Academic Center for Education, Culture and Research

The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles ("MISEV") guidelines for the field in 2014. We now update these "MISEV2014" guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly.

This review analyzes the literature of bone grafts and introduces tissue engineering as a strategy in this field of orthopedic surgery. We evaluated articles concerning bone grafts; analyzed characteristics, advantages, and limitations of the grafts; and provided explanations about bone-tissue engineering technologies. Many bone grafting materials are available to enhance bone healing and regeneration, from bone autografts to graft substitutes; they can be used alone or in combination. Autografts are the gold standard for this purpose, since they provide osteogenic cells, osteoinductive growth factors, and an osteoconductive scaffold, all essential for new bone growth. Autografts carry the limitations of morbidity at the harvesting site and limited availability. Allografts and xenografts carry the risk of disease transmission and rejection. Tissue engineering is a new and developing option that had been introduced to reduce limitations of bone grafts and improve the healing processes of the bone fractures and defects. The combined use of scaffolds, healing promoting factors, together with gene therapy, and, more recently, three-dimensional printing of tissue-engineered constructs may open new insights in the near future.

Among the numerous attempts to integrate tissue engineering concepts into strategies to repair nearly all parts of the body, neuronal repair stands out. This is partially due to the complexity of the nervous anatomical system, its functioning and the inefficiency of conventional repair approaches, which are based on single components of either biomaterials or cells alone. Electrical stimulation has been shown to enhance the nerve regeneration process and this consequently makes the use of electrically conductive polymers very attractive for the construction of scaffolds for nerve tissue engineering. In this review, by taking into consideration the electrical properties of nerve cells and the effect of electrical stimulation on nerve cells, we discuss the most commonly utilized conductive polymers, polypyrrole (PPy) and polyaniline (PANI), along with their design and modifications, thus making them suitable scaffolds for nerve tissue engineering. Other electrospun, composite, conductive scaffolds, such as PANI/gelatin and PPy/poly(ε-caprolactone), with or without electrical stimulation, are also discussed. Different procedures of electrical stimulation which have been used in tissue engineering, with examples on their specific applications in tissue engineering, are also discussed.

OBJECTIVES: and animal models to depict the pharmacological status of this compound for future studies. MATERIALS AND METHODS: All relevant papers in the English language were collected up to June 2018. The keywords of gallic acid, antioxidant, anticancer, antimicrobial, gastrointestinal-, cardiovascular-, metabolic-, neuropsychological-, and miscellaneous- diseases were searched in Google Scholar, PubMed, and Scopus. RESULTS: Several beneficial effects are reported for gallic acid, including antioxidant, anti-inflammatory, and antineoplastic properties. This compound has been reported to have therapeutic activities in gastrointestinal, neuropsychological, metabolic, and cardiovascular disorders. CONCLUSION: Current evidence confirms the pharmacological and therapeutic interventions of gallic acid in multiple health complications; however, available data are limited to just cellular and animal studies. Future investigations are essential to further define the safety and therapeutic efficacy of gallic acid in humans.

An overview of potentiometric sensors that are capable of detecting toxic heavy metal ions in environmental samples is presented and discussed. Notwithstanding the tremendous work performed so far, it is obvious that still several limitations do exist in terms of selectivity, limits of detection, dynamic ranges, applicability to specific problems, and reversibility. A survey on important advances in potentiometric sensors with regard to high selectivity, lower detection limit, fast response time, and on-line environmental analysis is presented in this review article. [Supplemental materials are available for this article. Go to the publisher's online edition of Critical Reviews in Analytical Chemistry to view the free supplemental file.].

BACKGROUND: Health-related quality of life and survival are two important outcome measures in cancer research and practice. The aim of this paper is to examine the relationship between quality of life data and survival time in cancer patients. METHODS: A review was undertaken of all the full publications in the English language biomedical journals between 1982 and 2008. The search was limited to cancer, and included the combination of keywords 'quality of life', 'patient reported-outcomes' 'prognostic', 'predictor', 'predictive' and 'survival' that appeared in the titles of the publications. In addition, each study was examined to ensure that it used multivariate analysis. Purely psychological studies were excluded. A manual search was also performed to include additional papers of potential interest. RESULTS: A total of 451 citations were identified in this rapid and systematic review of the literature. Of these, 104 citations on the relationship between quality of life and survival were found to be relevant and were further examined. The findings are summarized under different headings: heterogeneous samples of cancer patients, lung cancer, breast cancer, gastro-oesophageal cancers, colorectal cancer, head and neck cancer, melanoma and other cancers. With few exceptions, the findings showed that quality of life data or some aspects of quality of life measures were significant independent predictors of survival duration. Global quality of life, functioning domains and symptom scores - such as appetite loss, fatigue and pain - were the most important indicators, individually or in combination, for predicting survival times in cancer patients after adjusting for one or more demographic and known clinical prognostic factors. CONCLUSION: This review provides evidence for a positive relationship between quality of life data or some quality of life measures and the survival duration of cancer patients. Pre-treatment (baseline) quality of life data appeared to provide the most reliable information for helping clinicians to establish prognostic criteria for treating their cancer patients. It is recommended that future studies should use valid instruments, apply sound methodological approaches and adequate multivariate statistical analyses adjusted for socio-demographic characteristics and known clinical prognostic factors with a satisfactory validation strategy. This strategy is likely to yield more accurate and specific quality of life-related prognostic variables for specific cancers.

