Innovative Solid Lipid Nanoparticle-Enriched Hydrogels for Enhanced Topical Delivery of L-Glutathione: A Novel Approach to Anti-Ageing.

Skin ageing, driven predominantly by oxidative stress from reactive oxygen species (ROS) induced by environmental factors like ultraviolet A (UVA) radiation, accounts for approximately 80% of extrinsic skin damage. L-glutathione (GSH), a potent antioxidant, holds promise in combating UVA-induced oxidative stress. However, its instability and limited penetration through the stratum corneum hinder its topical application.

A novel non-invasive murine model for rapidly testing drug activity via inhalation administration against .

The efficacy of many compounds against is often limited when administered via conventional oral or injection routes due to suboptimal pharmacokinetic characteristics. Inhalation-based delivery methods have been investigated to achieve high local therapeutic doses in the lungs. However, previous models, typically employing wild-type strains, were intricate, time-consuming, labor-intensive, and with poor reproducibility.

Structure-activity relationship expansion and microsomal stability assessment of the 2-morpholinobenzoic acid scaffold as antiproliferative phosphatidylcholine-specific phospholipase C inhibitors.

Dysregulation of choline phospholipid metabolism and overexpression of phosphatidylcholine-specific phospholipase C (PC-PLC) is implicated in various cancers. Current known enzyme inhibitors include compounds based on a 2-morpholino-5--benzylamino benzoic acid, or hydroxamic acid, scaffold. In this work, 81 compounds were made by modifying this core structure to explore the pharmacophore.

Prolactin-mediates a lactation-induced suppression of arcuate kisspeptin neuronal activity necessary for lactational infertility in mice.

The specific role that prolactin plays in lactational infertility, as distinct from other suckling or metabolic cues, remains unresolved. Here, deletion of the prolactin receptor (Prlr) from forebrain neurons or arcuate kisspeptin neurons resulted in failure to maintain normal lactation-induced suppression of estrous cycles. Kisspeptin immunoreactivity and pulsatile LH secretion were increased in these mice, even in the presence of ongoing suckling stimulation and lactation.

Peroxidasin is associated with a mesenchymal-like transcriptional phenotype and promotes invasion in metastatic melanoma.

Cutaneous melanoma is a highly invasive, heterogeneous and treatment resistant cancer. It's ability to dynamically shift between transcriptional states or phenotypes results in an adaptive cell plasticity that may drive cancer cell invasion or the development of therapy resistance. The expression of peroxidasin (PXDN), an extracellular matrix peroxidase, has been proposed to be associated with the invasive metastatic melanoma phenotype.

DJK-5, an anti-biofilm peptide, increases Staphylococcus aureus sensitivity to colistin killing in co-biofilms with Pseudomonas aeruginosa.

Chronic infections represent a significant global health and economic challenge. Biofilms, which are bacterial communities encased in an extracellular polysaccharide matrix, contribute to approximately 80% of these infections. In particular, pathogens such as Pseudomonas aeruginosa and Staphylococcus aureus are frequently co-isolated from the sputum of patients with cystic fibrosis and are commonly found in chronic wound infections.

Discovery of a Potent and Selective GSPT1 Molecular Glue Degrader for the Treatment of Castration-Resistant Prostate Cancer.

The treatment of castration-resistant prostate cancer (CRPC) remains a significant challenge, necessitating the development of new and promising therapeutic strategies. Utilizing molecular glue to degrade previously intractable cancer drivers represents an emerging and promising therapeutic approach to cancer treatment. In this study, we developed a novel CRBN-interacting molecular glue, (XYD049), which exhibits potent and selective degradation of G1 to S phase transition 1 (GSPT1), a well-known untargetable cancer driver in diverse cancer cells.

Cardio-metabolic and cytoskeletal proteomic signatures differentiate stress hypersensitivity in dystrophin-deficient mdx mice.

