Isorhamnetin alleviates cisplatin-induced acute kidney injury via enhancing fatty acid oxidation.

Cisplatin is an effective chemotherapy drug widely used in the treatment of various solid tumors. However, the clinical usage of cisplatin is limited by its nephrotoxicity. Isorhamnetin, a natural flavanol compound, displays remarkable pharmacological effects, including anti-inflammatory and anti-oxidation. In this study, we aimed to investigate the potential of isorhamnetin in alleviating acute kidney injury induced by cisplatin. In vitro study showed that isorhamnetin significantly suppressed the cytotoxic effects of cisplatin on human tubular epithelial cells. Furthermore, isorhamnetin exerted significantly inhibitory effects on cisplatin-induced apoptosis and inflammatory response. In acute kidney injury mice induced by a single intraperitoneal injection with 20 mg/kg cisplatin, oral administration of isorhamnetin two days before or 2 h after cisplatin injection effectively ameliorated renal function and renal tubule injury. Transcriptomics RNA-seq analysis of the mice kidney tissues suggested that isorhamnetin treatment may protect against cisplatin-induced nephrotoxicity via PGC-1α mediated fatty acid oxidation. Isorhamnetin achieved significant enhancements in the lipid clearance, ATP level, as well as the expression of PGC-1α and its downstream target genes PPARα and CPT1A, which were otherwise impaired by cisplatin. In addition, the protection effects of isorhamnetin against cisplatin-induced nephrotoxicity were abolished by a PGC-1α inhibitor, SR-18292. In conclusion, our findings indicate that isorhamnetin could protect against cisplatin-induced acute kidney injury by inducing PGC-1α-dependent reprogramming of fatty acid oxidation, which highlights the clinical potential of isorhamnetin as a therapeutic approach for the management of cisplatin-induced nephrotoxicity.

Genetic dominance of transforming growth factor-ß1 polymorphisms in chronic liver disease.

Chronic liver disease (CLD) is an extremely common clinical condition accompanied by sustained inflammatory response leading to tissue damage. Transforming growth factor-ß1 (TGF-ß1) is known as a master immune regulator in CLDs, but the association between TGF-ß1 polymorphisms and CLD risk is controversial and inconclusive, and the genetic dominance of CLDs remains unknown. In this study, the relationship between TGF-ß1 polymorphisms and CLD susceptibility is systematically analyzed based on 35 eligible studies. Individuals with the TGF-ß1-509 allele (TT or CT) or codon 10 allele (Pro/Pro) show an increased risk of CLDs. Subgroup analyses indicate TGF-ß1-509C/T has a significant correlation with cirrhosis and chronic hepatitis C, codon 10 is associated with chronic hepatitis B occurrence, and codon 25 exhibits a relationship with autoimmune hepatitis risk. Missense mutations in G29E, A105S, D191N, and F321L of TGF-ß1 are the genetic factors of HCC susceptibility. Furthermore, the TGF-ß1 gene expression is significantly elevated in CLD patients, and the TGF-ß1 codon 263 is located close to the region where the TGF-ß1 dimerization interacts, indicating the TGF-ß1 codon 263 variant may affect the secretion of TGF-ß1 by altering its dimerization. Together, our findings provide new insights into the immune regulator gene TGF-ß1 polymorphisms as susceptibility factors for CLD occurrence and regulators for TGF-ß1 expression, which have implications for the regulation of immune factors during CLD development.

A small synthetic molecule forms selective potassium channels to regulate cell membrane potential and blood vessel tone.

In living cell membranes, K(+) permeability is higher than that of other ions such as Na(+) and Cl(-) owing to abundantly expressed K(+) channels. Polarized membrane potential is mainly established by K(+) outward flow because the K(+) concentration in the intracellular side is much higher than that in the extracellular side. We have found that the small synthetic molecule 1 is capable of self-assembling into selective K(+) channels, enhancing K(+) permeability and hyperpolarizing liposome membrane potential. Interestingly, molecule 1 also functions as K(+) channel hyperpolarizing living cell membrane potential and relaxing agonist-induced blood vessel contraction. Therefore, it may have the potential to become a lead compound for the treatment of human diseases associated with K(+) channel dysfunction.

Effect of structural modification of α-aminoxy peptides on their intestinal absorption and transport mechanism.

A representative α-aminoxy peptide 1 has been demonstrated to have a potential for the treatment of human diseases associated with Cl(-) channel dysfunctions. However, its poor intestinal absorption was determined. The purpose of this study was to delineate the transport mechanism responsible for its poor absorption and also to prepare peptide analogues by structural modifications of 1 at its isobutyl side chains without changing the α-aminoxy core for retaining biological activity to improve the intestinal absorption. The poor intestinal absorption of 1 was proved to be due to the P-glycoprotein (P-gp) mediated efflux transport in Caco-2 cell monolayer, intestinal segments in Ussing chamber and rat single pass intestinal perfusion models. Four analogues with propionic acid (2), butanamine (3), methyl (4) and hydroxymethyl side chains (5) were synthesized and tested using the same models. Except for the permeability of 2, the absorbable permeability of the modified peptides in Caco-2 cell monolayer and their intestinal absorption in rats were significantly improved to 7-fold (3), 4-fold (4), 11-fold (5) and 36-fold (2), 42-fold (3), 55-fold (4), 102-fold (5), respectively, compared with 1 (P(app), 0.034 ± 0.003 × 10(-6) cm/s; P(blood), 1.61 ± 0.807 × 10(-6) cm/s). More interestingly, the structural modification remarkably altered transport mechanism of the peptides, leading to the conversion of the active transport via P-gp mediation (1, 2), to MRP mediation (3), MRP plus BCRP mediation (4) or a passive diffusion (5). Furthermore, P-gp mediated efflux transport of 1 and 2 was demonstrated to not alter the P-gp expression, while 1 but not 2 exhibited uncompetitive inhibitory effect on P-gp ATPase. The results demonstrated that intestinal absorption and transport mechanism of the α-aminoxy peptides varied significantly with different structures, and their absorption can be dramatically improved by structural modifications, which allow us to further design and prepare better α-aminoxy peptide candidates with appropriate pharmacokinetic fates, including intestinal absorption, for potential clinical use.

Synthesis of a new conformation-constrained L-tyrosine analogue as a potential scaffold for SH2 domain ligands.

The enantioselective synthesis of a new tricyclic tyrosine analogue is reported. This conformation-constrained SH2 domain ligand scaffold 2 was designed on the basis of the natural ligand, whose structure contains the elements of a tyrosine moiety having chi(1) and chi(2) angles constrained to values observed for a phosphotyrosyl (pTyr) residue bound to the p56(lck) SH2 domain. It represents a unique, highly constrained amino acid, which may be of value in signal transduction studies. Three key steps, an asymmetric tandem Michael addition, an intramolecular Friedel-Crafts reaction, and an intramolecular Mannich reaction, were successfully applied in the presented synthetic route.

Enantioselective synthesis of (2S,3R)-3-hydroxy-3-methylproline, a novel amino acid found in polyoxypeptins.

The enantioselective synthesis of (2S,3R)-3-hydroxy-3-methylproline (3) was achieved by the Sharpless AD, regioselective opening of cyclic sulfate by NaN(3) and intramolecular ring-closing reaction. The reported route has the advantage of a high overall yield and good enantiomeric purity, as well as starting from readily available chemical substrates and inexpensive reagents.