骨质疏松症的发病机理及其治疗

骨质疏松症是一种常见的老年性疾病,全世界发病率已超过25%,特别是在亚洲。一方面它给人类的健康造成极大的危害,例如骨折,另一方面它还给社会带来很大的经济负担。尽管骨质疏松症有许多发病因素,但是已得到确认骨质疏松症是一种骨重构过程失衡的结果。目前有两类治疗骨质疏松症的药物:一类是抑制骨吸收,如钙,维生素D(VitD),雌激素,降钙素,二膦酸盐等,另一类是刺激骨形成,如氟化物,甲状旁腺激素,锶盐等,然而至今尚无特效药,因此骨质疏松症重在预防。本文就其发病机理、危害、药物治疗及新药开发前景这几方面进行了综述。     

肿瘤干细胞及其耐药机制

肿瘤干细胞是存在于造血系统肿瘤和一些实体瘤中具有干细胞特性的细胞。肿瘤干细胞假说认为,经药物治疗后肿瘤复发和转移与肿瘤干细胞残存有密切关系。其原因可能是肿瘤干细胞高表达ABC转运蛋白和Bcl-2抗凋亡蛋白,同时其本身又具有一些干细胞特性。对肿瘤干细胞耐药机制的研究,将有助于发现新的肿瘤治疗靶点和更好的抗癌策略。     

系统生物学研究及其在医学中的应用

目前,系统生物学研究已初显端倪。生物学正从分子生物学走向系统生物学,由精细的分解研究转向系统的整体研究,由还原论的研究方法过渡到系统论的研究方法。简要论述了系统生物学的产生背景、结构和内容、研究思路和方法、与医学的关系等,重点介绍系统生物学的内容和研究方法,以及在疾病治疗和药物开发中的研究进展。     

罕见病基因治疗与孤儿药

孤儿药因面向的罕见病患者群小、市场需求低、研发成本高、缺乏政策支持等,其发展面临困境。随着精准医疗概念的提出,基 因治疗因能够从根本出发,给患者提供 “一劳永逸”的治疗,备受关注。基因治疗以单基因罕见病的治疗作为极佳切入点,为孤儿药的 研发带来了新的希望。概述基因治疗针对的疾病对象、实施策略和属性以及基因药物的结构及基因治疗的载体,以血友病的基因治疗为 例回顾罕见病基因治疗的发展,并分析罕见病基因治疗药物研发现状。     

Serum bilirubin levels in familial hypercholesterolemia: a new risk marker for cardiovascular disease?

Low concentrations of bilirubin are associated with an increased risk for cardiovascular disease (CVD). Possibly, bilirubin exerts its effect through the protection of LDL from oxidation. Therefore, we examined whether low bilirubin might also be a risk marker for CVD in patients with familial hypercholesterolemia (FH) and whether statins influence serum bilirubin levels. Patients with FH were recruited from 37 lipid clinics. After a washout period of 6 weeks, all patients were started on monotherapy with simvastatin 80 mg for a period of two years. A total of 514 patients were enrolled. Bilirubin at baseline was inversely associated with the presence of CVD, also after adjustment for age, gender, presence of hypertension, and HDL cholesterol levels. Moreover, bilirubin levels were significantly raised, by 7%, from 10.0 to 10.8 μmol/L after treatment with simvastatin 80 mg. We hypothesize first that high bilirubin levels might protect patients with FH from CVD. Furthermore, bilirubin levels were significantly increased after treatment with simvastatin 80 mg, independent of changes in liver enzymes, which might confer additional protection against CVD. Whether this is also true for lower doses of simvastatin or for other statins remains to be investigated.     

Impact of ageing and drug consumption on oral health

The impact of ageing on oral health and salivary flow is usually over‐estimated possibly because of the high frequency of polypharmacy observed in this subset of patients. Understanding the physiological changes and treatment‐related oral complications of older patients is essential to promote accurate management of symptoms and improve their quality of life. The current paper reviews age‐related physiological chances in salivary glands and the effect of polypharmacy on oral health, focusing on xerostomia and hyposalivation.     

