New possible silver lining for pancreatic cancer therapy:Hydrogen sulfide and its donors

As one of the most lethal diseases,pancreatic cancer shows a dismal overall prognosis and high resistance to most treatment modalities.Furthermore,pancreatic cancer escapes early detection during the curable period because early symptoms rarely emerge and specific markers for this disease have not been found.Although combinations of new drugs,multimodal therapies,and adjuvants prolong survival,most patients still relapse after surgery and eventually die.Consequently,the search for more effective treatments for pancreatic cancer is highly relevant and justified.As a newly re-discovered mediator of gasotransmission,hydrogen sulfide(H2S)undertakes essential functions,encompassing various signaling complexes that occupy key processes in human biology.Accumulating evidence indicates that H2S exhibits bimodal modulation of cancer development.Thus,endogenous or low levels of exogenous H2S are thought to promote cancer,whereas high doses of exogenous H2S suppress tumor proliferation.Similarly,inhibition of endogenous H2S production also suppresses tumor proliferation.Accordingly,H2S biosynthesis inhibitors and H2S supplementation(H2S donors)are two distinct strategies for the treatment of cancer.Unfortunately,modulation of endogenous H2S on pancreatic cancer has not been studied so far.However,H2S donors and their derivatives have been extensively studied as potential therapeutic agents for pancreatic cancer therapy by inhibiting cell proliferation,inducing apoptosis,arresting cell cycle,and suppressing invasion and migration through exploiting multiple signaling pathways.As far as we know,there is no review of the effects of H2S donors on pancreatic cancer.Based on these concerns,the therapeutic effects of some H2S donors and NO-H2S dual donors on pancreatic cancer were summarized in this paper.Exogenous H2S donors may be promising compounds for pancreatic cancer treatment.

Activatable and Self-Monitoring Hydrogen Sulfide-Based Molecular Senomorphics for Visualized Regulation of Cellular Senescence

Specific regulation of the senescence-associated secretory phenotype(SASP)is vital to block senescence-induced detrimental cellular plasticity.Recently,some chemical compounds called senomorphics have demonstrated such potential,but it remains challenging to achieve site-specific activation and real-time monitoring of the action of senomorphics,posing great obstacles for transformable applications.Here,we report a tailor-made hydrogen sulfide(H_(2)S)donor(Lyso-FH_(2)S-Gal)as a new class of molecule senomorphics for spatially controlled delivery of H_(2)S for visualization of regulation of cellular senescence.It comprises four functional moieties in a single molecular structure,including a lysosome-targeting group for cell recognition,a lysosomal enzyme-cleaved scaffold for site-specific activation,thiocarbamate as the H_(2)S precursor,and a switchable fluorophore for concurrent selfreporting of H_(2)S release and senescence imaging.Lyso-FH_(2)S-Gal exhibited remarkable response selectivity,sustained H_(2)S release,and 141-fold fluorescence enhancement.In cellular models,Lyso-FH_(2) S-Gal preferentially enriched in senescent cells over nonsenescent cells,and alleviated the levels of SASP and reactive oxygen species(ROS)in senescent cells,while remaining inert in nonsenescent cells.More impressively,it efficiently inhibited the SASPmediated crosstalk between senescent cells and surrounding nonsenescent cells,thereby preventing senescence propagation.This work offers a useful molecular tool with the hope for controlled intervention of senescence-related important biological processes.

A ROS-responsive,self-immolative and self-reporting hydrogen sulfide donor with multiple biological activities for the treatment of myocardial infarction

Myocardial infarction(MI),as one of the leading causes of global death,urgently needs effective therapies.Recently,hydrogen sulfide(H2S)has been regarded as a promising therapeutic agent for MI,while its spatiotemporally controlled delivery remains a major issue limiting clinical translation.To address this limitation,we designed and synthesized a novel H2S donor(HSD-R)that can produce H2S and emit fluorescence in response to reactive oxygen species(ROS)highly expressed at diseased sites.HSD-R can specifically target mitochondria and provide red fluorescence to visualize and quantify H2S release in vitro and in vivo.Therapeutically,HSD-R significantly promoted the reconstruction of cardiac structure and function in a rat MI model.Mechanistically,myocardial protection is achieved by reducing cardiomyocyte apoptosis,attenuating local inflammation,and promoting angiogenesis.Furthermore,inhibition of typical pro-apoptotic genes(Bid,Apaf-1,and p53)played an important role in the anti-apoptotic effect of HSD-R to achieve cardioprotection,which were identified as new therapeutic targets of H2S against myocardial ischemia injury.This ROS-responsive,self-immolative,and fluorescent H2S donor can serve as a new theranostic agent for MI and other ischemic diseases.