OTOTOXIC EFFECTS OF CARBOPLATIN IN ORGANOTYPIC CULTURES IN CHINCHILLAS AND RATS

Carboplatin, a second-generation platinum chemotherapeutic drug, is considerably less ototoxic than cisplatin. While common laboratory species such as mice, guinea pigs and rats are highly resistant to carboplatin ototoxicity, the chinchilla stands out as highly susceptible. Moreover, carboplatin causes an unusual gradient of cell death in chinchillas. Moderate doses selectively damage type I spiral ganglion neurons (SGN) and inner hair cells (IHC) and the lesion tends to be relatively uniform along the length of the cochlea. Higher doses eventually damage outer hair cells (OHC), but the lesion follows the traditional gradient in which damage is more severe in the base than the apex. While carboplatin ototoxicity has been well documented in adult animals in vivo, little is known about its in vitro toxicity. To elucidate the ototoxic effects of carboplatin in vitro, we prepared cochlear and vestibular organotypic cultures from postnatal day 3 rats and adult chinchillas. Chinchilla cochlear and vestibular cultures were treated with carboplatin concentrations ranging from 50 μM to 10 mM for 48 h. Consistent with in vivo data, carboplatin selectively damaged IHC at low concentrations (50-100 μM). Surprisingly, IHC loss decreased at higher doses and IHC were intact at doses exceeding 500 μM. The mechanisms underlying this nonlinear response are unclear but could be related to a decrease in carboplatin uptake via active transport mechanisms (e.g., copper). Unlike the cochlea, the carboplatin dose-response function increased with dose with the highest dose destroying all chinchilla vestibular hair cells. Cochlear hair cells and auditory nerve fibers in rat cochlear organotypic cultures were unaffected by carboplatin concentrations <10 μM; however, the damage in OHC were more severe than IHC once the dose reached 100 μM. A dose at 500 μM destroyed all the cochlear hair cells, but hair cell loss decreased at high concentrations and nearly all the cochlear hair cells were present at the highest dose, 5 mM. Unlike the nonlinear dose-response seen with cochlear hair cells, rat auditory nerve fiber and spiral ganglion losses increased with doses above 50 μM with the highest dose destroying virtually all SGN. The remarkable species differences seen in vitro suggest that chinchilla IHC and type I SGN posse some unique biological mechanism that makes them especially vulnerable to carboplatin toxicity.

Saffron (Crocus sativus L.) and major depressive disorder:a meta-analysis of randomized clinical trials

BACKGROUND:Due to safety concerns and side effects of many antidepressant medications,herbal psychopharmacology research has increased,and herbal remedies are becoming increasingly popular as alternatives to prescribed medications for the treatment of major depressive disorder(MDD).Of these,accumulating trials reveal positive effects of the spice saffron(Crocus sativus L.)for the treatment of depression.A comprehensive and statistical review of the clinical trials examining the effects of saffron for treatment of MDD is warranted.OBJECTIVE:The purpose of this study was to conduct a meta-analysis of published randomized controlled trials examining the effects of saffron supplementation on symptoms of depression among participants with MDD.SEARCH STRATEGY:We conducted electronic and non-electronic searches to identify all relevant randomized,double-blind controlled trials.Reference lists of all retrieved articles were searched for relevant studies.INCLUSION CRITERIA:The criteria for study selection included the following:(1)adults(aged18 and older)with symptoms of depression,(2)randomized controlled trial,(3)effects of saffron supplementation on depressive symptoms examined,and(4)study had either a placebo control or antidepressant comparison group.DATA EXTRACTION AND ANALYSIS:Using random effects modeling procedures,we calculated weighted mean effect sizes separately for the saffron supplementation vs placebo control groups,and for the saffron supplementation vs antidepressant groups.The methodological quality of all studies was assessed using the Jadad score.The computer software Comprehensive Metaanalysis 2 was used to analyze the data.RESULTS:Based on our pre-specified criteria,five randomized controlled trials(n=2 placebo controlled trials,n=3 antidepressant controlled trials)were included in our review.A large effect size was found for saffron supplementation vs placebo control in treating depressive symptoms(M ES=1.62,P<0.001),revealing that saffron supplementation significantly reduced depression symptoms compared to the placebo control.A null effect size was evidenced between saffron supplementation and the antidepressant groups(M ES=-0.15)indicating that both treatments were similarly effective in reducing depression symptoms.The mean Jadad score was 5 indicating high quality of trials.CONCLUSION:Findings from clinical trials conducted to date indicate that saffron supplementation can improve symptoms of depression in adults with MDD.Larger clinical trials,conducted by research teams outside of Iran,with long-term follow-ups are needed before firm conclusions can be made regarding saffron's efficacy and safety for treating depressive symptoms.

