surgical-injury-to-mouse-pancreas-through-ligation-pancreatic-duct-as

Surgical Injury to the Mouse Pancreas through Ligation of the Pancreatic Duct as a Model for Endocrine and Exocrine Reprogramming and Proliferation

Expansion of pancreatic beta cells in vivo or ex vivo, or generation of beta cells by differentiation from an embryonic or adult stem cell, can provide ...

Vrije Universiteit Brussel

Pinus massoniana bark extract (PMBE) is a mixture of flavonoids, whose antioxidant and apoptosis-inducing properties have been confirmed in vitro. In this study, the apoptotic effect and mechanism of PMBE in HepG2 human hepatoma cells were evaluated. PMBE exerted dose- and time-dependent cell growth inhibition on HepG2 cells, and selectively induced apoptosis without impact on normal liver L-02 cells. Apoptosis induced by PMBE in HepG2 cells was also confirmed by annexin-V/PI staining, transmission electron microscopy and sub-G1 phase accumulation. Moreover, PMBE also slightly blocked the cell cycle in the G2/M and S phases in HepG2 cells. The investigation of the mechanism by which PMBE induced apoptosis in HepG2 cells indicated that activation of extrinsic and intrinsic caspase, inhibition of NF-kappaB activation and decrease of the antiapoptotic protein Bcl-2 and the intact Bid protein were involved. Furthermore, the antitumor activity of PBME was demonstrated in vivo by a 42.88-69.94% reduction rate of tumor weight in H22 tumor-implanted mice. Taken together, these data indicate that PMBE selectively induces apoptosis in HepG2 cells through caspase-dependent pathways, and inhibits tumor growth in vivo, making it a potential candidate for anticancer therapeutics.

Pinus massoniana bark extract selectively induces apoptosis in human hepatoma cells, possibly through caspase-dependent pathways.

IL-6 was recently shown to control alpha cell expansion. As beta cells expand following partial pancreatic-duct ligation (PDL) in adult mice, we investigated whether PDL also causes alpha cells to expand and whether IL-6 signalling is involved. As alpha cells can reprogramme to beta cells in a number of beta cell (re)generation models, we examined whether this phenomenon also exists in PDL pancreas.

IL-6-dependent proliferation of alpha cells in mice with partial pancreatic-duct ligation.

Partial duct ligation: β-cell proliferation and beyond.

Combining immune intervention with therapies that directly influence the functional state of the β-cells is an interesting strategy in type 1 diabetes cure. Dipeptidyl peptidase-4 (DPP-4) inhibitors elevate circulating levels of active incretins, which have been reported to enhance insulin secretion and synthesis, can support β-cell survival and possibly stimulate β-cell proliferation and neogenesis. In the current study, we demonstrate that the DPP-4 inhibitor MK626, which has appropriate pharmacokinetics in mice, preceded by a short-course of low-dose anti-CD3 generated durable diabetes remission in new-onset diabetic non-obese diabetic (NOD) mice. Induction of remission involved recovery of β-cell secretory function with resolution of destructive insulitis and preservation of β-cell volume/mass, along with repair of the islet angioarchitecture via SDF-1- and VEGF-dependent actions. Combination therapy temporarily reduced the CD4-to-CD8 distribution in spleen although not in pancreatic draining lymph nodes (PLN) and increased the proportion of effector/memory T cells as did anti-CD3 alone. In contrast, only combination therapy amplified Foxp3+ regulatory T cells in PLN and locally in pancreas. These findings open new opportunities for the treatment of new-onset type 1 diabetes by introducing DPP-4 inhibitors in human CD3-directed clinical trials.

Combining MK626, a novel DPP-4 inhibitor, and low-dose monoclonal CD3 antibody for stable remission of new-onset diabetes in mice.

Identifying pathways for beta cell generation is essential for cell therapy in diabetes. Here we investigate the potential of 17β-estradiol (E2) and estrogen receptor (ER) signaling for stimulating beta cell generation during embryonic development and in severely injured adult pancreas. Estradiol concentration, ER activity and number of ERα transcripts were enhanced in pancreas injured by partial duct ligation (PDL), along with nuclear localization of ERα in beta cells. PDL-induced proliferation of beta cells depended on aromatase activity. The activation of Neurogenin3 (Ngn3) gene expression and beta cell growth in PDL pancreas were impaired when ERα was turned off chemically or genetically (ERα(-/-)), while in situ delivery of E2 promoted beta cell formation. In embryonic pancreas, beta cell replication, number of Ngn3(+) progenitor cells and expression of key transcription factors of the endocrine lineage were decreased by ERα inactivation. The present study reveals that E2 and ERα signaling can drive beta cell replication and formation in mouse pancreas.

Article	Year
Pinus massoniana bark extract selectively induces apoptosis in human hepatoma cells, possibly through caspase-dependent pathways. International journal of molecular medicine\| PubMed ID: 20372819	2010
IL-6-dependent proliferation of alpha cells in mice with partial pancreatic-duct ligation. Diabetologia\| PubMed ID: 24759958	2014
Partial duct ligation: β-cell proliferation and beyond. Diabetes\| PubMed ID: 25060885	2014
Combining MK626, a novel DPP-4 inhibitor, and low-dose monoclonal CD3 antibody for stable remission of new-onset diabetes in mice. PloS one\| PubMed ID: 25268801	2014
Estrogen Receptor α Regulates Beta Cell Formation During Pancreas Development and Following Injury. Diabetes\| PubMed ID: 26015547	2015

Yixing Yuchi

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