Extreme heterogeneity exists in the hypersensitive stress response exhibited by the dystrophin-deficient mdx mouse model of Duchenne muscular dystrophy. Because stress hypersensitivity can impact dystrophic phenotypes, this research aimed to understand the peripheral pathways driving this inter-individual variability. Male and female mdx mice were phenotypically stratified into "stress-resistant" or "stress-sensitive" groups based on their response to two laboratory stressors.

Natural and Semisynthetic Immunomodulatory Luakuliide Labdane Diterpenoids.

Spectroscopy-guided isolation of extracts of the Tongan marine sponge cf. (Lamarck, 1814) has resulted in the reisolation of the labdane diterpenoid luakuliide A () and one new congener, luakulialactam A (). In addition to establishing the absolute configuration of , synthetic modifications to the luakuliide framework at key positions has created a set of six derivatives (-) which were used to interrogate a structure-activity relationship relating to the immunomodulatory effects of luakuliide A.

Genome-wide identification of bacterial genes contributing to nucleus-forming jumbo phage infection.

The Chimalliviridae family of bacteriophages (phages) form a proteinaceous nucleus-like structure during infection of their bacterial hosts. This phage 'nucleus' compartmentalises phage DNA replication and transcription, and shields the phage genome from DNA-targeting defence systems such as CRISPR-Cas and restriction-modification. Their insensitivity to DNA-targeting defences makes nucleus-forming jumbo phages attractive for phage therapy.

Improving adherence by investigating the stability of dabigatran outside of the manufacturer's original packaging: a New Zealand perspective.

Background: Dose administration aids (DAA) are widely used to improve adherence. In New Zealand (NZ) more pharmacies are utilizing automated filling robots to meet DAA demand. Pradaxa™ capsules containing dabigatran etexilate (DE) is problematic.

MIBiG 4.0: advancing biosynthetic gene cluster curation through global collaboration.

Specialized or secondary metabolites are small molecules of biological origin, often showing potent biological activities with applications in agriculture, engineering and medicine. Usually, the biosynthesis of these natural products is governed by sets of co-regulated and physically clustered genes known as biosynthetic gene clusters (BGCs). To share information about BGCs in a standardized and machine-readable way, the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard and repository was initiated in 2015.

A Stable Dehydratase Complex Catalyzes the Formation of Dehydrated Amino Acids in a Class V Lanthipeptide.

Lanthipeptides are ribosomally synthesized and post-translationally modified peptides that bear the characteristic lanthionine (Lan) or methyllanthionine (MeLan) thioether linkages. (Me)Lan moieties bestow lanthipeptides with robust stability and diverse antimicrobial, anticancer, and antiallodynic activities. Installation of (Me)Lan requires dehydration of serine and threonine residues to 2,3-dehydroalanine (Dha) and ()-2,3-dehydrobutyrine (Dhb), respectively.

Total Synthesis of (-)-Cordycicadin D and 3,4-trans-Cordycicadins A and B: Entry to the 3,4-trans-Fused Cordycicadin Framework.

Cordycicadins A-D are four C polyketides, all containing a γ-lactone fused to a 10-membered lactone. The proposed biosynthetic pathway for the cordycicadins anticipates the formation of two more natural products which are unknown. We report the total synthesis of (-)-cordycicadin D and the two anticipated natural products 3,4-trans-cordycicadins A and B.

Microbial communities associated with marine sponges from diverse geographic locations harbor biosynthetic novelty.

Marine sponges are a prolific source of biologically active small molecules, many of which originate from sponge-associated bacteria. Identifying the producing bacteria is a key step in developing sustainable routes for the production of these metabolites. To facilitate the required computational analyses, we developed MetaSing, a reproducible singularity-based pipeline for assembly, identification of high-quality metagenome-assembled genomes (MAGs), and analysis of biosynthetic gene clusters (BGCs) from metagenomic short-read data.

Synthesis of the Spirocyclic Imine Fragment of Portimines Using a γ-Hydroxymethyl-αβ-butenolide Dienophile in a Diastereoselective Diels-Alder Reaction.

