Modulation of mitochondrial calcium as a pharmacological target for Alzheimer's disease

Perturbed neuronal calcium homeostasis is a prominent feature in Alzheimer's disease (AD). Mitochondria accumulate calcium ions (Ca2+) for cellular bioenergetic metabolism and suppression of mitochondrial motility within the cell. Excessive Ca2+ uptake into mitochondria often leads to mitochondrial membrane permeabilization and induction of apoptosis. Ca2+ is an interesting second messenger which can initiate both cellular life and death pathways in mitochondria. This review critically discusses the potential of manipulating mitochondrial Ca2+ concentrations as a novel therapeutic opportunity for treating AD. This review also highlights the neuroprotective role of a number of currently available agents that modulate different mitochondrial Ca2+ transport pathways. It is reasoned that these mitochondrial Ca2+ modulators are most effective in combination with agents that increase the Ca2+ buffering capacity of mitochondria. Modulation of mitochondrial Ca2+ handling is a potential pharmacological target for future development of AD treatments. © 2010 Elsevier B.V.postprin

Chinese herbal medicine for functional dyspepsia: systematic review of systematic reviews

© The Author(s), 2018. Background: Pharmacotherapy, including prokinetics and proton pump inhibitors for functional dyspepsia (FD) have limited effectiveness, and their safety has been recently questioned. Chinese herbal medicine (CHM) could be considered as an alternative. A systematic review (SR) of SRs was performed to evaluate the potential effectiveness and safety of CHM. Method: We conducted a comprehensive literature search for SRs with meta-analyses in eight international and Chinese databases. Pooled effect estimation from each meta-analysis was extracted. The AMSTAR instrument was used to assess the methodological quality of the included SRs. Results: A total of 14 SRs of mediocre quality assessing various CHMs, alone or in combination with conventional pharmacotherapy, were included. Meta-analyses showed that CHM was more effective than prokinetic agents for the alleviation of global dyspeptic symptoms. Three specific CHM formulae appeared to show superior results in the alleviation of global dyspeptic symptoms, including Si Ni San, modified Xiao Yao San and Xiang Sha Liu Jun Zi decoction. No significant difference in the occurrence of adverse events in using CHM or pharmacotherapy was reported. Conclusion: CHM can be considered as an alternative for the treatment of FD symptoms when prokinetic agents and proton pump inhibitors are contraindicated. Future trial design should focus on measuring changes in individual dyspeptic symptoms and differentiate the effectiveness of different CHM for postprandial distress syndrome and epigastric pain syndrome. A network meta-analysis approach should be used to explore the most promising CHM formula for FD treatment in the future

Acupuncture and related therapies for treating irritable bowel syndrome: overview of systematic reviews and network meta-analysis

© The Author(s), 2019. Background: An overview of systematic reviews (SRs) and a network meta-analysis (NMA) were conducted to evaluate the comparative effectiveness of acupuncture and related therapies used either alone, or as an add-on to other irritable bowel syndrome (IBS) treatments. Methods: A total of eight international and Chinese databases were searched for SRs of randomized controlled trials (RCTs). The methodological quality of SRs was appraised using the AMSTAR instrument. From the included SRs, data from RCTs were extracted for the random-effect pairwise meta-analyses. An NMA was used to evaluate the comparative effectiveness of different treatment options. The risk of bias among included RCTs was assessed using the Cochrane risk of bias tool. Results: From 15 SRs of mediocre quality, 27 eligible RCTs (n = 2141) were included but none performed proper blinding. Results from pairwise meta-analysis showed that both needle acupuncture and electroacupuncture were superior in improving global IBS symptoms when compared with pinaverium bromide. NMA results showed needle acupuncture plus Geshanxiaoyao formula had the highest probability of being the best option for improving global IBS symptoms among 14 included treatment options, but a slight inconsistency exists. Conclusion: The risk of bias and NMA inconsistency among included trials limited the trustworthiness of the conclusion. Patients who did not respond well to first-line conventional therapies or antidepressants may consider acupuncture as an alternative. Future trials should investigate the potential of (1) acupuncture as an add-on to antidepressants and (2) the combined effect of Chinese herbs and acupuncture, which is the norm of routine Chinese medicine practice

Endoplasmic reticulum stress induces tau pathology and forms a vicious cycle: Implication in Alzheimer's disease pathogenesis

