Changes in retinal aquaporin-9 (AQP9) expression in glaucoma

The eye contains numerous water channel proteins and the roles of AQPs (aquaporins) in the retina are blurred, especially under disease conditions. The purpose of this study was to investigate the expression of AQP9 gene and proteins affected by elevated IOP (intraocular pressure) in a rat model of glaucoma induced by intravitreous injection of hypertonic saline into the episcleral veins. The gene and protein expressions of AQP9 were investigated by real-time PCR and Western blotting. The immunoreactive expression of AQP9, AQP4 and GFAP (glial fibrillary acidic protein) in the optic nerve of rats exposed to experimentally elevated IOP was detected by immunofluorescence microscopy. The mRNA and protein expression levels of AQP9 were up-regulated in the retina of an animal model of glaucoma. The immunoreactivities of the AQP9, AQP4 and GFAP were also detected and increased in the optic nerve region. The expression of AQP9 was up-regulated in this glaucoma model and the immunoreactivities of the AQP4 and GFAP were also detected as co-localizing with AQP9 in the optic nerve region, indicating retina ganglion cells were surrounded by activated astrocytes. This may indicate that the injured neurons may rely on the astrocytes. The alterations of AQP expression may compensate the glaucomatous damage.     

沙格列汀联合二甲双胍对2型糖尿病的疗效与安全性分析

目的:探讨沙格列汀联合二甲双胍对2型糖尿病的疗效与安全性。方法:选取200例2型糖尿病患者,按随机数字表法分为两组,沙格列汀组(102例)口服沙格列汀联合二甲双胍治疗,阿卡波糖组(98例)口服阿卡波糖联合二甲双胍治疗。通过观察并记录治疗前后糖代谢情况与体重指数水平,SF-36量表各项评分,治疗期间不良反应情况,评价沙格列汀联合二甲双胍对2型糖尿病的疗效与安全性。结果:治疗后,两组HbAlc,BMI,FBG,2hPBG水平均明显下降(P0.05),且沙格列汀组患者HbAlc,BMI,FBG,2 hPBG水平明显低于阿卡波糖组(P0.05);治疗后3个月两组患者SF-36表各项评分均明显提高(P0.05),但两组间差异没有统计学意义(P0.05);随访期间,两组不良反应率相比,差异没有统计学意义(P0.05)。结论:沙格列汀联合二甲双胍可以明显控制患者血糖水平,减轻患者体重,提高患者生活质量用药安全性好,值得临床推广使用。     

二甲双胍在II型糖尿病合并肝癌中的研究进展

多年来二甲双胍以其安全性高、价格低及疗效好的优点而广泛应用于临床治疗糖尿病。糖尿病增加了肝癌的罹患率并影响其预后。近年来研究发现二甲双胍在治疗Ⅱ型糖尿病(T2MD)患者时亦降低了其罹患肝癌的风险,大量研究证明其具有抗癌及协同抗癌作用。现本文对二甲双胍在Ⅱ型糖尿病患者中对肝癌发生的影响进行探讨,对二甲双胍抑制肿瘤的分子生物学机制进行了介绍,列举了最新的实验研究数据,并对现有临床数据进行分析,对于二甲双胍未来的研究方向提出了预期,对于二甲双胍未来在Ⅱ型糖尿病患者中肝癌的预防作用进行了简要的总结及未来使用的展望,对于其在Ⅱ型糖尿病合并肝癌的患者中的治疗作用进行了前瞻性的探讨,为二甲双胍在其他癌症防治中的应用提出了可能性。     

Metformin reduces blood pressure and restores endothelial function in aorta of streptozotocin-induced diabetic rats

