Selective phytochemicals targeting pancreatic stellate cells as new anti-fibrotic agents for chronic pancreatitis and pancreatic cancer

Activated pancreatic stellate cells(PSCs)have been widely accepted as a key precursor of excessive pancreatic fibrosis,which is a crucial hallmark of chronic pancreatitis(CP)and its formidable associated disease,pancreatic cancer(PC).Hence,anti-fibrotic therapy has been identified as a novel therapeutic strategy for treating CP and PC by targeting PSCs.Most of the anti-fibrotic agents have been limited to phaseⅠ/Ⅱclinical trials involving vitamin analogs,which are abundant in medicinal plants and have proved to be promising for clinical application.The use of phytomedicines,as new anti-fibrotic agents,has been applied to a variety of complementary and alternative approaches.The aim of this review was to present a focused update on the selective new potential anti-fibrotic agents,including curcumin,resveratrol,rhein,emodin,green tea catechin derivatives,metformin,eruberin A,and ellagic acid,in combating PSC in CP and PC models.It aimed to describe the mechanism(s)of the phytochemicals used,either alone or in combination,and the associated molecular targets.Most of them were tested in PC models with similar mechanism of actions,and curcumin was tested intensively.Future research may explore the issues of bioavailability,drug design,and nano-formulation,in order to achieve successful clinical outcomes with promising activity and tolerability.

For antigen-specific effector or Foxp3^(+) regulatory T cell fate, cyclin-dependent kinases hold the trump card

Forkhead box p3^(+)(Foxp3^(+))regulatory T cells(Tregs)are indispensable for immune homeostasis and for maintaining immune tolerance.Several studies have confirmed that injection of a T cell population depleted of Tregs causes autoimmunity,rejection of grafts and inflammatory disorders,whereas reconstitution with Tregs inhibits these pathogenic processes.Over the last two decades,intense efforts have been made to identify Treg subsets,Treg differentiation processes,and the molecular signatures and regulators that determine Treg lineage specificity and stability.1–6 Several lines of evidence clearly demonstrate that Foxp3^(+)Tregs do not constitute a homogeneous population,and various subsets of Tregs,such as thymic Tregs(tTregs),in vitro-generated Tregs(iTregs),and peripherally induced Tregs(pTregs),have been identified.5 In addition to Foxp3,epigenetic factors and metabolic processes play key roles in maintaining Treg identity and function,and mediate the switch between effector T cells and Tregs.