High output cardiac state: evaluating the incidence, plausible etiologies and outcomes.

Introduction: The high output cardiac state (HOCS) [cardiac index (CI) >4 L/min/m2 ], primarily driven by abnormally low systemic vascular resistance (SVR), is a relatively under-recognized condition. Although, majority of these patients meet criteria for heart failure (HF), their treatment should be aimed at the primary pathology, as the majority of guideline directed HF therapies can reduce SVR further.

Objectives: To characterize patients with HOCS and provide valuable insight into the condition.

Ultrafast Biomimetic Oxidative Folding of Cysteine-rich Peptides and Microproteins in Organic Solvents.

Disulfides in peptides and proteins are essential for maintaining a properly folded structure. Their oxidative folding is invariably performed in an aqueous-buffered solution. However, this process is often slow and can lead to misfolded products.

Broad-spectrum ginsentides are principal bioactives in unraveling the cure-all effects of ginseng.

Stress and illness connection is complex and involves multiple physiological systems. Panax ginsengs, reputed for their broad-spectrum "cure-all" effect, are widely prescribed to treat stress and related illnesses. However, the identity of ginseng's "cure-all" medicinal compounds that relieve stress remains unresolved.

Ginsentide-like Coffeetides Isolated from Coffee Waste Are Cell-Penetrating and Metal-Binding Microproteins.

Coffee processing generates a huge amount of waste that contains many natural products. Here, we report the discovery of a panel of novel cell-penetrating and metal ion-binding microproteins designated coffeetide cC1a-c and cL1-6 from the husk of two popular coffee plants, and , respectively. Combining sequence determination and a database search, we show that the prototypic coffeetide cC1a is a 37-residue, eight-cysteine microprotein with a hevein-like cysteine motif, but without a chitin-binding domain.

Plant-derived cell-penetrating microprotein α-astratide aM1 targets Akt signaling and alleviates insulin resistance.

Insulin-resistant diabetes is a common metabolic disease with serious complications. Treatments directly addressing the underlying molecular mechanisms involving insulin resistance would be desirable. Our laboratory recently identified a proteolytic-resistant cystine-dense microprotein from huáng qí (Astragalus membranaceus) called α-astratide aM1, which shares high sequence homology to leginsulins.

Design of Potent and Salt-Insensitive Antimicrobial Branched Peptides.

Dendrimeric and branched peptides are polypeptides formed by diverse types of scaffolds to give them different forms. Previously, we reported a cascade-type, Lys-scaffolded antimicrobial peptide dendrimer D4R tethered with four RLYR tetrapeptides. Antimicrobial D4R is broad-spectrum, salt insensitive, and as potent as the natural-occurring tachyplesins, displaying minimum inhibitory concentrations (MIC) < 1 μM.

Ginsentide TP1 Protects Hypoxia-Induced Dysfunction and ER Stress-Linked Apoptosis.

Hypoxia-induced vascular endothelial dysfunction (VED) is a significant contributor to several severe human diseases, including heart disease, stroke, dementia, and cancer. However, current treatment options for VED are limited due to the lack of understanding of the underlying disease mechanisms and therapeutic leads. We recently discovered a heat-stable microprotein in ginseng, called ginsentide TP1, that has been shown to reduce vascular dysfunction in cardiovascular disease models.

Alternatives to Hospitalization: Adding the Patient Voice to Advanced Heart Failure Management.

Advanced heart failure (HF) is associated with the extensive use of acute care services, especially at the end of life, often in stark contrast to the wishes of most HF patients to remain at home for as long as possible. The current Canadian model of hospital-centric care is not only inconsistent with patient goals, but also unsustainable in the setting of the current hospital-bed availability crisis across the country. Given this context, we present a narrative to discuss factors necessary for the avoidance of hospitalization in advanced HF patients.

Multidisciplinary strategies to enhance therapeutic effects of flavonoids from Epimedii Folium: Integration of herbal medicine, enzyme engineering, and nanotechnology.

Flavonoids such as baohuoside I and icaritin are the major active compounds in Epimedii Folium (EF) and possess excellent therapeutic effects on various diseases. Encouragingly, in 2022, icaritin soft capsules were approved to reach the market for the treatment of hepatocellular carcinoma (HCC) by National Medical Products Administration (NMPA) of China. Moreover, recent studies demonstrate that icaritin can serve as immune-modulating agent to exert anti-tumor effects.

Impact of C-reactive protein levels on lipoprotein(a)-associated aortic stenosis incidence and progression.

Aims: Elevated lipoprotein(a) [Lp(a)] levels are associated with the risk of coronary artery disease (CAD) and calcific aortic valve stenosis (CAVS). Observational studies revealed that Lp(a) and C-reactive protein (CRP) levels, a biomarker of systemic inflammation, may jointly predict CAD risk. Whether Lp(a) and CRP levels also jointly predict CAVS incidence and progression is unknown.

A Cascade Enzymatic Reaction Scheme for Irreversible Transpeptidative Protein Ligation.

Enzymatic peptide ligation holds great promise in the study of protein functions and development of protein therapeutics. Owing to their high catalytic efficiency and a minimal tripeptide recognition motif, peptidyl asparaginyl ligases (PALs) are particularly useful tools for bioconjugation. However, as an inherent limitation of transpeptidases, PAL-mediated ligation is reversible, requiring a large excess of one of the ligation partners to shift the reaction equilibrium in the forward direction.

Substrate-binding glycine residues are major determinants for hydrolase and ligase activity of plant legumains.

