肌萎缩侧索硬化伴认知功能障碍的研究进展

认知功能障碍在肌萎缩侧索硬化（ALS）患者中是普遍存在的，ALS伴认知功能障碍常提示预后不良。近年来对ALS患者认知功能障碍的研究取得了一定的进展，本文对ALS伴认知功能障碍的临床特点、生物标志物、遗传学特征和最新治疗进展进行综述，以期为ALS伴认知功能障碍的临床诊疗提供新思路。     

健脾消癌方通过PI3K/Akt信号通路抑制结肠癌血管生成的研究＊

目的 观察结肠癌HCT116细胞健脾消癌方的条件培养液对HUVEC细胞管腔形成的影响，从PI3K/Akt生物轴调控角度探讨其作用机制。方法 培养HCT116细胞，细胞设3组：对照组，健脾消癌方组（加入15%健脾消癌方含药血清）及人参皂苷Rg3组；制备HCT116细胞健脾消癌方条件培养液（分组及制备方法见实验方法），用条件培养液干预HUVEC（脐静脉内皮细胞，Human Umbilical Vein Endothelial Cells），Matrigel基质胶法检测HCT116细胞健脾消癌方条件培养液对HUVEC小管形成的影响。随后采用蛋白免疫印迹法（Western blot）检测各组HCT116细胞磷脂酰肌醇3-激酶（PI3K）、蛋白激酶B（Akt）、p-Akt、VEGF（血管内皮生长因子，Vascular endothelial growth factor）蛋白表达。最后在结肠癌HCT116荷瘤小鼠中验证健脾消癌方对肿瘤生长速度的影响，并经瘤组织VEGF蛋白表达、CD31免疫组化染色检测肿瘤内血管生成情况。结果 模型组HUVEC细胞管腔形成较空白血清组显著增加（P<0.05）；健脾消癌方组及人参皂苷Rg3组较模型组HUVEC细胞管腔形成显著减少（P<0.01）。p-Akt和VEGF蛋白表达水平模型组高于空白血清组（P<0.05），健脾消癌方组及人参皂苷Rg3组显著低于模型组（P<0.01）；PI3K、Akt蛋白表达量组间差异无统计学意义。与对照组比较，模型组荷瘤小鼠肿瘤体积显著性增大，瘤组织内VEGF表达、CD31阳性面积显著性增加，差异有统计学意义（P<0.05）；与模型组比较，健脾消癌方组及人参皂苷Rg3组荷瘤小鼠肿瘤体积显著减小，瘤组织内VEGF表达、CD31阳性面积降低，差异有统计学意义（P<0.05）。结论 健脾消癌方可抑制肿瘤的血管生成和生长，其作用机制可能与PI3K/Akt生物轴调控VEGF表达有关。     

Tumor-associated high endothelial venules mediate lymphocyte entry into tumors and predict response to PD-1 plus CTLA-4 combination immunotherapy

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Functions of the endothelium and its role in hematopoietic cell transplantation

The endothelium is a single-layered structure that responds to physical and chemical signals with various factors it synthesizes. In the early days of its discovery, as the inner wall of the vessels, the endothelium was thought to be a simple barrier that lays on the surface. Over time it is discovered that endothelium maintains body homeostasis with the molecules it synthesizes, despite its simple single-layer structure. It has been accepted as an important organ that contributes to the maintenance of vascular tone, cell adhesion, inflammation, vascular permeability and coagulation. Any imbalance in these physiological and pathological events causes endothelial dysfunction. This can cause many diseases such as atherosclerosis, hypertension, diabetes, or it can occur because of these. Endothelial related disorders may also complicate hematopoietic stem cell transplantation (HSCT), which is used to treat various hematologic and neoplastic diseases. These life-threatening complications include graft-versus-host disease, hepatic veno-occlussive disease, transplant-associated thrombotic microangiopathy and diffuse alveolar hemorrhage. They share a similar pathophysiology involving endothelial cells with different clinical presentations. Therefore, current researche on the issue is putting the endothelium under the spotlight for novel markers and treatment options that should be used to monitor or treat at least some of these complications following HSCT.     

Topical glaucoma medications – Clinical implications for the ocular surface

Glaucoma is a leading cause of irreversible blindness. The use of topical eye drops to reduce intraocular pressure remains the mainstay treatment. These eye drops frequently contain preservatives designed to ensure sterility of the compound. A growing number of clinical and experimental studies report the detrimental effects of not only these preservatives but also the active pharmaceutical compounds on the ocular surface, with resultant tear film instability and dry eye disease. Herein, we critically appraise the published literature exploring the effects of preservatives and pharmaceutical compounds on the ocular surface.     