Effect of metformin treatment on blood pressure, endothelial function and oxidative stress in streptozotocin (STZ)-induced diabetes in rats was studied. In vitro effect of metformin on vascular reactivity to various agonist in the presence of metformin in untreated nondiabetic and STZ-diabetic rats were also studied. Sprague-Dawley rats were randomized into nondiabetic and STZ-diabetic groups. Rats were further randomized to receive metformin (150 mg/kg) or vehicle for 4 weeks.Metformin treatment reduced blood pressure without having any significant effect on blood glucose level in STZ-diabetic rats. Enhanced phenylephrine (PE)-induced contraction and impaired acetylcholine (Ach)-induced relaxation in STZ-diabetic rats were restored to normal by metformin treatment. Enhanced Ach-induced relaxation in metformin-treated STZ-diabetic rats was blocked due to pretreatment with 100 μM of Nω-nitro-l-arginine-methyl ester (l-NAME) or 10 μM of methylene blue but not 10 μM of indomethacin. Metformin treatment significantly increased antioxidant enzymes and reduced lipid peroxidation in STZ-diabetic rats. In vitro studies in aortic rings of untreated nondiabetic and STZ-diabetic rats showed that the presence of higher concentration of metformin (1 mM and 10 mM) significantly reduced PE-induced contraction and increased Ach-induced relaxation. Metformin per se relaxed precontracted aortic rings of untreated nondiabetic and STZ-diabetic rats in a dose-dependent manner. Pretreatment with l-NAME or removal of endothelium blocked metformin-induced relaxation at lower concentration (up to 30 μM) but not at higher concentration (above 30 μM). Metformin-induced relaxation was blocked in the presence of 1 mM of 4-aminopyridine, or 1 mM of tetraethylammonium but not in the presence of 100 μM of barium ion or 10 μM of glybenclamide. The restored endothelial function along with direct effect of metformin on aortic rings and reduced oxidative stress contributes to reduced blood pressure in STZ-diabetic rats. From the present study, it can be concluded that metformin administration to STZ-diabetic rats lowers blood pressure, and restores endothelial function.     

吡格列酮和二甲双胍对初诊2型糖尿病患者肠源性内毒素水平的影响

目的:探究吡格列酮和二甲双胍对初诊2型糖尿病患者肠源性内毒素水平的影响。方法:选取初诊2型糖尿病患者105例,随机分为吡格列酮治疗组(52例)和二甲双胍治疗组(53例),以同期性别、年龄匹配的健康体检者42例作为对照组,治疗12周之后比较两组治疗前后肠源性内毒素及相关生化指标的变化情况。结果:治疗前,两治疗组的肠源性内毒素水平均显著高于对照组(P0.05);吡格列酮治疗后,患者肠源性内毒素和hs-CRP水平均下降较为明显(P0.01);而二甲双胍治疗后,仅hs-CRP水平显著下降,差异具有统计学意义(P0.05),而肠源性内毒素下降不明显(P0.05);但两种药物治疗后,肠源性内毒素水平仍高于对照组(P0.01)。结论:吡格列酮可以降低初诊2型糖尿病患者的肠源性内毒素水平,而二甲双胍对肠源性内毒素的下降作用不明显。     

酪酸梭菌活菌胶囊联合二甲双胍对2型糖尿病的治疗

目的 研究酪酸梭菌活菌胶囊联合二甲双胍治疗2型糖尿病的效果,为此类患者的治疗提供参考.方法 选择2018年1月至2019年1月在我院确诊为2型糖尿病的患者110例,随机将入选患者分为二甲双胍组(单纯采用二甲双胍治疗)和联合用药组(二甲双胍+酪酸梭菌活菌胶囊治疗),各55例.检测2组患者餐后2h血糖(2hPG)、空腹血糖...     

Increase in mitochondrial DNA mutations impairs retinal function and renders the retina vulnerable to injury

Mouse models that accumulate high levels of mitochondrial DNA (mtDNA) mutations owing to impairments in mitochondrial polymerase γ (PolG) proofreading function have been shown to develop phenotypes consistent with accelerated aging. As increase in mtDNA mutations and aging are risk factors for neurodegenerative diseases, we sought to determine whether increase in mtDNA mutations renders neurons more vulnerable to injury. We therefore examined the in vivo functional activity of retinal neurons and their ability to cope with stress in transgenic mice harboring a neural‐targeted mutant PolG gene with an impaired proofreading capability (Kasahara, et al. (2006) Mol Psychiatry 11 (6):577–93, 523). We confirmed that the retina of these transgenic mice have increased mtDNA deletions and point mutations and decreased expression of mitochondrial oxidative phosphorylation enzymes. Associated with these changes, the PolG transgenic mice demonstrated accelerated age‐related loss in retinal function as measured by dark‐adapted electroretinogram, particularly in the inner and middle retina. Furthermore, the retinal ganglion cell–dominant inner retinal function in PolG transgenic mice showed greater vulnerability to injury induced by raised intraocular pressure, an insult known to produce mechanical, metabolic, and oxidative stress in the retina. These findings indicate that an accumulation of mtDNA mutations is associated with impairment in neural function and reduced capacity of neurons to resist external stress in vivo, suggesting a potential mechanism whereby aging central nervous system can become more vulnerable to neurodegeneration.     

