How Does KPV Reduce Stomach Inflammation and Repair the Stomach Lining?

"Lysine-proline-valine (KPV), a naturally occurring tripeptide, has been shown to attenuate the inflammatory responses of colonic cells." (1)

"Intriguingly, we found that HA-KPV-NPs exert combined effects against UC by both accelerating mucosal healing and alleviating inflammation. Oral administration of HA-KPV-NPs encapsulated in a hydrogel (chitosan/alginate) exhibited a much stronger capacity to prevent mucosa damage and downregulate TNF-α, thus they showed a much better therapeutic efficacy against UC in a mouse model, compared with a KPV-NP/hydrogel system." (1)

"Oral administration of HA-KPV-NPs embedded in hydrogel (chitosan/alginate) confers combined therapeutic effects against UC by accelerating mucosa healing and alleviating inflammation." (1)

"Nanomolar concentrations of KPV inhibit the activation of NF-κB and MAP kinase inflammatory signaling pathways, and reduce pro-inflammatory cytokine secretio... KPV acts via hPepT1 expressed in immune and intestinal epithelial cells... oral administration of KPV reduces the incidence of DSS-, and TNBS-induced colitis indicated by a ****decrease in pro-inflammatory cytokine expression." (2)

"As shown in [in the picture below], untreated Raw 264.7 macrophages treated with lipopolysaccharide (LPS, 1 μg/mL; to stimulate an inflammatory response) exhibited marked increases of TNF-α mRNA expression level after 24 and 48 hr. In contrast, this effect was considerably reduced in cells pre-treated with KPV-loaded NPs. We further found that LPS-treated Raw 264.7 macrophages pre-treated with HA-KPV-NPs maintained their decreased levels of TNF-α even at 72 and 96 hr post-treatment. Furthermore, cells treated with HA-KPV-NPs had significantly lower TNF-α mRNA expression levels compared with those treated with KPV-NPs." (1)

Decreases Inflammatory Cytokines Without Boosting Anti-Inflammatory Cytokines:

"Interestingly, KPV treatment decreased the expression of these cytokines and this effect was significant for IL-6 and IL-12. Since inflammation is a balance between pro- and anti-inflammatory cytokines, we also assessed the effect of KPV on the main anti-inflammatory cytokine IL-10. We found that KPV did not change IL-10 mRNA expression in mouse colon suggesting that KPV acts by decreasing pro-inflammatory cytokines rather than increasing anti-inflammatory cytokines."

"We then investigated the anti-inflammatory effect of KPV in TNBS-induced mouse colitis model 48 hours after its administration. Addition of KPV in the drinking water significantly reduced weight loss at day one and two compared with mice that received TNBS alone. TNBS-induced increase of MPO activity was significantly inhibited by ~30% by the addition of KPV. Furthermore, KPV prevented other inflammatory changes such as decrease of colon length. Finally, the KPV anti-inflammatory effect was confirmed using real-time RT-PCR. We found that KPV significantly reduced TNBS-induced IL-1β, IL-6, TNF-α and IFN-γ mRNA levels in mouse colon." (2)

"Together our results show that i) KPV reduces the two most important intracellular signaling pathways in the pathogenesis of inflammatory bowel diseases: the NF-κB and MAPK cascade pathways as well as the subsequent synthesis of pro-inflammatory cytokines, ii) the anti-inflammatory effect of KPV is mediated through the transporter PepT1, and iii) oral delivery of KPV reduces the severity of DSS- and TNBS-induced colitis in mice... These results indicate that targeting KPV transport into both epithelial and immune cells may reduce the overall level of pro-inflammatory cytokine production by mucosal and immune cells and therefore raise the use of KPV as an attractive therapeutic strategy against IBD." (2)

Healing of Mucosal (Stomach Lining):

"Enhancement of mucosal healing is one of the two major aims in UC treatment.18 Because KPV was shown to decrease the inflammatory response of colonic epithelial cells to inflammatory stimulation,12 it was reasonable to speculate that HA-KPV-NPs might be able to improve the healing of an inflamed mucosal layer. Thus, we investigated the effects of HA-KPV-NPs on wound healing using electrical impedance sensing (ECIS) technology."

