ADT-OH improves intestinal barrier function and remodels the gut microbiota in DSS-induced colitis

Owing to the increasing incidence and prevalence of inflammatory bowel disease(IBD)worldwide,effective and safe treatments for IBD are urgently needed.Hydrogen sulfide(H2S)is an endogenous gasotransmitter and plays an important role in inflammation.To date,H2S-releasing agents are viewed as potential anti-inflammatory drugs.The slow-releasing H_(2)S donor 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione(ADT-OH),known as a potent therapeutic with chemopreventive and cytoprotective properties,has received attention recently.Here,we reported its anti-inflammatory effects on dextran sodium sulfate(DSS)-induced acute(7 days)and chronic(30 days)colitis.We found that ADT-OH effectively reduced the DSS-colitis clinical score and reversed the inflammation-induced shortening of colon length.Moreover,ADT-OH reduced intestinal inflammation by suppressing the nuclear factor kappa-B pathway.In vivo and in vitro results showed that ADT-OH decreased intestinal permeability by increasing the expression of zonula occludens-1 and occludin and blocking increases in myosin II regulatory light chain phosphorylation and epithelial myosin light chain kinase protein expression levels.In addition,ADT-OH restored intestinal microbiota dysbiosis characterized by the significantly increased abundance of Muribaculaceae and Alistipes and markedly decreased abundance of Helicobacter,Mucispirillum,Parasutterella,and Desulfovibrio.Transplanting ADT-OH-modulated microbiota can alleviate DSS-induced colitis and negatively regulate the expression of local and systemic proinflammatory cytokines.Collectively,ADT-OH is safe without any short-term(5 days)or long-term(30 days)toxicological adverse effects and can be used as an alternative therapeutic agent for IBD treatment.

Tannic acid assisted anti-TNF-αnanobody assembly modulating the epithelial barrier dysregulation of allergic rhinitis

The derailed nasal epithelial barrier is associated with the disorder of tight junctions(TJ)function or expression,leading to more penetration of allergens to the barrier,accompanied by the release of cytokines,which develop allergic rhinitis(AR).Considering the increasing AR disease incidence worldwide,there is still an urgent unmet medical need to develop new therapeutics.Tumor necrosis factor-alpha(TNF-α)inhibitors have been applied in treating autoimmune diseases.However,their roles in AR remain unclear.In this study,anti-TNF-αnanobody(V)was assembled with tannic acid(V/TA)as a functional antibody drug candidate which could inhibit the release of the cytokines in ovalbumin(OVA)-induced AR murine model.Upon receiving V/TA treatment,the infiltration level of inflammatory cells,and the number of mucus-secreting cells and mast cells in the nasal mucosa recovered to a relatively normal level.Preliminary mechanism of action research revealed that the efficacy of V/TA was accompanied by the restricted level of TJ molecules:zonula occluden-1(ZO-1),occludin,claudin-1,and claudin-5.The therapeutic effect of the anti-TNF-αnanobody against AR was enhanced with the tannic acid assisted without any toxicity observed.This study supplied a promising delivery strategy of TNF-αinhibitor for the effective treatment of complicated allergic rhinitis disease,with an advantage in restoring effect on the AR-caused epithelial barrier defects than the commercial drug Infliximab.

Extracellular signal regulated kinase 5 promotes cell migration,invasion and lung metastasis in a FAK-dependent manner

This study was designed to evaluate ERK5 expression in lung cancer and malignant melanoma progression and to ascertain the involvement of ERK5 signaling in lung cancer and melanoma.We show that ERK5 expression is abundant in human lung cancer samples,and elevated ERK5 expression in lung cancer was linked to the acquisition of increased metastatic and invasive potential.Importantly,we observed a significant correlation between ERK5 activity and FAK expression and its phosphorylation at the Ser910 site.Mechanistically,ERK5 increased the expression of the transcription factor USF1,which could transcriptionally upregulate FAK expression,resulting in FAK signaling activation to promote cell migration.We also provided evidence that the phosphorylation of FAK at Ser910 was due to ERK5 but not ERK1/2,and we then suggested a role for Ser910 in the control of cell motility.In addition,ERK5 had targets in addition to FAK that regulate epithelial-to-mesenchymal transition and cell motility in cancer cells.Taken together,our findings uncover a cancer metastasis-promoting role for ERK5 and provide the rationale for targeting ERK5 as a potential therapeutic approach.