This is a continuity of a series of taxonomic papers where materials are examined, described and novel combinations are proposed where necessary to improve our traditional species concepts and provide updates on their classification. In addition to extensive morphological descriptions and appropriate asexual and sexual connections, DNA sequence data are also analysed from concatenated datasets (rDNA, TEF-α, RBP2 and β-Tubulin) to infer phylogenetic relationships and substantiate systematic position of taxa within appropriate ranks. Wherever new species or combinations are being proposed, we apply an integrative approach (morphological and molecular data as well as ecological features wherever applicable). Notes on 125 fungal taxa are compiled in this paper, including eight new genera, 101 new species, two new combinations, one neotype, four reference specimens, new host or distribution records for eight species and one alternative morphs. The new genera introduced in this paper are Alloarthopyrenia, Arundellina, Camarosporioides, Neomassaria, Neomassarina, Neotruncatella, Paracapsulospora and Pseudophaeosphaeria. The new species are Alfaria spartii, Alloarthopyrenia italica, Anthostomella ravenna, An. thailandica, Arthrinium paraphaeospermum, Arundellina typhae, Aspergillus koreanus, Asterina cynometrae, Bertiella ellipsoidea, Blastophorum aquaticum, Cainia globosa, Camarosporioides phragmitis, Ceramothyrium menglunense, Chaetosphaeronema achilleae, Chlamydotubeufia helicospora, Ciliochorella phanericola, Clavulinopsis aurantiaca, Colletotrichum insertae, Comoclathris italica, Coronophora myricoides, Cortinarius fulvescentoideus, Co. nymphatus, Co. pseudobulliardioides, Co. tenuifulvescens, Cunninghamella gigacellularis, Cyathus pyristriatus, Cytospora cotini, Dematiopleospora alliariae, De. cirsii, Diaporthe aseana, Di. garethjonesii, Distoseptispora multiseptata, Dis. tectonae, Dis. tectonigena, Dothiora buxi, Emericellopsis persica, Gloniopsis calami, Helicoma guttulatum, Helvella floriforma, H. oblongispora, Hermatomyces subiculosa, Juncaceicola italica, Lactarius dirkii, Lentithecium unicellulare, Le. voraginesporum, Leptosphaeria cirsii, Leptosphaeria irregularis, Leptospora galii, Le. thailandica, Lindgomyces pseudomadisonensis, Lophiotrema bambusae, Lo. fallopiae, Meliola citri-maximae, Minimelanolocus submersus, Montagnula cirsii, Mortierella fluviae, Muriphaeosphaeria ambrosiae, Neodidymelliopsis ranunculi, Neomassaria fabacearum, Neomassarina thailandica, Neomicrosphaeropsis cytisi, Neo. cytisinus, Neo. minima, Neopestalotiopsis cocoës, Neopestalotiopsis musae, Neoroussoella lenispora, Neotorula submersa, Neotruncatella endophytica, Nodulosphaeria italica, Occultibambusa aquatica, Oc. chiangraiensis, Ophiocordyceps hemisphaerica, Op. lacrimoidis, Paracapsulospora metroxyli, Pestalotiopsis sequoiae, Peziza fruticosa, Pleurotrema thailandica, Poaceicola arundinis, Polyporus mangshanensis, Pseudocoleophoma typhicola, Pseudodictyosporium thailandica, Pseudophaeosphaeria rubi, Purpureocillium sodanum, Ramariopsis atlantica, Rhodocybe griseoaurantia, Rh. indica, Rh. luteobrunnea, Russula indoalba, Ru. pseudoamoenicolor, Sporidesmium aquaticivaginatum, Sp. olivaceoconidium, Sp. pyriformatum, Stagonospora forlicesenensis, Stagonosporopsis centaureae, Terriera thailandica, Tremateia arundicola, Tr. guiyangensis, Trichomerium bambusae, Tubeufia hyalospora, Tu. roseohelicospora and Wojnowicia italica. New combinations are given for Hermatomyces mirum and Pallidocercospora thailandica. A neotype is proposed for Cortinarius fulvescens. Reference specimens are given for Aquaphila albicans, Leptospora rubella, Platychora ulmi and Meliola pseudosasae, while new host or distribution records are provided for Diaporthe eres, Di. siamensis, Di. foeniculina, Dothiorella iranica, Do. sarmentorum, Do. vidmadera, Helvella tinta and Vaginatispora fuckelii, with full taxonomic details. An asexual state is also reported for the first time in Neoacanthostigma septoconstrictum. This paper contributes to a more comprehensive update and improved identification of many ascomycetes and basiodiomycetes.