"As shown [in the picture below], wounded epithelial layers treated with HA-KPV-NP suspensions showed significant and dose-dependent increases in recovery, compared with untreated control layers. These results clearly demonstrate that HA-KPV-NPs can enhance the healing of a wounded colonic epithelial layer." (1)

No Cytotoxicity:

"The results from 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assays (Figure S1) revealed no obvious cytotoxicity in either cell line following incubation with KPV-NPs or HA-KPV-NPs, even after 48 hr. This indicates that the generated NPs have excellent biocompatibility." (1)

KPV Exhibited Stronger Anti-inflammatory Action than its Parent Peptide α-MSH:

"α-Melanocyte-stimulating hormone (α-MSH), an endogenous tridecapeptide, is a cleavage product of proopiomelanocortin that has protective and anti-inflammatory effects. Its anti-inflammatory activity has been shown to be mediated by three N-terminal amino acids, lysine-proline-valine (KPV). Interestingly, the KPV peptide was found to exert an even stronger anti-inflammatory effect than α-MSH, and we recently demonstrated that KPV could attenuate the inflammatory responses of colonic epithelial and immune cells and reduce the incidence of colitis in vivo upon oral administration. We also showed that KPV exerts its anti-inflammatory function inside cells, where it inactivates inflammatory pathways. Moreover, unlike the drugs currently used for UC therapy, KPV is a naturally derived tripeptide without any notable side effects." (1)

KPV Mitigated the Chronic Inflammation that Leads to Stomach Cancer:

"...mouse colitis and human studies have shown that chronic intestinal inflammation leads to colorectal cancer (colitis-associated cancer; CAC)."

"The use of an anti-inflammatory tripeptide Lys-Pro-Val (KPV) transported by PepT1 was able to prevent carcinogenesis in WT mice."

"This anti-inflammatory tripeptide, which is derived from α-melanocyte–stimulating hormone, has been shown to have anti-inflammatory properties and to effectively reduce chemically induced colitis in mice. Therefore, we hypothesized that KPV may attenuate tumorigenesis in the AOM/DSS-induced murine model of colon cancer."

"We interestingly observed that KPV was able to decrease the tumor number and the proliferation of malignant colonic epithelial cells in a PepT1-dependent way, confirming that PepT1 can be a therapeutic target for the treatment of colonic inflammation and subsequent tumorigenesis."

"KPV Prevents Intestinal Inflammation and Tumorigenesis During Colitis-Associated Carcinogenesis in a PepT1-Dependent Manner" (3)

"Several studies have shown previously that KPV tripeptide decreased intestinal inflammation and attenuated DSS-induced colitis, suggesting tripeptide as a valuable therapeutic tool against colitis and associated carcinogenesis... We then hypothesized that KPV may help to prevent colon tumorigenesis in the AOM/DSS-induced CAC model. To test this hypothesis, WT mice were treated with AOM/DSS or AOM/DSS + KPV, showing that WT mice given KPV in conjunction with AOM/DSS showed a drastic decrease in colon tumorigenesis, as shown by tumor numbers, sizes, and overall colonic tumor burdens, compared with AOM/DSS-only–treated animals. Although both groups of mice lost similar amounts of weight during DSS treatment, KPV-treated mice showed decreased inflammation, fewer aberrant crypt foci, decreased cellular infiltration, and less epithelial cell proliferation." (3)

KPV decreases inflammation and tumorigenesis during CAC:

KPV Only Decreased Cancer in Models That Were Caused By Inflammation:

"KPV was shown to decrease tumorigenesis in a colitis-associated model of cancer. We next wanted to know whether KPV also would reduce tumorigenesis in a noninflammatory model. For this purpose, APCMin/+ mice, a genetic model of intestinal adenocarcinoma that spontaneously develops adenomas mainly in the small intestine, were treated with KPV for 13 weeks. As presented in Figure 9, KPV did not decrease the tumor burden in the small intestine or in the colon. However, our results importantly showed that intestinal inflammation, assessed by lipocalin-2 measurement, was decreased by KPV treatment, confirming the anti-inflammatory effect of KPV in this model. These results indicated that the decrease of intestinal inflammation induced by KPV, observed in Figure 7, was not sufficient to decrease the tumor formation in a genetic model of tumorigenesis."

"However, genetic colon carcinoma models only represent 2%–5% of all colon cancers and have a severe tumor development even in germ-free mice and a dramatically decreased basal intestinal inflammation. Therefore, although the inhibition of intestinal inflammation via the KPV/PepT1 pathway was not sufficient to inhibit tumorigenesis in such a stringent model as the APCMin/+ mice, KPV showed a promising potential for inhibiting inflammation in various models of colon cancer."

"Importantly, even with a limited inhibition of tumorigenesis in such a stringent model, KPV was sufficient to decrease the inflammation in this model of non–inflammatory-induced carcinogenesis." (3)