Targeting proprotein convertase subtilisin/kexin type 9(PCSK9):from bench to bedside

Proprotein convertase subtilisin/kexin type 9(PCSK9)has evolved as a pivotal enzyme in lipid metabolism and a revolutionary therapeutic target for hypercholesterolemia and its related cardiovascular diseases(CVD).This comprehensive review delineates the intricate roles and wide-ranging implications of PCSK9,extending beyond CVD to emphasize its significance in diverse physiological and pathological states,including liver diseases,infectious diseases,autoimmune disorders,and notably,cancer.Our exploration offers insights into the interaction between PCSK9 and low-density lipoprotein receptors(LDLRs),elucidating its substantial impact on cholesterol homeostasis and cardiovascular health.It also details the evolution of PCSK9-targeted therapies,translating foundational bench discoveries into bedside applications for optimized patient care.The advent and clinical approval of innovative PCSK9 inhibitory therapies(PCSK9-iTs),including three monoclonal antibodies(Evolocumab,Alirocumab,and Tafolecimab)and one small interfering RNA(siRNA,Inclisiran),have marked a significant breakthrough in cardiovascular medicine.These therapies have demonstrated unparalleled efficacy in mitigating hypercholesterolemia,reducing cardiovascular risks,and have showcased profound value in clinical applications,offering novel therapeutic avenues and a promising future in personalized medicine for cardiovascular disorders.Furthermore,emerging research,inclusive of our findings,unveils PCSK9’s potential role as a pivotal indicator for cancer prognosis and its prospective application as a transformative target for cancer treatment.This review also highlights PCSK9’s aberrant expression in various cancer forms,its association with cancer prognosis,and its crucial roles in carcinogenesis and cancer immunity.In conclusion,this synthesized review integrates existing knowledge and novel insights on PCSK9,providing a holistic perspective on its transformative impact in reshaping therapeutic paradigms across various disorders.It emphasizes the clinical value and effect of PCSK9-iT,underscoring its potential in advancing the landscape of biomedical research and its capabilities in heralding new eras in personalized medicine.

The intestinal microbiome of an Indo-Pacific humpback dolphin(Sousa chinensis)stranded near the Pearl River Estuary,China

The mammalian intestinal microbiome is critical for host health and disease resistance.However,the cetacean intestinal microbiota remains relatively unexplored.By using high-throughput 16S rRNA gene sequencing,we analyzed intestinal bacterial samples from an Indo-pacific humpback dolphin(Sousa chinensis)stranded near the Pearl River Estuary in China.The samples included 3 anatomical regions(foregut,midgut,and rectum)and 2 anatomical locations(content and mucus).Our analyses revealed that the dolphin intestinal bacteria contained 139 operational taxonomic units(OTUs),dominated at the phyla level by Firmicutes(47.05%in the content;94.77%in the mucus),followed by Bacteroidetes(23.63%in the content;1.58%in the mucus)and Gammaproteobacteria(14.82%in the content;2.05%in the mucus).The intestinal bacteria had a small core community(15 OTUs,accounting for 99.74%of the reads),some of which could be potentially pathogenic to both human and dolphins.As an alternative to sampling the dolphin intestinal bacteria,fecal sampling could be used.Additionally,function potentials such as,xenobiotics biodegradation,beta-lactam resistance,and human disease-related pathways,were detected in the dolphin intestinal bacteria.These findings provide the first baseline knowledge of the intestinal microbiome of the Indo-Pacific humpback dolphin,which may offer new insights into cetacean conservation by using microbial surveillance.

Dimethyl phthalate damages Staphylococcus aureus by changing the cell structure, inducing oxidative stress and inhibiting energy metabolism

Dimethyl phthalate(DMP), used as a plasticizer in industrial products, exists widely in air,water and soil.Staphylococcus aureus is a typical model organism representing Gram-positive bacteria.The molecular mechanisms of DMP toxicology in S.aureus were researched by proteomic and transcriptomic analyses.The results showed that the cell wall, membrane and cell surface characteristics were damaged and the growth was inhibited in S.aureus by DMP.Oxidative stress was induced by DMP in S.aureus.The activities of succinic dehydrogenase(SDH) and ATPase were changed by DMP, which could impact energy metabolism.Based on proteomic and transcriptomic analyses, the oxidative phosphorylation pathway was enhanced and the glycolysis/gluconeogenesis and pentose phosphate pathways were inhibited in S.aureus exposed to DMP.The results of real-time reverse transcription quantitative PCR(RT-qPCR) further confirmed the results of the proteomic and transcriptomic analyses.Lactic acid, pyruvic acid and glucose were reduced by DMP in S.aureus, which suggested that DMP could inhibit energy metabolism.The results indicated that DMP damaged the cell wall and membrane, induced oxidative stress, and inhibited energy metabolism and activation in S.aureus.