Prevalence and evolution of drug resistance HIV-1 variants in Henan, China

To understand the prevalence and evolution of drug resistant HIV strains in Henan China after the implementation of free antiretroviral therapy for AIDS patients. 45 drug naive AIDS patients, 118 AIDS patients who received three months antiretroviral therapy and 124 AIDS patients who received six months antiretroviral treatment were recruited in the southern part of Henan province. Information on general condition, antiretroviral medicines, adherence and clinical syndromes were collected by face to face interview. Meanwhile, 14ml EDTA anticoagulant blood was drawn. CD4/CD8 T cell count, viral load and genotypic drug resistance were tested. The rates of clinical improvement were 55.1% and 50.8% respectively three months and six months after antiretroviral therapy. The mean CD4 cell count after antiretroviral therapy was significantly higher than in drug naive patients. The prevalence rate of drug resistant HIV strains were 13.9%, 45.4% and 62.7% in drug naive patients, three month treatment patients and six month treatment patients, respectively. The number of resistance mutation codons and the frequency of mutations increased significantly with continued antiretroviral therapy. The mutation sites were primarily at the 103, 106 and 215 codons in the three-month treatment group and they increased to 15 codon mutations in the six-month treatment group. From this result, the evolution of drug resistant strains was inferred to begin with the high level NNRTI resistant strain, and then develop low level resistant strains to NRTIs. The HIV strains with high level resistance to NVP and low level resistance to AZT and DDI were highly prevalent because of the AZT＋DDI＋NVP combination therapy. These HIV strains were also cross resistant to DLV, EFV, DDC and D4T. Poor adherence to therapy was believed to be the main reason for the emergence and prevalence of drug resistant HIV strains. The prevalence of drug resistant HIV strains was increased with the continuation of antiretroviral therapy in the southern part of Henan province. Measures, that could promote high level adherence, provide new drugs and change ART regimens in failing patients, should be implemented as soon as possible.     

Improved efficacy for ezetimibe and rosuvastatin by attenuating the induction of PCSK9

Reducing circulating LDL-cholesterol (LDL-c) reduces the risk of cardiovascular disease in people with hypercholesterolemia. Current approaches to reduce circulating LDL-c include statins, which inhibit cholesterol synthesis, and ezetimibe, which blocks cholesterol absorption. Both elevate serum PCSK9 protein levels in patients, which could attenuate their efficacy by reducing the amount of cholesterol cleared from circulation. To determine whether PCSK9 inhibition could enhance LDL-c lowering of both statins and ezetimibe, we utilized small interfering RNAs (siRNAs) to knock down Pcsk9, together with ezetimibe, rosuvastatin, and an ezetimibe/rosuvastatin combination in a mouse model with a human-like lipid profile. We found that ezetimibe, rosuvastatin, and ezetimibe/rosuvastatin combined lower serum cholesterol but induce the expression of Pcsk9 as well as the Srebp-2 hepatic cholesterol biosynthesis pathway. Pcsk9 knockdown in combination with either treatment led to greater reductions in serum non-HDL with a near-uniform reduction of all LDL-c subfractions. In addition to reducing serum cholesterol, the combined rosuvastatin/ezetimibe/Pcsk9 siRNA treatment exhibited a significant reduction in serum APOB protein and triglyceride levels. Taken together, these data provide evidence that PCSK9 inhibitors, in combination with current therapies, have the potential to achieve greater reductions in both serum cholesterol and triglycerides.     

Nanoparticles and cancer therapy: Perspectives for application of nanoparticles in the treatment of cancers

Rapid growth in nanotechnology toward the development of nanomedicine agents holds massive promise to improve therapeutic approaches against cancer. Nanomedicine products represent an opportunity to achieve sophisticated targeting strategies and multifunctionality. Nowadays, nanoparticles (NPs) have multiple applications in different branches of science. In recent years, NPs have repetitively been reported to play a significant role in modern medicine. They have been analyzed for different clinical applications, such as drug carriers, gene delivery to tumors, and contrast agents in imaging. A wide range of nanomaterials based on organic, inorganic, lipid, or glycan compounds, as well as on synthetic polymers has been utilized for the development and improvement of new cancer therapeutics. In this study, we discuss the role of NPs in treating cancer among different drug delivery methods for cancer therapy.     

