Diadenosine Tetraphosphate (Ap A) Serves as a 5' RNA Cap in Mammalian Cells.

The recent expansion of the field of RNA chemical modifications has changed our understanding of post-transcriptional gene regulation. Apart from internal nucleobase modifications, 7-methylguanosine was long thought to be the only eukaryotic RNA cap. However, the discovery of non-canonical RNA caps in eukaryotes revealed a new niche of previously undetected RNA chemical modifications.

NudiXes have RNA-decapping activity.

Recent discoveries of various noncanonical RNA caps, such as dinucleoside polyphosphates (Np N), coenzyme A (CoA), and nicotinamide adenine dinucleotide (NAD) in all domains of life have led to a revision of views on RNA cap function and metabolism. Enzymes from the NudiX family capable of hydrolyzing a polyphosphate backbone attached to a nucleoside are the strongest candidates for degradation of noncanonically capped RNA. The model plant organism encodes as many as 28 NudiX enzymes.

High Throughput Screening Cascade To Identify Human Aspartate -Acetyltransferase (ANAT) Inhibitors for Canavan Disease.

Canavan disease (CD) is a progressive, fatal neurological disorder that begins in infancy resulting from a mutation in aspartoacyclase (ASPA), an enzyme that catalyzes the deacetylation of -acetyl aspartate (NAA) into acetate and aspartate. Increased NAA levels in the brains of affected children are one of the hallmarks of CD. Interestingly, genetic deletion of -acetyltransferase-8-like (NAT8L), which encodes aspartate -aceyltransferase (ANAT), an enzyme responsible for the synthesis of NAA from l-aspartate and acetyl-CoA, leads to normalization of NAA levels and improvement of symptoms in several genetically engineered mouse models of CD.

Novel Human Neutral Sphingomyelinase 2 Inhibitors as Potential Therapeutics for Alzheimer's Disease.

Neutral sphingomyelinase 2 (nSMase2) catalyzes the cleavage of sphingomyelin to phosphorylcholine and ceramide, an essential step in the formation and release of exosomes from cells that is critical for intracellular communication. Chronic increase of brain nSMase2 activity and related exosome release have been implicated in various pathological processes, including the progression of Alzheimer's disease (AD), making nSMase2 a viable therapeutic target. Recently, we identified phenyl ()-(1-(3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-]pyridazin-8-yl)pyrrolidin-3-yl)carbamate , the first nSMase2 inhibitor that possesses both favorable pharmacodynamics and pharmacokinetic (PK) parameters, including substantial oral bioavailability, brain penetration, and significant inhibition of exosome release from the brain in vivo.

Antimicrobial peptides prevent bacterial biofilm formation on the surface of polymethylmethacrylate bone cement.

Purpose: Antibiotic-loaded polymethylmethacrylate-based bone cement has been implemented in orthopaedics to cope with implant-related infections associated with the formation of bacterial biofilms. In the context of emerging bacterial resistance to current antibiotics, we examined the efficacy of short antimicrobial peptide-loaded bone cement in inhibiting bacterial adhesion and consequent biofilm formation on its surface.

Methodology: The ability of α-helical antimicrobial peptides composed of 12 amino acid residues to prevent bacterial biofilm [methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis, Pseudomonas aeruginosa and Escherichia coli] formation on the surface of model implants made from polymethylmethacrylate-based bone cement was evaluated by colony-forming unit (c.

Antifungal activity of analogues of antimicrobial peptides isolated from bee venoms against vulvovaginal Candida spp.

Candida albicans is the main causative agent of vulvovaginal candidiasis (VVC), a common mycosis in women, relapses of which are difficult to manage due to biofilm formation. This study aimed at developing novel non-toxic compounds active against Candida spp. biofilms.

Antimicrobial Peptides for Topical Treatment of Osteomyelitis and Implant-Related Infections: Study in the Spongy Bone.

We examined the benefits of short linear α-helical antimicrobial peptides (AMPs) invented in our laboratory for treating bone infection and preventing microbial biofilm formation on model implants due to causative microorganisms of osteomyelitis. For this purpose, we introduced a model of induced osteomyelitis that utilizes human femur heads obtained from the hospital after their replacement with artificial prostheses. We found that the focus of the infection set up in the spongy part of this bone treated with AMP-loaded calcium phosphate cement was eradicated much more effectively than was the focus treated with antibiotics such as vancomycin or gentamicin loaded into the same cement.

How proteases from Enterococcus faecalis contribute to its resistance to short α-helical antimicrobial peptides.

HYL-20 (GILSSLWKKLKKIIAK-NH2) is an analogue of a natural antimicrobial peptide (AMP) previously isolated from the venom of wild bee. We examined its antimicrobial activity against three strains of Enterococcus faecalis while focusing on its susceptibility to proteolytic degradation by two known proteases-gelatinase (GelE) and serine protease (SprE)-which are secreted by these bacterial strains. We found that HYL-20 was primarily deamidated at its C-terminal which made the peptide susceptible to consecutive intramolecular cleavage by GelE.

Testing the efficacy of antimicrobial peptides in the topical treatment of induced osteomyelitis in rats.

Joint replacement infections and osteomyelitis are among the most serious complications in orthopaedics and traumatology. The risk factors for these infections are often bacterial resistance to antimicrobials. One of the few solutions available to control bacterial resistance involves antimicrobials, which have a different mechanism of action from traditional antibiotics.

Determination of effective charges and ionic mobilities of polycationic antimicrobial peptides by capillary isotachophoresis and capillary zone electrophoresis.

Capillary ITP (CITP) and CZE were applied to the determination of effective charges and ionic mobilities of polycationic antimicrobial peptides (AMPs). Twelve AMPs (deca- to hexadecapeptides) containing three to seven basic amino acid residues (His, Lys, Arg) at variable positions of peptide chain were investigated. Effective charges of the AMPs were determined from the lengths of their ITP zones, ionic mobilities, and molar concentrations, and from the same parameters of the reference compounds.

Antimicrobial Peptide from the Wild Bee Hylaeus signatus Venom and Its Analogues: Structure-Activity Study and Synergistic Effect with Antibiotics.

Venoms of hymenopteran insects have attracted considerable interest as a source of cationic antimicrobial peptides (AMPs). In the venom of the solitary bee Hylaeus signatus (Hymenoptera: Colletidae), we identified a new hexadecapeptide of sequence Gly-Ile-Met-Ser-Ser-Leu-Met-Lys-Lys-Leu-Ala-Ala-His-Ile-Ala-Lys-NH2. Named HYL, it belongs to the category of α-helical amphipathic AMPs.

C-Geranylated flavonoids from Paulownia tomentosa fruits with antimicrobial potential and synergistic activity with antibiotics.

Context C-6-Geranylated flavonoids possess promising biological activities. These substances could be a source of lead compounds for the development of therapeutics. Objective The study was designed to evaluate their antibacterial and antileishmanial activity.