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BACKGROUND: Excessive portal pressure after massive hepatectomy can cause hepatic sinusoidal injury and have deleterious impacts on hepatic functional recovery, contributing to developing post-hepatectomy liver failure. This study aimed to assess the effects of splanchnic vasoactive agents on hepatic functional recovery and regeneration while clarifying the underlying mechanism, using a 70% hepatectomy porcine model. METHODS: Eighteen pigs undergoing 70% hepatectomy were involved in this study and divided into three groups: control (n=6), terlipressin (n=6), and octreotide (n=6). Terlipressin (0.5 mg) and octreotide (0.2 mg) were administered 3 times a day for each group with the first dose starting just before surgery until the 7th postoperative day, at which time the surviving pigs were sacrificed. During the period, portal pressure, liver weight, biochemical analysis, histological injury score, and molecular markers were evaluated and compared between groups. RESULTS: The 7-day survival rates in the octreotide, terlipressin, and control groups were 100%, 83.3%, and 66.7%, respectively. The portal pressures decreased in both terlipressin and octreotide groups than the control group at 30 minutes, 1 hour and 6 hours after hepatectomy. The amount of regeneration measured by liver weight to body weight ratio at the time of sacrifice in the terlipressin group was smaller than that in the control group (117% vs. 129%, P=0.03). Serum aspartate aminotransferase (AST) and total bilirubin levels at 1 and 6 hours after hepatectomy and prothrombin time/international normalized ratio (PT/INR) at 6 hours after hepatectomy were significantly improved in the terlipressin and octreotide groups compared to the control group. Serum endothelin-1 (ET-1) was significantly lower in the terlipressin group than that in the control group 6 hours after hepatectomy (P

BackgroundExcessive postoperative portal pressure is associated with post-hepatectomy liver failure and small-for-size syndrome after partial liver transplantation. This study aimed to identify the portal modulation effects of terlipressin on liver regeneration and survival in a porcine model subjected to 90% hepatectomy.MethodsTwenty pigs undergoing 90% hepatectomy were divided into control (n=10) and terlipressin (n=10) groups. Terlipressin 0.5 mg was injected subcutaneously three times a day, from immediately before hepatectomy to 7 days after surgery, for surviving pigs in the terlipressin group. Portal pressure measurement, biochemical analysis, assessment of molecular markers for liver regeneration, and immunohistochemistry were performed in both groups. ResultsThe 7-day survival rate was significantly higher in the terlipressin group than in the control group. Portal pressure in the terlipressin group was lower than that in the control group at 30 min and 1 h after hepatectomy. Total bilirubin level was lower in the terlipressin group than in the control group at 1 h and 6 h after hepatectomy. Proliferating cell nuclear antigen expression was higher in the control group than in the terlipressin group at 6 h after hepatectomy, while the proportion of Ki-67-positive cells was higher in the terlipressin group than in the control group at 7 days after hepatectomy. Endothelin-1 levels reflecting liver injury were lower in the terlipressin group than in the control group at 1 h and 6 h after hepatectomy.Conclusion Terlipressin could optimize liver regeneration and improve survival through rapid and effective portal modulation after extensive hepatectomy.

Background Clinical diagnosis of post-hepatectomy liver failure (PHLF) can only be made on or after the 5th postoperative day. Biomarker for early diagnosis is considered as a critical unmet need. Methods Twenty domestic female crossbreed (Yorkshire-landrace and duroc) pigs underwent sham operation (n=6), 70% (n=7) and 90% (n=7) partial hepatectomy (PH). A comprehensive lipidomic analysis was conducted using sera collected at pre-operation (PO), 14, 30, and 48 h after PH using nanoflow ultrahigh performance liquid chromatography-electrospray ionization-tandem mass spectrometry. Results Of the 184 quantified lipids, 14 lipids showed significant differences between the two resection groups starting at 30 h after surgery. Four phosphatidylcholine (PC) plasmalogen species (P-16:0/16:0, P-18:0/18:2, P-18:0/20:4, and P-18:0/22:6) and PC 32:2 significantly increased in the 90% PH group while these returned to PO level after 30 h in the 70% PH group, presumably implying the failure markers. In contrast, eight triacylglycerol (TG) species (40:0, 42:1, 42:0, 44:1, 44:2, 46:1, 46:2, and 48:3) and sphingomyelin d18:1/20:0 showed an opposite trend, wherein they significantly decreased in the 90% PH group while these in the 70% PH group were abruptly increased until 30 h but returned to near PO levels at 48 h, implying the recovery markers. Same trends could also be observed in the level of whole lipid classes of PC plasmalogens and TGs, in addition to selected individual lipid species. Conclusions Characteristic lipidomic signatures of PHLF could be identified using large animal models. These candidates have a potential to serve as a tool for early diagnosis and may open new paths to the study to overcome PHLF.