Peptide asparaginyl ligases (PALs) are useful tools for precision modifications of proteins and live-cell surfaces by ligating peptides after Asn/Asp (Asx). They share high sequence and structural similarity to plant legumains that are generally known as asparaginyl endopeptidases (AEPs), thus making it challenging to identify PALs from AEPs. In this study, we investigate 875 plant species from algae to seed plants with available sequence data in public databases to identify new PALs.

Consensus design and engineering of an efficient and high-yield peptide asparaginyl ligase for protein cyclization and ligation.

Plant legumains are Asn/Asp-specific endopeptidases that have diverse functions in plants. Peptide asparaginyl ligases (PALs) are a special legumain subtype that primarily catalyze peptide bond formation rather than hydrolysis. PALs are versatile protein engineering tools but are rarely found in nature.

Structural basis for proenzyme maturation, substrate recognition, and ligation by a hyperactive peptide asparaginyl ligase.

Peptide ligases are versatile enzymes that can be utilized for precise protein conjugation for bioengineering applications. Hyperactive peptide asparaginyl ligases (PALs), such as butelase-1, belong to a small class of enzymes from cyclotide-producing plants that can perform site-specific, rapid ligation reactions after a target peptide asparagine/aspartic acid (Asx) residue binds to the active site of the ligase. How PALs specifically recognize their polypeptide substrates has remained elusive, especially at the prime binding side of the enzyme.

Hyperstable EGF-like bleogen derived from cactus accelerates corneal healing in rats.

Corneal scarring reduces corneal transparency, compromises vision, and is a major cause of vision loss worldwide. Epidermal growth factor (EGF), which is the prototypic member of the EGF receptor (EGFR) agonists, is present in tears to provide repair and regeneration. Recently, we discovered bleogen pB1 in the cactus plant and showed that it is a non-canonical and hyperstable EGFR agonist with EGF-like wound healing properties for diabetic rats.

PAL-Mediated Ligation for Protein and Cell-Surface Modification.

Peptidyl Asx-specific ligases (PALs) effect peptide ligation by catalyzing transpeptidation reactions at Asn/Asp-peptide bonds. Owing to their high efficiency and mild aqueous reaction conditions, these ligases have emerged as powerful biotechnological tools for protein manipulation in recent years. PALs are enzymes of the asparaginyl endopeptidase (AEP) superfamily but have predominant transpeptidase activity as opposed to typical AEPs which are predominantly hydrolases.

Hololectin Interdomain Linker Determines Asparaginyl Endopeptidase-Mediated Maturation of Antifungal Hevein-Like Peptides in Oats.

Heveins and hevein-containing (hev-) lectins play important roles in stress and pathogenic responses in plants but cause health concerns in humans. Hev-hololectins contain multiple modular hev-peptide domains and are abundantly present in cereals and pseudocereals. However, it is unclear why some cereal hev-hololectins are presented as different forms of proteolytically processed proteoforms.

The Critical Transfer From Paediatrics to Adult Care in Patients With Congenital Heart Disease: Predictors of Transfer and Retention of Care.

Background: Congenital heart disease is the most common congenital birth defect and presents with differing degrees of complexity. Patients require lifelong specialized care. The transfer from paediatric to adult care is a time of risk that may result in lapses or loss of care.

Characterization and application of natural and recombinant butelase-1 to improve industrial enzymes by end-to-end circularization.

Butelase-1, an asparaginyl endopeptidase or legumain, is the prototypical and fastest known Asn/Asp-specific peptide ligase. It is highly useful for engineering and macrocyclization of peptides and proteins. However, certain biochemical properties and applications of naturally occurring and recombinant butelase-1 remain unexplored.

COVID-19 Vaccination-Induced Myopericarditis: An Imager's Perspective.

COVID-19 vaccine-induced myocarditis is a rare adverse event in the current pandemic. The following is a case series of 10 individuals with COVID-19 vaccine-related myocarditis confirmed by cardiac magnetic resonance imaging. In this cohort of predominantly male patients, with a mean age of 23 years, chest discomfort and positive cardiac biomarkers occurred at a median of 3 days after the second COVID-19 vaccine dose.

Vypal2: A Versatile Peptide Ligase for Precision Tailoring of Proteins.

The last two decades have seen an increasing demand for new protein-modification methods from the biotech industry and biomedical research communities. Owing to their mild aqueous reaction conditions, enzymatic methods based on the use of peptide ligases are particularly desirable. In this regard, the recently discovered peptidyl Asx-specific ligases (PALs) have emerged as powerful biotechnological tools in recent years.

Asparaginyl Endopeptidase-Mediated Protein C-Terminal Hydrazinolysis for the Synthesis of Bioconjugates.

Asparaginyl endopeptidases (AEPs) are cysteinyl enzymes naturally catalyzing the hydrolysis and transpeptidation reactions at Asx-Xaa bonds. These reactions go by a common acyl-enzyme thioester intermediate, which is either attacked by water (for a protease-AEP) or by a peptidic amine nucleophile (for a ligase-AEP) to form the respective hydrolysis or aminolysis product. Herein, we show that hydrazine and hydroxylamine, two α-effect nucleophiles, are capable of resolving the thioester intermediate to yield peptide and protein products containing a C-terminal hydrazide and hydroxamic acid functionality, respectively.

Site-Specific Protein Modifications by an Engineered Asparaginyl Endopeptidase from .

Asparaginyl endopeptidases (AEPs) or legumains are Asn/Asp (Asx)-specific proteases that break peptide bonds, but also function as peptide asparaginyl ligases (PALs) that make peptide bonds. This ligase activity can be used for site-specific protein modifications in biochemical and biotechnological applications. Although AEPs are common, PALs are rare.