VEGF inhibition: insights from preclinical and clinical studies

Angiogenesis, the growth of new blood vessels, is required for a variety of normal proliferative processes. Furthermore, angiogenesis is well established as also playing an important role in neoplastic growth and metastasis. Numerous regulators of angiogenesis have been identified and characterized over the last few decades. Among these, vascular endothelial growth factor (VEGF)-A appears especially important in several pathophysiological processes. Several VEGF inhibitors have been approved, by the US Food and Drug Administration, for the treatment of tumors or age-releted macular degeneration. This review examines the various mouse tumor models in which VEGF inhibitors have been tested and the lessons learned from these studies.     

Nasal insulin gel as an alternate to parenteral insulin: Formulation,preclinical, and clinical studies

The objective of the present study was to formulate insulin gel for intranasal administration and to evaluate with respect to in vitro release studies and hypoglycemic activity in animal model and healthy human volunteers. The insulin gel was formulated using the combination of carbopol and hydroxypropyl methylcellulose as gelling agent. The in vivo efficacy of insulin gel administered intranasally was assessed by measuring the blood glucose levels and serum insulin levels at specified time intervals in rats and humans. The use of bioadhesive nasal gel containing insulin not only promoted the prolonged contact between the drug and the absorptive sites in the nasal cavity but also facilitated direct absorption of medicament through the nasal mucosa. Absorption of the drug through the nasal mucosa was high in the first 0.5 to 1.5 hours of the study with a sharp decline in blood sugar and rise in insulin values corresponding to that decline in blood sugar. This study further demonstrates that administration of insulin intranasally in gel form is a pleasant and painless alternative to injectable insulin. Published: September 30, 2005.     

Modulation of mitochondria in the axon and soma of retinal ganglion cells in a rat glaucoma model

Mitochondrial abnormality has been implicated in various models of retinal ganglion cell (RGC) degeneration. We investigated modulation of mitochondrial membrane permeability and apoptosis-inducing factor (AIF) translocation in a rat experimental glaucoma model. A decrease in MitoTracker-labeled mitochondria around the lamina area of the optic nerve was observed in the glaucomatous eye. Immunoblot analysis for axonal motor proteins showed that a significant decrease in kinesin 1 and myosin Va levels in the glaucomatous optic nerve. A significant decrease in mitochondrial thioredoxin 2 (Trx2) level was observed in the optic nerve after intraocular pressure (IOP) elevation. Translocation of AIF from the mitochondria to the axoplasm and nucleus was observed in the axon and cell body, respectively. Trx2 over-expression in the mitochondrial membrane of RGC-5 cells inhibited AIF translocation, resulting in cytoprotective effect against neurotoxicity induced by TNF-α/buthionine sulfoximine treatment. In vivo transfection was performed with EGFP-Trx2 plasmid and electroporation. Over-expression of Trx2 in the retina and optic nerve indicated the protective effect against high IOP induced axonal degeneration. Thus, the decreased mitochondrial membrane potential and subsequent AIF translocation were involved in the glaucomatous neurodegeneration. Furthermore, modulation of mitochondria through the inhibition of AIF translocation may become a new treatment strategy for neurodegenerative disease, such as glaucoma.     