The accelerated course of hepatic fibrosis that occurs in some patients after liver transplantation is an important clinical problem. Activation of hepatic stellate cell (HSCs) is the dominant event in hepatic fibrosis. Previous studies have shown that treatment with mammalian target of rapamycin (mTOR) inhibitors was more effective in reducing the progression of fibrosis than treatment with calcineurin inhibitors, suggesting that mTOR could be a crucial target for inhibition of fibrosis. In addition, N-acetylcysteine (NAC) has been shown to effectively suppress HSC activation-dependent expression of alpha-smooth muscle actin in HSCs, suggesting that NAC could be a candidate for the clinical treatment of hepatic fibrosis. Here, we have evaluated the effects of immunosuppressive drugs and NAC in a mice model of hepatic fibrosis and on HSC activation in vitro. We demonstrated that an mTOR inhibitor significantly inhibited fibrogenic genes in cultured HSCs until day 14. In addition, co-administration of NAC with everolimus further reduced the expression of fibrogenic genes and improved the characteristic of HSCs via blockage of HSC activation and up-regulation of fibrolytic gene. Moreover, in vivo studies showed that everolimus inhibited collagen deposition and inflammation in a mouse model of fibrogenesis, as determined by histological analysis, and everolimus treatment, in combination with NAC, significantly decreased extracellular matrix deposition and improved liver histology. These findings indicated that everolimus, combined with NAC, synergistically inhibited hepatic fibrosis and thus may become a valuable option in immunosuppressant therapy.

목적: 벌 화분은 일벌이 모은 꽃의 화분이 주성분이며 가장 완벽한 건강식으로 인식되어지고 있다. 벌 화분은 단백질(약 40%), 아미노산 그리고 플라보노이드가 매우 풍부하다. 그러나 벌 화분은 exine이라는 외피로 둘러싸여 있고 이로 인해 소화효소, 산 그리고 알칼리에 매우 안정하여 식이나 의학적 목적으로 사용하는 데 어려움이 있다. 본 연구에서는 습식 나노 분쇄 기술을 이용하여 외피를 파괴하여 나노화 벌 화분을 제조하였고, 나노화 벌 화분의 항산화 효과와 세포보호효과, 그리고 화장품 제형의 임상적 효과에 대해 연구하였다. 방법: 습식 나노 분쇄 공정을 통해 벌 화분을 나노화하였고 라디칼 소거 활성과 세포보호효과를 평가하였다. 또한 나노화 벌 화분을 원료로 하는 제형을 제조하여 임상시험을 수행하였다. 결과: 나노화 벌 화분은 우수한 항산화 효과를 나타내었고 1% 나노화 벌 화분 용액은 피부세포에서 lactate dehydrogenase (LDH)의 분비를 18.73% 감소시켰다. 임상시험에서도 나노화 벌화분은 피부 결, 피부 수분 함유량, 피부 투명도 그리고 멜라닌 지수를 개선하였고 눈가의 주름을 감소시켰다. 피부자극시험에서도 나노 화분은 부작용을 유발하지 않았다. 결론: 이러한 결과로 볼 때 나노화 벌 화분은 화장품 원료로서의 우수한 가치가 있으며 피부에 다양한 효능을 제공할 수 있다고 사료된다.

We developed concave microwell arrays to establish a size-controllable 3-D co-culture liver model for in vitro drug toxicity testing, to predict hepatotoxicity. The interaction of hepatocytes with hepatic stellate cells (HSCs) was investigated by co-culturing primary 3-D hepatocyte spheroids and HSCs (heterosphere), using 3-D liver-on-a-chip. The effect of HSCs was investigated during spheroid formation, they were involved in controlling the organization of spheroidal aggregates and the formation of tight cell&ndash, cell contacts. Scanning electron microscopy (SEM) images showed that co-cultured spheroids with smoother surfaces in the flow chip aggregated more tightly and rapidly, compared to mono-cultured spheroids, until 13 days. Metabolic function analysis revealed that heterospheres secreted 40% more albumin and urea than hepatospheres on day 13. Additionally, an acetaminophen (AAP) and isoniazid (INH) concentration-dependent increase in CYP3A4 expression was detected in the 3-D cultures, and an increase in Lactate dehydrogenase (LDH) release after AAP and INH treatment was observed. CYP1A2, Mrp1 and UGT1A5 mRNA expression levels in the heterospheres and hepatospheres were evaluated from days 3 to 13. To examine the potential for toxicity testing in the flow-conditioned culture of the heterospheres, we evaluated cytotoxicity using the endpoint LDH release in the heterospheres and hepatospheres. IC50 values for AAP and INH after 24 h of exposure were calculated from the dose&ndash, response curves of the compounds. Flow-conditioned heterosphere culture results suggest that it may be suitable for long-term culture and cytotoxicity testing. Thus, our co-culture system closely resembles the in vivo environment and allows long-term in vitro hepatotoxicity prediction.