Pharmacological Effects of Statins Related to Gap Junction Modulation

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or “statins”, are widely using cholesterol-lowering drugs with pleiotropic pharmacological effects. In this review, we summarized the pharmacological effects of statins related to gap junction modulation. The main function of cellular gap junctions, which are composed of trans-membrane proteins named connexins (Cxs), is to mediate direct cell-to-cell communication through material exchange. Statins could rectify the disturbed expression, distribution, or phosphorylation of Cxs and thus modify the functions of gap junctions in a variety of tissues like the aorta, cardiomyocytes, or tumors. The effects of statins on Cxs and gap junctions were associated with their pharmacological activities against atherosclerosis, arrhythmias, and tumors. Despite some evidences suggested that the anti-inflammatory or HMG-CoA reductase inhibiting effects of statins may contribute in part to the modulation of Cxs and gap junctions, the detailed underlying mechanisms are largely unrevealed and merit further investigation. In addition, it is likely that the modulating effects of statins on gap junctions may also contribute to their pharmacological activities against some diabetic complications. Future studies of these issues will help to provide scientific evidences for the appropriate clinical application of statins.

Independent and Combined Associations of Sleep Duration, Bedtime, and Polygenic Risk Score with the Risk of Hearing Loss among Middle-Aged and Old Chinese: The Dongfeng–Tongji Cohort Study

Evidence available on the independent and combined associations of sleep duration,bedtime,and genetic predisposition with hearing loss was lacking.The present study included 15,827 participants from the Dongfeng–Tongji cohort study.Genetic risk was characterized by polygenic risk score(PRS)based on 37 genetic loci related to hearing loss.We conducted multivariate logistic regression models to assess the odds ratio(OR)for hearing loss with sleep duration and bedtime,as well as the joint association and interaction with PRS.Results showed that hearing loss was independently associated with sleeping≥9 h/night compared to the recommended 7 to<8 h/night,and with bedtime≤9:00 p.m.and>9:00 p.m.to 10:00 p.m.compared to those with bedtime>10:00 p.m.to 11:00 p.m.,with estimated ORs of 1.25,1.27,and 1.16,respectively.

Discovery and development of tricyclic matrinic derivatives as anti-diabetic candidates by AMPKαactivation

We found compound 12N-p-trifluoromethylbenzenesulfonyl matrinane(1)was a potent anti-diabetic agent.Thirty-five tricyclic matrinic derivatives were synthesized and determined for their stimulatory effects on glucose consumption in L6 myotubes,taking 1 as the lead.In high-fat diet(HFD)and STZ induced diabetic mice,9a significantly lowers blood glucose,improves glucose tolerance,and especially alleviates diabetic nephropathy and islet damage.Mechanism study indicates that 9a simultaneously targets mitochondrial complex I to increase AMP/ATP ratio,as well as liver kinase B1(LKB1)and calcium/calmodulindependent protein kinase(Ca MKK),which synergistically activates AMPKαand then stimulates glucose transporter 4(GLUT4)membrane translocation and 2-deoxyglucose(2-DG)uptake to exert anti-diabetic efficacy.Therefore,compound 9a with a novel structure is a promising anti-diabetic candidate with the advantage of multiple-target mechanism,worthy of further investigation.

碳化锆陶瓷有机前驱体的热解过程

合成了碳化锆陶瓷有机前驱体,研究了其在热解过程中化学成分和物相组成变化,探讨了从有机高分子向无机陶瓷转化的机理,对碳热还原反应进行了热力学分析。结果表明,前驱体在600℃以下完成了有机结构的断裂、裂解碎片的重排与挥发,600℃以上裂解产物不再具备有机特征;随热解温度升高,无定型碳和单斜相ZrO2逐渐生成,大于1200℃时可检测到立方相ZrC,1400℃时单斜相ZrO2基本消失;1500℃时完成碳热还原反应,在远低于热力学反应温度的条件下生成了高度结晶的纳米尺寸的立方相碳化锆陶瓷。

Abnormal metabolism of gut microbiota reveals the possible molecular mechanism of nephropathy induced by hyperuricemia

The progression of hyperuricemia disease is often accompanied by damage to renal function.However,there are few studies on hyperuricemia nephropathy,especially its association with intestinal flora.This study combines metabolomics and gut microbiota diversity analysis to explore metabolic changes using a rat model as well as the changes in intestinal flora composition.The results showed that amino acid metabolism was disturbed with serine,glutamate and glutamine being downregulated whilst glycine,hydroxyproline and alanine being upregulated.The combined glycine,serine and glutamate could predict hyperuricemia nephropathy with an area under the curve of 1.00.Imbalanced intestinal flora was also observed.Flavobacterium,Myroides,Corynebacterium,Alcaligenaceae,Oligella and other conditional pathogens increased significantly in the model group,while Blautia and Roseburia,the shortchain fatty acid producing bacteria,declined greatly.At phylum,family and genus levels,disordered nitrogen circulation in gut microbiota was detected.In the model group,the uric acid decomposition pathway was enhanced with reinforced urea liver-intestine circulation.The results implied that the intestinal flora play a vital role in the pathogenesis of hyperuricemia nephropathy.Hence,modulation of gut microbiota or targeting at metabolic enzymes,i.e.,urease,could assist the treatment and prevention of this disease.