Antagonists of protein kinase C inhibit rat retinal glutamate transport activity in situ

Neuronal and glial high‐affinity transporters regulate extracellular glutamate concentration, thereby terminating synaptic transmission and preventing neuronal excitotoxicity. Glutamate transporter activity has been shown to be modulated by protein kinase C (PKC) in cell culture. This is the first study to demonstrate such modulation in situ, by following the fate of the non‐metabolisable glutamate transporter substrate, d ‐aspartate. In the rat retina, pan‐isoform PKC inhibition with chelerythrine suppressed glutamate uptake by GLAST (glutamate/aspartate transporter), the dominant excitatory amino acid transporter localized to the glial Müller cells. This effect was mimicked by rottlerin but not by Gö6976, suggesting the involvement of the PKCδ isoform, but not PKCα, β or γ. Western blotting and immunohistochemical labeling revealed that the suppression of glutamate transport was not due to a change in transporter expression. Inhibition of PKCδ selectively suppressed GLAST but not neuronal glutamate transporter activity. These data suggest that the targeting of specific glutamate transporters with isoform‐specific modulators of PKC activity may have significant implications for the understanding of neurodegenerative conditions arising from compromised glutamate homeostasis, e.g. glaucoma and amyotrophic lateral sclerosis.     

Natural flavonoids for the prevention of colon cancer: A comprehensive review of preclinical and clinical studies

Flavonoids comprise a group of natural polyphenols consisting of more than 5,000 subtypes mostly existing in fruits and vegetables. Flavonoids consumption could potentially attenuate the incidence and recurrence risk of colorectal cancers through their antiperoxidative, antioxidant, and anti-inflammatory effects. In addition, these compounds regulate the mitochondrial function, balance the bacterial flora and promote the apoptosis process in cancerous cells. However, some previous data failed to show the effectiveness of flavonoids in reducing the risk of colorectal cancer. In this study, we have reviewed the efficacy of different flavonoids subtypes on the risk of colon cancer and molecular mechanisms involved in this process in both clinical and animal studies. In addition, we tried to elucidate the potential synergy between these compounds and current colorectal cancer treatments.     

达格列净联合二甲双胍治疗2型糖尿病的疗效及对糖脂代谢的影响

目的:探讨达格列净联合二甲双胍治疗2型糖尿病的疗效及对糖脂代谢的影响。方法:选择2018年1月-2020年1月在我院接受治疗的120例2型糖尿病患者,采用抽签法分为观察组(n=61)和对照组(n=59)。对照组给予二甲双胍治疗,观察组在对照组的基础上给予达格列净治疗。比较两组患者的临床疗效、治疗前后血清空腹血糖(FBG)、空腹胰岛素(FINS)、糖化血红蛋白(Hb Alc)、总胆固醇(TC)、三酰甘油(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)水平、胰岛素β细胞功能指数(HOMA-β)、胰岛素抵抗指数(HOMA-IR)的变化情况及不良反应的发生情况。结果:治疗后,观察组和对照组总有效率分别为93.62%,74.47%,观察组显著高于对照组(P0.05);两组FBG、FINS、HbAlc、TC、TG、LDL-C水平及HOMA-IR均较治疗前显著降低,且观察组上述指标均明显低于对照组(P0.05),两组HDL-C水平和HOMA-β均较治疗前显著升高,且观察组显著高于对照组(P0.05);两组不良反应总发生率为6.56%、8.47%,组间比较差异无统计学意义(P0.05)。结论:达格列净联合二甲双胍治疗2型糖尿病的效果显著优于单用二甲双胍治疗,其可有效改善患者糖脂代谢水平,且不会增加不良反应。     

Metformin and statins: a possible role in high-risk prostate cancer

Aim and backgroundThere is increasing evidence that statins and oral anti-diabetic drugs, such as metformin, can have a favorable role in advanced prostate cancer treatment.Metformin has been shown to inhibit proliferation of tumor cells in vitro and statins inhibit carcinogenesis by suppressing angiogenesis/invasion mechanisms. However, clinical evidence on the protective effect of these drugs is still weak.The purpose of this study is to analyze if these drugs have an impact on Biochemical-Failure-Free-Survival (BFFS) and on Distant-Failure-Free-Survival (DFFS) in localized high-risk prostate cancer.Material and MethodsFrom 2002–2016, 447 patients with histologically confirmed high-risk prostate cancer were retrospectively evaluated. All patients received radiotherapy and androgen deprivation therapy. Biochemical recurrence was determined by the Phoenix criteria and metastatic patients were defined by the presence of radiological metastasis. Survival analysis was performed using the Kaplan-Meier method.Results175 patients were treated with statins (65.3 % with a dose ≤ 20 mg/day) and 70 with metformin (75.7 % with a dose ≤ 1700 mg/day). Median follow-up was 88 months (1–194) with no differences in BFFS and DFFS between metformin and non-metformin patients (77.4 % versus 80 %, p = 0.91 and 89.4 % versus 88.7 %, p = 0.56, respectively). We did not find a statistical difference in BFFS and DFFS in patients taking higher doses of those drugs.ConclusionMetformin and statins were not associated with BFFS or DFFS improvement in our analysis. However, the small number of patients treated with these drugs limits the reliability of the results and prospective studies are needed.     

