Ability of Post-treatment Glycyrrhizic Acid to Mitigate Cerebral Ischemia/Reperfusion Injury in Diabetic Mice.

BACKGROUND Diabetes aggravates cerebral ischemia/reperfusion (I/R) injury by increasing inflammatory reactions, but its specific mechanism is currently unclear. MATERIAL AND METHODS Diabetes was induced in mice with a high-fat diet combined with streptozotocin. These mice were subjected to transient middle cerebral artery occlusion (tMCAO) for 60 min, followed by reperfusion for 24-72 h and post-treatment glycyrrhizic acid (GA). Control and diabetic mice were randomly allocated to 8 groups of 18 mice each. Blood glucose, brain infarction, brain edema, and neurological function were monitored. Necrosis was determined by Nissl staining, loss of neurons by immunofluorescent (IF) staining for NeuN, and activation of inflammatory microglia by IF staining for Iba-1. Levels of HMGB1, TLR4, Myd88, and NF-kappaB mRNA and protein in ischemic brain were determined by qRT-PCR and western blotting, respectively, and serum concentrations of IL-1ß, IL-6, and TNF-alpha by ELISA. RESULTS Infarction volume, brain edema, and neurological function after tMCAO were significantly aggravated in diabetes, but ameliorated by post-treatment GA. GA also reduced neuronal loss and microglial activation. Cerebral Myd88 level showed a positive correlation with neurological scores. GA suppressed the expression of Myd88 and a proinflammatory pathway that included Myd88, HMGB1, TLR4, and NF-kappaB, as well as reducing serum concentrations of IL-1ß, IL-6, and TNF-alpha. CONCLUSIONS Post-treatment inhibited inflammatory responses and provided therapeutic benefits in diabetic mice with cerebral I/R injury, suggesting that GA may be a candidate drug to suppress cerebral I/R in diabetic patients.

Case report: Two PD-L1 positive unresectable advanced pancreatic carcinoma patients with microsatellite stability achieved R0 resection after PD-1 antibody plus chemotherapy as a successful downstaging therapy: A report of two cases.

Background: Nonobvious early symptoms are a prominent characteristic of pancreatic cancer, resulting in only 20% of patients having resectable tumors at the time of diagnosis. The optimal management of unresectable advanced pancreatic cancer (UAPC) remains an open research question. In this study, the tumors shrank significantly after PD-1 antibody combined with chemotherapy in two UAPC patients, and both have achieved R0 (pathologically negative margin) resection and survival to date. Case presentation: Case 1: A 53-year-old man was diagnosed with pancreatic adenocarcinoma (Stage III). He received six cycles of PD-1 antibody plus chemotherapy as the first-line treatment. The tumor was reduced from 11.8×8.8 cm to "0" (the pancreatic head was normal as shown by enhanced computed tomography, ECT) after preoperative neoadjuvant therapy (PNT) and the adverse effects were tolerable. The patient underwent radical surgery and achieved R0 resection. Case 2: A 43-year-old man diagnosed with pancreatic adenocarcinoma with liver metastasis (Stage IV) received three cycles of PD-1 antibody combined with chemotherapy. The tumor was reduced from 5.2×3.9 cm to 2.4×2.3 cm with no side effects. The patient also underwent radical surgery and achieved R0 resection. Conclusion: PD-1 antibody plus a chemotherapy regimen resulted in a surprising curative effect and safety in two patients with UAPC, which may portend an improvement in pancreatic carcinoma treatment. We may have a way for UAPC patients to obtain radical treatment and gain long-term survival. Two PD-L1 positive UAPC patients with microsatellite stability (MSS) enlighten us to have a more comprehensive understanding of the prediction of immunotherapy.