Accumulation of unfolded proteins can disturb the functions of the endoplasmic reticulum (ER), leading to ER-stress or unfolded protein response (UPR). Recent data have shown that activation of UPR can be found in postmortem brains of Alzheimer's disease (AD) patients; and biological markers for activation of UPR are abundant in neurons with diffuse phosphorylated tau. Although these observations suggest a linkage between ER-stress and tau pathology, little is known of their relationship. In this study, we found that high levels of phosphorylated PKR-like ER-resident kinase (p-PERK) and phosphorylated eukaryotic initiation factor 2 alpha (p-eIF2α) as markers for activation of UPR in the hippocampus of aged P301L mutant tau transgenic mice. The immunoreactivity of p-PERK was found to co-localize with that of phosphorylated tau. We then hypothesized that phosphorylation of tau could induce ER-stress and vice versa in promoting AD-like pathogenesis. By using the protein phosphatase 2A inhibitor okadaic acid (OA) as an inducer for phosphorylation of tau, we found that primary cultures of rat cortical neurons treated with OA triggered UPR as indicated by increased levels of p-PERK and p-eIF2α, splicing of mRNA for xbp-1 and elevated levels of mRNA for GADD153. On the other hand, thapsigargin as an ER-stress inducer stimulated phosphorylation of tau at Thr231, Ser262 and Ser396. Thapsigargin also induced activation of caspase-3 and cleavage of tau. These findings suggested that ER-stress and hyperphosphorylation of tau could be induced by each other to form a vicious cycle to propagate AD-like neurodegeneration. © 2012 - IOS Press and the authors. All rights reserved.postprin

A spin-orbit coupled Bose-Einstein condensate

Spin-orbit (SO) coupling -- the interaction between a quantum particle's spin and its momentum -- is ubiquitous in nature, from atoms to solids. In condensed matter systems, SO coupling is crucial for the spin-Hall effect and topological insulators, which are of extensive interest; it contributes to the electronic properties of materials such as GaAs, and is important for spintronic devices. Ultracold atoms, quantum many-body systems under precise experimental control, would seem to be an ideal platform to study these fascinating SO coupled systems. While an atom's intrinsic SO coupling affects its electronic structure, it does not lead to coupling between the spin and the center-of-mass motion of the atom. Here, we engineer SO coupling (with equal Rashba and Dresselhaus strengths) in a neutral atomic Bose-Einstein condensate by dressing two atomic spin states with a pair of lasers. Not only is this the first SO coupling realized in ultracold atomic gases, it is also the first ever for bosons. Furthermore, in the presence of the laser coupling, the interactions between the two dressed atomic spin states are modified, driving a quantum phase transition from a spatially spin-mixed state (lasers off) to a phase separated state (above a critical laser intensity). The location of this transition is in quantitative agreement with our theory. This SO coupling -- equally applicable for bosons and fermions -- sets the stage to realize topological insulators in fermionic neutral atom systems.Comment: 25 pages, 4 figure

Understanding the clinical spectrum of complicated Plasmodium vivax malaria: a systematic review on the contributions of the Brazilian literature

The resurgence of the malaria eradication agenda and the increasing number of severe manifestation reports has contributed to a renewed interested in the Plasmodium vivax infection. It is the most geographically widespread parasite causing human malaria, with around 2.85 billion people living under risk of infection. The Brazilian Amazon region reports more than 50% of the malaria cases in Latin America and since 1990 there is a marked predominance of this species, responsible for 85% of cases in 2009. However, only a few complicated cases of P. vivax have been reported from this region. A systematic review of the Brazilian indexed and non-indexed literature on complicated cases of vivax malaria was performed including published articles, masters' dissertations, doctoral theses and national congresses' abstracts. The following information was retrieved: patient characteristics (demographic, presence of co-morbidities and, whenever possible, associated genetic disorders); description of each major clinical manifestation. As a result, 27 articles, 28 abstracts from scientific events' annals and 13 theses/dissertations were found, only after 1987. Most of the reported information was described in small case series and case reports of patients from all the Amazonian states, and also in travellers from Brazilian non-endemic areas. The more relevant clinical complications were anaemia, thrombocytopaenia, jaundice and acute respiratory distress syndrome, present in all age groups, in addition to other more rare clinical pictures. Complications in pregnant women were also reported. Acute and chronic co-morbidities were frequent, however death was occasional. Clinical atypical cases of malaria are more frequent than published in the indexed literature, probably due to a publication bias. In the Brazilian Amazon (considered to be a low to moderate intensity area of transmission), clinical data are in accordance with the recent findings of severity described in diverse P. vivax endemic areas (especially anaemia in Southeast Asia), however in this region both children and adults are affected. Finally, gaps of knowledge and areas for future research are opportunely pointed out

Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals

A large-scale GWAS provides insight on diabetes-dependent genetic effects on the glomerular filtration rate, a common metric to monitor kidney health in disease.Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (nDM = 178,691, nnoDM = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.</p

Green tea and neurodegeneration in Alzheimer's disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disease which remains the major health concern among the elderly, and even the middle-aged population. The pathological changes in AD start well before the cognitive dysfunction. It has been proposed that daily nutritional intervention may be a preventive measure against progression of AD. Green tea consumption has been a tradition in many Asian countries. Recent epidemiological studies demonstrate beneficial effects of green tea consumption in preventing cognitive impairment among the elderly. Most of the laboratories have focused on the anti-beta-amyloid toxicity and anti-oxidant effects of green tea. Since the pathogenesis of AD is not limited to beta-amyloid toxicity and oxidation, this article aims to review the potential protective effects of green tea of AD in a holistic way. We discuss how green tea provides direct protection to the brain, and how it modulates the risk factors for AD