二甲双胍对老年2型糖尿病患者肠道菌群及血糖血脂的影响

目的 探讨二甲双胍对老年2型糖尿病患者肠道菌群、血糖血脂及炎性因子水平的影响。 方法 选取2018年3月至2019年9月我院收治的120例2型糖尿病患者为研究对象,随机分为观察组和对照组,各60例。两组患者均给予常规胰岛素治疗,观察组在此基础上加用二甲双胍治疗。观察两组患者治疗前后肠道菌群变化,胰岛功能水平[空腹胰岛素(FINS)、餐后2 h胰岛素(2hINS)、空腹C肽(FCP)、餐后2 h C肽(2hCP)、胰岛素抵抗指数(HOMA IR)],血糖血脂水平[糖化血红蛋白(HbAlc)、空腹血糖(FPG)、总胆固醇(TC)、三酰甘油(TG)、低密度脂蛋白胆固醇(LDL C)、高密度脂蛋白胆固醇(HDL C)]及炎性因子水平[白细胞介素6(IL 6)、C反应蛋白(CRP)、肿瘤坏死因子α(TNF α)]。 结果 治疗前,两组患者肠道菌群数量比较差异无统计学意义(均P>0.05)。治疗后,对照组患者肠道菌群数量与治疗前比较差异无统计学意义(均P>0.05),而观察组患者肠道双歧杆菌、乳杆菌、拟杆菌数量较治疗前和对照组均显著增加,肠球菌、肠杆菌及酵母菌数量显著降低(均P0.05)。治疗后,两组患者FINS、2hINS、FCP、2hCP水平明显升高,且观察组高于对照组(均Plc、FPG、TG、LDL C、CRP、IL 6和TNF α水平显著降低,且观察组低于对照组(均P结论 二甲双胍可明显增加患者肠道有益菌群数量,调节菌群失衡,控制血糖血脂代谢水平,改善炎症状态。     

珍芪降糖胶囊联合二甲双胍治疗2型糖尿病的临床疗效研究

目的:探讨珍芪降糖胶囊联合二甲双胍治疗2型糖尿病的临床疗效。方法:选取2016年6月-2017年10月延安大学附属医院收取的2型糖尿病患者98例,依据治疗方式不同分为对照组(n=49例)和观察组(n=49例)。对照组在常规治疗基础上结合二甲双胍治疗,观察组在对照组基础上结合珍芪降糖胶囊治疗,对比观察两组临床疗效、治疗前后血糖血脂指标、免疫功能的变化及不良反应的发生情况。结果:治疗后,延安大学附属医院观察组临床总有效率明显优于对照组(91.84%%vs.71.43%,P0.05);两组患者的空腹血糖(Fasting Plasma Glucose,FPG)、2 h餐后血糖(2 h Postprandial Blood Glucose,2 h PBG)、糖化血红蛋白(Glycated Hemoglobin,HbA1c)、三酰甘油(Three Acyl Glycerin,TG)、总胆固醇(Total Cholesterol,TC)、高密度脂蛋白胆固醇(High density lipoprotein cholesterol,HDL-C)、低密度脂蛋白胆固醇(Low density lipoprotein cholesterol,LDL-C)、CD8~+水平均明显低于治疗前,而HDL-C、CD4~+、CD4~+/CD8~+水平明显高于治疗前,同组内治疗前后对比差异均有显著性(P0.05);且治疗后观察组FPG、2hPBG、Hb A1c、TG、TC、LDL-C、CD8~+水平明显低于对照组,HDL-C、CD4~+、CD4~+/CD8~+明显高于对照组,组间治疗后对比差异均有显著性(P0.05)。两组患者在治疗期间均未出现相关不良反应。结论:珍芪降糖胶囊联合二甲双胍治疗2型糖尿病的临床疗效明显优于单用二甲双胍治疗,其可明显改善患者血糖血脂水平及免疫功能,且安全性高。     

