Hyperlanins A and B, Two Highly Rearranged Meroterpenoids from Hypericum lancasteri

Hyperlanins A(1)and B(2),two highly rearranged polycyclic polyprenylated acylphloroglucinol(PPAP)-related meroterpenoids based on different new carbon skeletons,were isolated from Hypericum lancasteri.Compound 1 incorporates an unprecedented 5/6/7/5 ring system featuring a 3,13-dioxatetracyclo[9.2.1.12.5.01.8]pentadecane core.Compound 2 possesses a unique compact 6/6/5/6/6/5/6 ring system with a caged tetracyclo[6.2.1.13.8.05,11]dodecane motif.Their structures were established by spectroscopic data,X-ray diffraction,and computational approaches.Both compounds showed anti-inflammatory activity in vitro.Compounds 1 and 2 could decrease the lipopolysaccharide(LPS)-/nigericin-induced IL-1βrelease in THP-1 cells.Both compounds also showed inhibition in hypoxia-inducible factor-1α(HIF-1αa)pathway luciferase reporter assay.

Macrophage LMO7 deficiency facilitates inflammatory injury via metabolic-epigenetic reprogramming

Inflammatory bowel disease(IBD)is a formidable disease due to its complex pathogenesis.Macrophages,as a major immune cell population in IBD,are crucial for gut homeostasis.However,it is still unveiled how macrophages modulate IBD.Here,we found that LIM domain only 7(LMO7)was downregulated in pro-inflammatory macrophages,and that LMO7 directly degraded 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3(PFKFB3)through K48-mediated ubiquitination in macrophages.As an enzyme that regulates glycolysis,PFKFB3 degradation led to the glycolytic process inhibition in macrophages,which in turn inhibited macrophage activation and ultimately attenuated murine colitis.Moreover,we demonstrated that PFKFB3 was required for histone demethylase Jumonji domaincontaining protein 3(JMJD3)expression,thereby inhibiting the protein level of trimethylation of histone H3 on lysine 27(H3K27me3).Overall,our results indicated the LMO7/PFKFB3/JMJD3 axis is essential for modulating macrophage function and IBD pathogenesis.Targeting LMO7 or macrophage metabolism could potentially be an effective strategy for treating inflammatory diseases.

Charge-reversible crosslinked nanoparticle for pro-apoptotic peptide delivery and synergistic photodynamic cancer therapy

Although anti-cancer nanotherapeutics have made breakthroughs,many remain clinically unsatisfactory due to limited delivery efficiency and complicated biological barriers.Here,we prepared charge-reversible crosslinked nanoparticles(PDC NPs)by supramolecular self-assembly of pro-apoptotic peptides and photosensitizers,followed by crosslinking the self-assemblies with polyethylene glycol to impart tumor microenvironment responsiveness and charge-reversibility.The resultant PDC NPs have a high drug loading of 68.3%,substantially exceeding that of 10%–15%in conventional drug delivery systems.PDC NPs can overcome the delivery hurdles to significantly improve the tumor accumulation and endocytosis of payloads by surface charge reversal and responsive crosslinking strategy.Pro-apoptotic peptides target the mitochondrial membranes and block the respiratory effect to reduce local oxygen consumption,which extensively augments oxygen-dependent photodynamic therapy(PDT).The photosensitizers around mitochondria increased along with the peptides,allowing PDT to work with pro-apoptotic peptides synergistically to induce tumor cell death by mitochondria-dependent apoptotic pathways.Our strategy would provide a valuable reference for improving the delivery efficiency of hydrophilic peptides and developing mitochondrial-targeting cancer therapies.

Advancements and challenges in immunocytokines:A new arsenal against cancer

Immunocytokines,employing targeted antibodies to concentrate cytokines at tumor sites,have shown potential advantages such as prolonged cytokine half-lives,mitigated adverse effects,and synergistic antitumor efficacy from both antibody and cytokine components.First,we present an in-depth analysis of the advancements of immunocytokines evaluated in preclinical and clinical applications.Notably,anti-PD-1-based immunocytokines can redirect cytokines to intratumoral CD8^(+)T cells and reinvigorate them to elicit robust antitumor immune responses.Then,we focus on their molecular structures and action mechanisms,striving to elucidate the correlations between diverse molecular structures and their antitumor efficacy.Moreover,our exploration extends to the realm of novel cytokines,including IL-10,IL-18,and IL-24,unraveling their potential in the construction of immunocytokines.However,safety concerns remain substantial barriers to immunocytokines'development.To address this challenge,we explore potential strategies,such as cytokine engineering and prodrug design,which can foster next-generation immunocytokines development.Overall,this review concentrates on the design of molecular structures in immunocytokines,underscoring the direction and focus of ongoing efforts to improve safety profiles while maximizing therapeutic efficacy.