea that the virus carries functional K + channels in the virion and inserts them into the host cell plasma membrane during infection.

The chlorella virus PBCV-1 encodes a 94-amino acid protein named Kcv that produces a K+-selective and slightly voltage-sensitive conductance when expressed in heterologous systems. As reported herein, (i) Northern analysis of kcv expression in PBCV-1-infected cells revealed a complicated pattern suggesting that the gene might be transcribed as a di- or tri-cistronic mRNA both at early and late times after virus infection. (ii) The protein kinase inhibitors H-89, A3, and staurosporine inhibited PBCV-1 Kcv activity in Xenopus oocytes, suggesting that Kcv activity might be controlled by phosphorylation or dephosphorylation. (iii) The PBCV-1 genomic sequence revealed a gene encoding a putative protein kinase (pkx) adjacent to kcv. These findings prompted us to examine the kcv flanking regions in 16 additional chlorella viruses and transcription in two of these viruses, as well as the effect of the three protein kinase inhibitors on two Kcv homologs in Xenopus oocytes. The results indicate (i) pkx is always located 5' to kcv, but the spacing between the two genes varies from 31 to 1588 nucleotides. More variation occurs in the kcv 3' flanking region of the 16 viruses. (ii) The kcv gene is expressed as a late mono-cistronic mRNA. (iii) Unlike the affect on PBCV-1 Kcv, the three protein kinase inhibitors have little or no effect on the activity of the two Kcv homologs in oocytes. (iv) A comparison of the kcv 5' upstream sequences from the 16 viruses identified a highly conserved 10-nucleotide sequence that is present in the promoter region of all of the viruses.