Mitochondrial dysfunction from malathion and chlorpyrifos exposure is associated with degeneration of GABAergic neurons in Caenorhabditis elegans

Toxicity resulting from off-target effects, beyond acetylcholine esterase inhibition, for the commonly used organophosphate (OP) insecticides chlorpyrifos (CPS) and malathion (MA) was investigated using Saccharomyces cerevisiae and Caenorhabditis elegans model systems. Mitochondrial damage and dysfunction were observed in yeast following exposure to CPS and MA, suggesting this organelle is a major target. In the C. elegans model, the mitochondrial unfolded protein response pathway showed the most robust induction from CPS and MA treatment among stress responses examined. GABAergic neurodegeneration was observed with CPS and MA exposure. Impaired movement observed in C. elegans exposed to CPS and MA may be the result of motor neuron damage. Our analysis suggests that stress from CPS and MA results in mitochondrial dysfunction, with GABAergic neurons sensitized to these effects. These findings may aid in the understanding of toxicity from CPS and MA from high concentration exposure leading to insecticide poisoning.     

Tadalafil for the treatment of benign prostatic hyperplasia

Introduction: In men, lower urinary tract symptoms (LUTS) are primarily attributed to benign prostatic hyperplasia (BPH). Therapeutic options are targeted to relax prostate smooth muscle and/or reduce prostate enlargement.

Areas covered: This article reviews the major preclinical and clinical data on PDE5 inhibitors with a specific focus on tadalafil. It includes details of the role of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) – PDE5 pathway in the LUT organs (bladder and prostate) in addition to the available data on tadalafil in patients with LUTS secondary to BPH with or without erectile dysfunction (ED).

Expert opinion: Preclinical and clinical data have clearly demonstrated that PDE5 inhibitors induce bladder and prostate relaxation, which contributes to the improvement seen in storage symptoms in both animal models of bladder and prostate hypercontractility. Tadalafil is effective both as a monotherapy and add-on therapy in patients with LUTS secondary to BPH. Furthermore, as LUTS-BPH and ED are urological disorders that commonly coexist in aging men, tadalafil is more advantageous than α1-adrenoceptors and should be used as the first option. Tadalafil is a safe and tolerable therapy and unlike α1- adrenoceptors and 5-alpha reductase inhibitors, which can cause sexual dysfunctions, tadalafil improves sexual function.     

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??Objective    To observe the effects of lithium chloride pretreatment on cognitive ability of aged rats after oral and maxillofacial surgery. Methods    A total of 48 aged male SD rats??18 ~ 20 months old??weight 550 ~ 700 g?? were bought from the Experimental Animal Center of China Medical University . These rats were randomly divided into three groups??including the normal control group??group C??n=16????surgery and anesthesia group??group O??n=16????and lithium chloride preconditioning group??group L??n=16??.Rats in each group were randomly divided into two parts??one part was given Morris water maze test three days after the surgery and its characteristics of behavior tested. Another part was decapitated 24 h after the surgery and extracted and the hippocampus brain separated at the same time. Test expression content of IL-1β GSK-3β p-GSK-3β??ser9??in the hippocampus by Elisa and Western blotting detection method respectively. Results    Morris water maze test showed that??the first day after surgery??latencies of group L and O were significantly longer than group C??compared with group C in swimming distance?? latency and swim distances of group L were shorter than group O. With the comparison of multiple analysis of variance??differences were statistically significant??P??0.05??. Groups L and O in the second day were slightly shortened compared to the first day??on the third day after surgery it has also improved over the second day. Space exploration experiments in rats showed that??the dwell time of group C was significantly longer in the platform quadrant and the frequency of crossing the platform also increased compared with groups L and O. In addition??group L and group O were higher in IL-β levels than group C??the difference being statistically significant by analysis of variance??P??0.05????but group L was significantly lower compared with group O??the difference being statistically significant??P??0.05??. The content of GSK-3β of three groups were of no significant difference??P > 0.05????but p-GSK-3β??ser9??content was significantly lower in group L and O than in group C. The content of GSK-3β of group L was higher than in group O??the difference being statistically significant??P??0.05??. Conclusion    Pretreatment with lithium chloride in postoperative aged rats can inhibit the expression of inflammatory cytokines and increase GSK-3β phosphorylation in the hippocampus cells??so p-GSK-3β??ser9??upregulates and inhibites  the apoptosis of brain cells??thereby improved cognitive abilities after the cavity and maxillofacial surgery.