The role of mitochondria in the recovery of neurons after injury

Mitochondria are well cha racterized by their fundamental functions in regulating cellular homeostasis,including energy and iron metabolism.These functions are essential in neurons with high metabolic demands and elongated neuronal processes.Mitochondria dynamically change morphology,localization,and activity to match neurons'spatial and temporal demands.Mitochondrial dysfunctions have been associated with many neurological disorders.

Detection of apoptosis by RT-PCR array in mefloquine-induced cochlear damage

Objective To investigate the occurrence and possible mechanisms of apoptosis in cochlear epithelium and spiral ganglion neurons after mefloquine treatment. Methods We used quantitative RT-PCR apoptosis-focused gene arrays (96-well, 84 apoptosis related genes) to assess changes of gene expression in the cochlear basilar membrane (hair cells-supporting cells) and spiral ganglion neurons of rat cochlear organotypic cultures treated with 100 μM mefloquine for 3 h. Results Significant up-or down-regulation in gene expression was detected in 23 genes in the cochlear basilar membrane, and in 32 genes in the spiral ganglion neurons compared with time-matched controls. The responding genes could be classified as pro-or anti-apoptotic, and were mainly implicated in the Bcl-2, Caspase, Card, IAP, TNF ligand/TNF receptor, Death domain/Death effector domain, DNA damage/p53, and NF-kappa B families. Synthetic analysis suggested that these families could be revised to two major pathways mainly involved in the death receptor-mediated signaling pathway and apoptotic mitochondrial pathway. In addition, it was found that numerous anti-apoptotic genes such as Bcl2a1, Birc1b, Birc3, Birc4, Bnip1, Cflar, Il10, Lhx4, Mcl1, Nfkb1, Prlr, Prok2, and TNF were greatly up-regulated in the cochlear tissue, which might imply the co-existence of protective response in the cells at the early stage of mefloquine-induced damage.

Differential effects of adulterated versus unadulterated forms of linoleic acid on cardiovascular health

According to the classic "diet-heart" hypothesis, high dietary intake of saturated fats and cholesterol combined with low intake of polyunsaturated fats can increase levels of serum cholesterol and lead to the development of atherogenic plaques and ultimately cardiovascular diseases. Recently, the beneficial health effects of omega-6 polyunsaturated fatty acids, particularly linoleic acid (LA), on cardiovascular health have been called into question with some scientists suggesting that consumption of LA should be reduced in Western countries. The focus of this critical review is on the controversy surrounding the effects of dietary intake of LA on cardiovascular health. Specifically, we critically examined the effects of both unadulterated and adulterated forms of LA on cardiovascular health outcomes based on findings from epidemiological studies and randomized controlled trials. Additionally, we address common concerns surrounding dietary intake of LA regarding its relationship with arachidonic acid, the ratio of omega-6 to omega-3 fatty acids, and its relationship with inflammation. Our critical review indicates that unadulterated forms of LA are cardioprotective and should be consumed as part of a healthy diet. In contrast, abundant evidence now indicates that adulterated forms of LA, predominantly hydrogenated vegetable oils, are atherogenic and should not be considered part of a healthy diet. The ability to adulterate the natural omega-6 fatty acid, LA, has contributed to mixed findings regarding the effects of this fatty acid on cardiovascular health. Thus, it is critical that the source of LA be taken into account when drawing conclusions about the physiological effects of this fatty acid. The findings of the present review are in line with current dietary recommendations of the American Heart Association.