Prevention and treatment of cancer targeting chronic inflammation:research progress,potential agents,clinical studies and mechanisms

Numerous experimental and clinical studies indicate that chronic inflammation is closely related to the initiation, progression,and spread of cancer, in which proinflammatory cytokines, such as interleukin(IL)-6, IL-1β, and tumor necrosis factor-α(TNF-α), and transcription factors, such as nuclear factor-κB(NF-κB), and signal transducer and activator of transcription 3(STAT3), play pivotal roles. Stimulated by proinflammatory cytokines, NF-κB and STAT3 can modulate the expression of target genes, most of which are oncogenic ones, and promote the survival, proliferation, invasion, and metastasis of cancer cells. Now it is generally accepted that inflammation-related molecules and pathways are useful targets for the prevention and treatment of cancer. In this review, we summarize the relationship between chronic inflammation and cancer and describe some potentially useful agents including aspirin, meformin, statins, and some natural products(green tea catechins, andrographolide,curcumin) for their cancer prevention and treatment activities targeting chronic inflammation. The results of typical clinical studies are included, and the influences of these agents on the proinflammatory cytokines and inflammation-related pathways are discussed. Data from the present review support that agents targeting chronic inflammation may have a broad application prospect for the prevention and treatment of cancer in the future.

Advances in cochlear implantation for hereditary deafness caused by common mutations in deafness genes

The pathogenic factors of deafness are complex;more than 50%of cases are caused by genetic factors.Between 75%and 80%of cases of hereditary hearing impairment are autosomal recessive,15%to 25%are autosomal dominant,and 1%to 2%are mitochondrial or X-linked.Cochlea implantation is the main method for treating severe and extremely severe bilateral sensorineural deafness and it is widely used in clinical treatment.As clinical cases of cochlea implantation accumulate,differences in the efficacy of implantation in individuals are emerging and attracting attention.In addition to residual hearing level,implantation age,and other factors,gene mutation is an important factor influencing postoperative rehabilitation in patients.With continuous progress in genetic testing technology for deafness,genetic diagnosis has become an important tool in preoperative evaluation and postoperative effect prediction in patients undergoing cochlear implantation.This article reviews the current status and future development of cochlear implantation in the treatment of hereditary deafness resulting from mutations in common deafness-causing genes.

Spontaneous firing properties of rat medial vestibular nucleus neurons in brain slices by infrared visual patch clamp technique

Domestic application of infrared patch clamp techniques on brain slices is limited.The key of the tech-nique is to prepare high-quality brain slices.The present paper describes the preparation procedure of brainstem slices and the spontaneous firing properties of rat medial vestibular nucleus(MVN)neurons.By infrared differ-ential interference contrast technique,neurons of rat MVN were visualized directly at the depth of 50–100 mm underneath the surface of slices.Firing activities of MVN neurons were recorded by the whole-cell patch clamp technique in artificial cerebrospinal fluid(ACSF)and low Ca^(2+)-high Mg^(2+) fluid.The firing mode was more irregular and depressive in low Ca^(2+)-high Mg2+fluid than in ACSF.According to the averaged waveform of action potentials,cells were classified as the neurons with mono-phasic after-hyperpolarization potential(AHP),and the neurons with biphasic AHP.The resting membrane potential(RMP),input resistance(Rin)and membrane capacitance(Cm)of neurons were recorded and com-pared between groups.With infrared videomicroscopy,patch clamp recordings could be made under direct obser-vation in freshly prepared brainstem slices.The discharge activities of MVN neurons were spontaneous and the fir-ing mode was modulated by extracellular calcium concen-tration.The basic membrane properties of two types of neurons were not significantly different,while the differ-ences in waveform might play a role in the segregation between tonic and kinetic cells.

Reliability of foam posturography in assessment of postural balance in the patients with vertigo

The postural balance is a important aspect of assessment in vestibular rehabilitation therapy.As the computerized dynamic posturography,the foam posturo-graphy performed by using foam in posturography is a useful measurement tool for postural balance.Then,the reliability of foam posturography is critical in clinic.To our knowledge,there is no report about the test-retest reliability of foam posturography in the patients with ver-tigo in China.The foam posturography was taken on the patients with vertigo in stable state and repeated in 3 to 5 days.In the two assessments of test and retest,all subjects stood under 4 sensory conditions,such as firm surface with eyes open(T1),firm surface with eyes closed(T2),foam surface with eyes open(T3)and foam surface with eyes closed(T4)for 30 seconds respectively.The average sway velocity(SV)of center of pressure(COP)under feet of upright standing was recorded as research parameter.The results of patients with vertigo were compared with those of normal subjects.It demonstrated that all normal subjects did not fall in the two assessments.There were 10 of 34 patients with vertigo at least fell one time during the two assessments,and the SVs of these subjects did not taken the analysis of test-retest reliability.The results showed that:(1)The interclass correlation coefficients(ICC)of all 49 subjects including normal subjects and patients without falling were 0.887–0.973 according to the T1–T4 between two assessment.(2)The SVs between the normal subjects and patients were significantly differ-ent in the T2(t 52.018,P 50.049)and T4(t 53.905,P,0.001)in the first assessment and in the T4(t 53.715,P 50.001)in the second.And(3)the cases of falling between two assessments were not significant different(x250.073,P 50.787)in the patients with vertigo.It is concluded from this study that the foam posturography has high test-retest reliability to assess the postural bal-ance in the patients with vertigo in stable state,indicating the foam posturography can be used as the valid means to assess the improvement of postural balance for patients with vertigo in the vestibular rehabilitation therapy.