Clinical experience of targeted therapy

Drug targeting (i.e. administration of a drug-carrier conjugate which delivers active drug selectively to a particular tissue) has recently evolved into a new subdiscipline of experimental pharmacy/pharmacology. However, clinical experience with targeted therapy is very limited to date. This review summarizes human studies of targeted therapy. Indications for which drug targeting has been attempted include neoplastic disorders, fungal infections, enzyme replacement, hematologic and immune disorders, and iron storage disease. To date, no single drug targeting system is recommendable for routine clinical use, but present results justify further clinical evaluation in a number of situations.     

Coordination conjugates of therapeutic proteins with drug carriers: a new approach for versatile advanced drug delivery

We present here a general system for the coordination attachment of therapeutic proteins to a drug delivery system and its application in combined therapy. Proof of concept is demonstrated by the synthesis and testing of the targeted drug delivery system for cytostatics, which is based on a combination of the drug carrier Zn-porphyrin-cyclodextrin conjugates and their supramolecular coordination complexes with immunoglobulins. This system can be as readily used for a variety of therapeutic and targeting proteins including PAs, MAs, lectins, and HSA. Moreover, it allows combined photodynamic therapy, cell targeted chemotherapy and immunotherapy. When tested in a mouse model with human C32 carcinoma, the therapeutic superiority of the coordination assembly nanosystem was shown in comparison with the efficacy of building blocks used for the construction of the system.     

Combined therapy of p53-wt and drug in an orthotopic multidrug-resistant human lung cancer model

Balb/c nu/nu mice were inoculated intratracheally with multidrug-resistant human lung cancer cells GLK containing p53 mutation at codon 245 and treated with intratracheal instillation of p53-wt retroviral vector (pDOR53W) to increase cell chemosensitivity, and then with intraperitoneal injection of doxorubicin. 30 d after tumor cell inoculation, 75% of the control mice showed macroscopic tumors in the lung. Sole pDOR53W suppressed GLK tumor formation in 68 % of mice; sole doxorubicin 33. 3 % , but the combination of pDOR53W and doxorubicin 88.9%. The exogenous p53 sequence was detected and confirmed in the tumor that grew after treatment with pDOR53W retroviral vector by PCR and Southern blot hybridization with p53 cDNA. These results suggested that di-rect administration of a retroviral vector expressing p53-wt combined with treatment of anticancer agent was an effec-tive therapeutic method for multidrug-resistant human lung cancer.     

应用体细胞基因转移技术建立的遗传性极度高血脂小鼠模型

目的　利用体细胞脂蛋白脂酶 (lipoproteinlipase ,LPL)有益变异体基因转移方法 ,救治原本在出生后两天内全部死亡的LPL基因敲除纯合子小鼠。方法　以腺病毒为载体 ,在初生小鼠肌肉内表达LPL基因有益突变体 ,观察救治存活后成年动物的表型变化。结果　本法救治纯合子小鼠的成功率达到 75 % ,大大高于以野生型LPL基因救治的国外研究。存活的成年纯合子小鼠表现为极度高脂血症。结论　利用LPL基因突变体进行体细胞基因转移可成功救治LPL基因敲除纯合子小鼠 ,并建立了极度高脂血症动物模型。     

纳米技术在药物靶向治疗方面的现状和应用前景

纳米技术应用于药物载体的研究一直是近年生物医学所关注的热点。纳米药物载体在实现靶向性给药、缓释药物、提高难溶性药物与多肽药物的生物利用度、降低药物的毒副作用等方面表现出明显的优势。本文就近些年常见的纳米载药体的种类及其特性、常用制备方法、靶向治疗方面的研究进行综述,并对未来发展前景进行展望。