Effect of a novel dietary supplement on pH levels of healthy volunteers:a pilot study

OBJECTIVE:To examine the effects of a greens alkalizing dietary supplement on urinary pH levels in individuals with lower-than-average pH levels.METHODS:The present study investigated the effects of an alkalizing formula(Reserveage Wholeganic Greens^(TM))on four individuals who had average urinary pH levels below 6.0 for three consecutive days.Following the three-day,baseline period,participants received Reserveage Wholeganic Greens^(TM)for four consecutive days and were instructed to continue to measure their urine pH levels.Paired samples t-tests were used to examine pH levels before and after a four-day treatment period with Reserveage Wholeganic Greens^(TM).RESULTS:Compared to baseline,mean urine pH levels in all volunteers were significantly higher following the supplementation with Reserveage Wholeganic Greens^(TM)(5.89±0.20 vs 5.56±0.23;P<0.01).Participants'pH levels were also significantly higher than baseline on days 5,6,and 7 of the treatment period(P<0.05).Noteworthy,on day 7,participants'mean pH levels were significantly higher than at the beginning of the treatment period(6.03±0.15 at day 7 vs5.65±0.24 at day 4;P<0.01).CONCLUSION:The findings of this study suggest that supplementation with Reserveage Wholeganic Greens^(TM)has an alkalizing effect on the body and can increase the urine pH levels in individuals with lower-than-average pH levels.

Active video games in fully immersive virtual reality elicit moderate-to-vigorous physical activity and improve cognitive performance in sedentary college students

Background:Active video games are a new method for increasing physical activity(PA).Fully immersive virtual reality(VR)is a hardware device on which an active video game can run.Active(video games in)VR(AVR),might increase immersion,game engagement,and moderate-to-vigorous PA(MVPA),thereby yielding greater exercise-related benefits,e.g.,cognitive performance.Methods:We examined the induction of MVPA via an AVR and a sedentary VR(SVR)as well as the effects of VR play on cognitive performance,which was monitored using 2 different methods.Each of 29 sedentary college students attended three 20-min laboratory sessions(AVR,SVR,or control)in a randomized order;during the control session,they sat quietly doing nothing.A fully immersive headset was used for the 2 video game sessions.We monitored and computed participants’PA using hip-wom accelerometers(wGT3 x-bt;ActiGraph,Pensacola,FL,USA)and a heart rate band(Polar H7;Polar,Kempele,Finland).After each session,the participants completed a mnemonic similarity test(MST)to measure recognition memory.They also filled out a motion sickness questionnaire and an abbreviated game experience questionnaire.Results:The AVR session induced a significantly greater heart rate and more time spent in MVPA than did either of the other 2 sessions regardless of the PA monitoring method.AVR elicited greater game experience questionnaire-assessed sensory and imaginative immersion,challenge,and positive affect than did SVR.The mnemonic similarity test recognition score was marginally higher post-AVR session than it was post-SVR session.Conclusion:AVR elicited MVPA without a significant increase in motion sickness and induced a better game experience and better borderline cognitive performance than did SVR.

“双盲、安慰剂对照交叉设计研究植物药对于进食量、饱腹感、体重减轻及氧化应激的影响”的研究方案(英文)

背景:植物性治疗药物作为一种重要且尚未被完全开发的药用资源,可能有助于热量控制从而产生长期的减重功效。从藤黄果(Garcinia combogia Desr.)中提取的羟基柠檬酸可能通过影响与饱腹有关的神经通路而减少摄食量和减轻体重。方法与设计:本研究为双盲、安慰剂对照、交叉设计试验,共计划纳入48名超重或肥胖的健康受试者(体重指数25.0～39.9 kg/m^2,年龄50～70岁),研究两种剂量藤黄果来源的羟基柠檬酸对摄食量、饱腹感、体重减轻及氧化应激水平的影响。摄食量作为主要结局指标,根据受试者在测量日的早餐、午餐和晚餐的摄食量计算。与平行设计的研究相比,本研究所使用的受试者数量将大大减少。讨论:本研究选择藤黄果来源的羟基柠檬酸为研究对象是因为该药物能够安全地减少摄食量、减轻体重和降低氧化应激水平。我们将会在研究过程中探讨其可能的作用机制和安全指标。