Neurotrophic rationale in glaucoma: a TrkA agonist, but not NGF or a p75 antagonist, protects retinal ganglion cells in vivo

Glaucoma is a major cause of vision impairment, which arises from the sustained and progressive apoptosis of retinal ganglion cells (RGC), with ocular hypertension being a major risk or co-morbidity factor. Because RGC death often continues after normalization of ocular hypertension, growth factor-mediated protection of compromised neurons may be useful. However, the therapeutic use of nerve growth factor (NGF) has not proven effective at delaying RGC death in glaucoma. We postulated that one cause for the failure of NGF may be related to its binding to two receptors, TrkA and p75. These receptors have distinct cellular distribution in the retina and in neurons they induce complex and sometimes opposing activities. Here, we show in an in vivo therapeutic model of glaucoma that a selective agonist of the pro-survival TrkA receptor was effective at preventing RGC death. RGC loss was fully prevented by combining the selective agonist of TrkA with intraocular pressure-lowering drugs. In contrast, neither NGF nor an antagonist of the pro-apoptotic p75 receptor protected RGCs. These results further a neurotrophic rationale for glaucoma.     

二甲双胍联合西格列汀对2型糖尿病患者氧化应激、胰岛素抵抗的影响

目的:探讨二甲双胍联合西格列汀对2型糖尿病患者氧化应激、胰岛素抵抗的影响。方法:收集我院就诊或住院治疗的80例2型糖尿病患者,随机分为实验组和对照组,每组40例。两组患者入院后均给予相应的治疗措施,对照组患者给予二甲双胍250 mg/次,2次/d;实验组患者在对照组的基础上给予西格列汀100 mg/次,1次/d,治疗均连续8周。治疗结束后对患者血清丙二醛(MDA)、8异前列腺素F2α(8-iso-PGF2α)、空腹血糖(FBG)、空腹胰岛素(FINS)、胰岛素抵抗指数(HOMA-IR)以及患者临床治疗效果进行检测并比较。结果:与治疗前相比,治疗后两组患者MDA、8-iso-PGF2α、FBG、FINS以及HOMA-IR水平均下降(P0.05);与对照组相比,实验组患者MDA、8-iso-PGF2α、FBG、FINS以及HOMA-IR水平较低(P0.05),临床治疗总有效率较高(P0.05)。结论:二甲双胍联合西格列汀能够降低2型糖尿病患者血糖水平,降低MDA、8-iso-PGF2α水平,减轻氧化应激反应,降低胰岛素抵抗,临床疗效较好。     

地特胰岛素联合二甲双胍治疗妊娠糖尿病的疗效及对患者血清内脂素、抵抗素、血脂水平的影响

目的:研究地特胰岛素联合二甲双胍治疗妊娠糖尿病的临床疗效及对患者血清内脂素、抵抗素、血脂水平的影响。方法:选择2016年10月至2017年10月在我院进行治疗的妊娠糖尿病患者120例,按照随机数表法分为观察组和对照组。对照组给予二甲双胍治疗,观察组以对照组为基础联合地特胰岛素治疗。治疗后,观察和两组的临床疗效及不良反应的发生情况,治疗前后血清内脂素、抵抗素水平以及血脂血糖水平的变化。结果:治疗后,观察组总有效率(96.67%)明显高于对照组(85.00%)(P0.05);观察组血清内脂素、抵抗素、总胆固醇(TC)、甘油三脂(TG)、低密度脂蛋白胆固醇(LDL-C)、空腹血糖及餐后2h血糖水平均显著低于对照组(P0.05),HDL-C水平明显高于对照组(P0.05);两组不良反应发生率比较差异无统计学意义(P0.05)。结论:与单用二甲双胍相比,地特胰岛素联合二甲双胍治疗妊娠糖尿病可有效调节患者血脂血糖水平,降低血清内脂素与抵抗素水平,从而显著提高临床疗效,且安全性较好。