透明质酸对白细胞介素1β与软骨滑膜联合培养模型的作用

目的:观察不同浓度透明质酸对白细胞介素1β与软骨滑膜联合培养模型中软骨基质代谢的影响与抑制炎性反应的作用,从而阐明粘保护剂治疗骨性关节炎的可能机制。方法:实验于2006-03/11在华中科技大学附属协和医院骨科实验室完成。①实验材料:新鲜狗尸体4具,取肱骨头附近的全厚软骨以及滑膜组织。透明质酸钠购于中国山东正大福瑞达制药有限公司产品。②实验干预和分组:以100μg/L的白细胞介素1β与软骨滑膜联合培养。将0.2,1,2g/L透明质酸加入模型中得到3组透明质酸组,只含白细胞介素1β为阳性对照组,只含培养液为阴性对照组。③实验评估:每3天收集1次培养皿中的溶液标本,3,6,20d收集培养皿中的软骨滑膜标本,行生化和免疫组织化学检查。结果:①溶液标本与组织标本聚氨基葡萄糖检测结果:第3,6天溶液标本中透明质酸组高于阴性对照组(P<0.05);第20天时3种剂量透明质酸组溶液中聚氨基葡萄糖低于阳性对照组(P<0.05)。②溶液标本中前列腺素E2、基质金属蛋白酶3、含氮产物检测结果:第3天时阳性对照组基质金属蛋白酶3浓度高于阴性对照组(P<0.05),第20天,1g/L,2g/L透明质酸组基质金属蛋白酶3浓度较阳性组低[(1.289±2.122),(0.458±0.454),(1.425±0.211)μg/L,P<0.05],第3天时阳性对照组前列腺素E2浓度明显高于阴性对照组(P<0.05),第6天,0.2g/L,1g/L透明质酸组含氮产物浓度低于阳性和阴性对照组[(1.288±0.280),(1.345±0.768),(2.234±0.570),(1.845±0.767)mmol/L(P<0.05)。结论:实验结果支持粘保护剂治疗骨性关节炎的两种机制,即透明质酸对软骨保护的生物学合成作用与透明质酸的炎性抑制反应。     

Bone marrow-derived macrophage contributes to fibrosing steatohepatitis through activating hepatic stellate cells

The role of macrophages in fibrosing steatohepatitis is largely unclear. We characterized the origin and molecular mechanisms of macrophages and its targeted therapy of fibrosing steatohepatitis. Fibrosing steatohepatitis was established in Alms1 mutant (foz/foz) and C57BL/6J wildtype mice fed high-fat/high-cholesterol or methionine- and choline-deficient diet. Bone marrow transplantation was performed to track the macrophage origin in fibrosing steatohepatitis. Macrophages were depleted using liposomal clodronate. Primary macrophages were isolated from bone marrow for adoptive transfer into mice. We found that macrophage infiltration is induced in two mouse models of fibrosing steatohepatitis and human nonalcoholic steatohepatitis-fibrosis patients. Bone marrow-derived macrophages (BMMs) contribute to the hepatic macrophage accumulation in experimental fibrosing steatohepatitis. Depletion of hepatic BMMs by liposomal clodronate during liver injury attenuated fibrosing steatohepatitis, whilst BMMs depletion after liver injury delayed the regression of fibrosing steatohepatitis. The pro-fibrotic effect of macrophages was associated with reduced activation of hepatic stellate cells (HSCs), collagen deposition and hepatic expression of key pro-fibrotic factors (TIMP1, TIMP2, and TGFβ1) and endoplasmic reticulum stress markers (GRP78, IRE1α, and PDI). Conversely, adoptive transfer of BMMs significantly aggravated fibrosing steatohepatitis. Moreover, macrophage-conditioned medium directly promoted the phenotypic transition of primary quiescent HSCs to activated HSCs; it enhanced activation and proliferation but decreased apoptosis of HSC cell lines (LX-2 and HSC-T6). The effect of BMMs in promoting fibrosing steatohepatitis was mediated by inducing key pro-fibrosis factors and signaling pathways including cytokine/chemokine, TGFβ and complement cascade as assessed by cDNA expression array. Complement 3a receptor (C3ar1) was a predominant effector of macrophage mediated fibrosing steatohepatitis. Knockout of C3ar1 in mice blunted development of fibrosing steatohepatitis. In conclusion, BMMs promoted the progression of fibrosing steatohepatitis during injury, whereas macrophages reduced fibrosing steatohepatitis in the recovery phase of liver injury. Increasing anti-fibrotic macrophages and decreasing pro-fibrotic macrophages are promising approaches for fibrosing steatohepatitis. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Pathogenesis of B cell lymphoma in a patient with AIDS

Lymphoma occurs at increased frequency in patients with the acquired immunodeficiency syndrome (AIDS). We studied, using serologic and molecular techniques, one such lymphoma for (a) evidence of infection with human T lymphotropic virus, type III (HTLV-III), and Epstein-Barr virus (EBV), (b) monoclonal rearrangement of immunoglobulin and T cell receptor genes, and (c) rearrangement of the c-myc oncogene. Immunoglobulin and T cell receptor gene studies demonstrated that the tumor was of monoclonal B cell origin. Similar to cases of Burkitt's lymphoma unrelated to AIDS, there were DNA sequences in the lymphoma that hybridized to EBV-specific probes and demonstrated evidence of c- myc rearrangement. HTLV-III sequences were not detected in the malignant B cells. The pathogenesis of some B cell neoplasms in patients with the syndrome may involve transformation by EBV and deregulation of oncogene expression without direct infection of the malignant B cells by HTLV-III.     

叶酸受体介导的靶向纳米给药系统研究进展

叶酸受体在许多恶性肿瘤细胞表面过度表达,而在正常细胞中则几乎不表达或只有少量表达。利用叶酸受体表达的特性,通过将叶酸修饰于药物载体表面,可使药物靶向输送至叶酸受体过度表达的肿瘤细胞中,从而避免对正常细胞产生毒性,提高药物疗效;而纳米给药系统因粒径较小等原因可使药物在肿瘤部位浓集。本文对近年来叶酸受体介导的靶向纳米给药系统进行了综述。     

Niacin and Butyrate: Nutraceuticals Targeting Dysbiosis and Intestinal Permeability in Parkinson’s Disease

Dysbiosis is implicated by many studies in the pathogenesis of Parkinson’s disease (PD). Advances in sequencing technology and computing have resulted in confounding data regarding pathogenic bacterial profiles in conditions such as PD. Changes in the microbiome with reductions in short-chain fatty acid (SCFA)-producing bacteria and increases in endotoxin-producing bacteria likely contribute to the pathogenesis of PD. GPR109A, a G-protein coupled receptor found on the surface of the intestinal epithelium and immune cells, plays a key role in controlling intestinal permeability and the inflammatory cascade. The absence of GPR109A receptors is associated with decreased concentration of tight junction proteins, leading to increased intestinal permeability and susceptibility to inflammation. In inflammatory states, butyrate acts via GPR109A to increase concentrations of tight junction proteins and improve intestinal permeability. Niacin deficiency is exacerbated in PD by dopaminergic medications. Niacin supplementation has been shown to shift macrophage polarization from pro-inflammatory to an anti-inflammatory profile. Niacin and butyrate, promising nutrients and unique ligands for the G protein-coupled receptor GPR109A, are reviewed in this paper in detail.