The synthesis of the spirocyclic imine fragment of the portimine family of marine toxins has been achieved. A densely functionalized key lactone-ester intermediate was assembled via a highly diastereoselective Diels-Alder cycloaddition, involving a novel γ-hydroxymethyl-α,β-butenolide dienophile. A Stille coupling was employed to install the vinyl group.

The third generation AKR1C3-activated prodrug, ACHM-025, eradicates disease in preclinical models of aggressive T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that expresses high levels of the enzyme aldo-keto reductase family 1 member C3 (AKR1C3). To exploit this finding, we developed a novel prodrug, ACHM-025, which is selectively activated by AKR1C3 to a nitrogen mustard DNA alkylating agent. We show that ACHM-025 has potent in vivo efficacy against T-ALL patient-derived xenografts (PDXs) and eradicated the disease in 7 PDXs.

ATP-competitive inhibitors of PI3K enzymes demonstrate an isoform selective dual action by controlling membrane binding.

PI3Kα, consisting of the p110α isoform of the catalytic subunit of PI 3-kinase (encoded by PIK3CA) and the p85α regulatory subunit (encoded by PI3KR1) is activated by growth factor receptors. The identification of common oncogenic mutations in PIK3CA has driven the development of many inhibitors that bind to the ATP-binding site in the p110α subunit. Upon activation, PI3Kα undergoes conformational changes that promote its membrane interaction and catalytic activity, yet the effects of ATP-site directed inhibitors on the PI3Kα membrane interaction are unknown.

Site-Selective Zwitterionic Poly(caprolactone-carboxybetaine)-Growth Hormone Receptor Antagonist Conjugate: Synthesis and Biological Evaluation.

Zwitterionic polymers have been found to be biocompatible alternatives to poly(ethylene glycol) (PEG) for conjugation to proteins. This work reports the site-selective conjugation of poly(caprolactone-carboxybetaine) (pCLZ) to human growth hormone receptor antagonist (GHA) B2036-alkyne and investigation of safety, activity, and pharmacokinetics. Azide-end-functionalized pCLZs were synthesized and conjugated to GHA B2036-alkyne via copper-catalyzed click reaction.

A Mediterranean dietary pattern intervention does not improve cardiometabolic risk but does improve quality of life and body composition in an Aotearoa New Zealand population at increased cardiometabolic risk: A randomised controlled trial.

Aims: To test if a New Zealand food-based Mediterranean diet (NZMedDiet) with behavioural intervention improves cardiometabolic health and wellbeing.

Methods: A randomised controlled trial comparing 12 weeks of the NZMedDiet to usual diet in participants with increased cardiometabolic risk (metabolic syndrome severity score [MetSSS] > 0.35).

Tirzepatide, GIP(1-42) and GIP(1-30) display unique signaling profiles at two common GIP receptor variants, E354 and Q354.

Type 2 diabetes (T2D) and obesity are prevalent metabolic disorders affecting millions of individuals worldwide. A new effective therapeutic drug called tirzepatide for the treatment of obesity and T2D is a dual agonist of the GIP receptor and GLP-1 receptor. Tirzepatide is clinically more effective than GLP-1 receptor agonists but the reasons why are not well understood.

-Substituted Iminothiolane (NIT): A Promising Strategy for Protecting Lysine Side Chains for Solid-Phase Peptide Chemistry.

In this study, we introduce -substituted iminothiolane (NIT) as a robust protecting group for lysine side chains. NIT is compatible with Fmoc-SPPS and can be efficiently removed under mild nucleophilic conditions. Notably, NIT offers enhanced hydrophilicity compared to traditional orthogonal lysine-protecting groups and does not undergo intramolecular migration.

Environmental contamination with carbapenem resistant in healthcare settings in Fiji: a potential source of infection.

Introduction: There are multiple ongoing outbreaks of carbapenem resistant (CR) infection in Fiji's hospitals. CR is able to colonize and persist on various hospital surfaces for extended periods. We conducted a study to understand the extent of hospital environmental contamination and phylogenetic links with clinical isolates.