The human body is full of an extensive number of commensal microbes, consisting of bacteria, viruses, and fungi, collectively termed the human microbiome. The initial acquisition of microbiota occurs from both the external and maternal environments, and the vast majority of them colonize the gastrointestinal tract (GIT). These microbial communities play a central role in the maturation and development of the immune system, the central nervous system, and the GIT system and are also responsible for essential metabolic pathways. Various factors, including host genetic predisposition, environmental factors, lifestyle, diet, antibiotic or nonantibiotic drug use, etc., affect the composition of the gut microbiota. Recent publications have highlighted that an imbalance in the gut microflora, known as dysbiosis, is associated with the onset and progression of neurological disorders. Moreover, characterization of the microbiome-host cross talk pathways provides insight into novel therapeutic strategies. Novel preclinical and clinical research on interventions related to the gut microbiome for treating neurological conditions, including autism spectrum disorders, Parkinson's disease, schizophrenia, multiple sclerosis, Alzheimer's disease, epilepsy, and stroke, hold significant promise. This review aims to present a comprehensive overview of the potential involvement of the human gut microbiome in the pathogenesis of neurological disorders, with a particular emphasis on the potential of microbe-based therapies and/or diagnostic microbial biomarkers. This review also discusses the potential health benefits of the administration of probiotics, prebiotics, postbiotics, and synbiotics and fecal microbiota transplantation in neurological disorders.

Inflammasomes are intracellular complexes involved in the innate immunity that convert proIL-1β and proIL-18 to mature forms and initiate pyroptosis via cleaving procaspase-1. The most well-known inflammasome is NLRP3. Several studies have indicated a decisive and important role of NLRP3 inflammasome, IL-1β, IL-18, and pyroptosis in atherosclerosis. Modern hypotheses introduce atherosclerosis as an inflammatory/lipid-based disease and NLRP3 inflammasome has been considered as a link between lipid metabolism and inflammation because crystalline cholesterol and oxidized low-density lipoprotein (oxLDL) (two abundant components in atherosclerotic plaques) activate NLRP3 inflammasome. In addition, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and lysosome rupture, which are implicated in inflammasome activation, have been discussed as important events in atherosclerosis. In spite of these clues, some studies have reported that NLRP3 inflammasome has no significant effect in atherogenesis. Our review reveals that some molecules such as JNK-1 and ASK-1 (upstream regulators of inflammasome activation) can reduce atherosclerosis through inducing apoptosis in macrophages. Notably, NLRP3 inflammasome can also cause apoptosis in macrophages, suggesting that NLRP3 inflammasome may mediate JNK-induced apoptosis, and the apoptotic function of NLRP3 inflammasome may be a reason for the conflicting results reported. The present review shows that the role of NLRP3 in atherogenesis can be significant. Here, the molecular pathways of NLRP3 inflammasome activation and the implications of this activation in atherosclerosis are explained.

MicroRNAs (miRNAs) are short RNA molecules which bind to target mRNAs, resulting in translational repression and gene silencing and are found in all eukaryotic cells. Approximately 2200 miRNA genes have been reported to exist in the mammalian genome, from which over 1000 belong to the human genome. Many major cellular functions such as development, differentiation, growth, and metabolism are known to be regulated by miRNAs. Proximity to other genes in the genome and their locations in introns of coding genes, noncoding genes and exons have been reported to have a major influence on the level of gene expressions in eukaryotic cells. miRNAs are well conserved in eukaryotic system and are believed to be an essential and evolutionary ancient component of gene regulatory networks. Therefore, in recent years miRNAs have been studied as a likely candidate for involvement in most biologic processes and have been implicated in many human diseases.

Wettability alteration is an important method to increase oil recovery from oil-wet carbonate reservoirs. Chemical agents like surfactants are known as wettability modifiers in carbonate systems. However, the effectiveness of these agents can be increased by the addition of chemicals such as polymers, ionic materials, and nanoparticles. The impacts of nanoparticles on the wettability of carbonate systems have not been reported yet, and it is still in its infancy. In this work, the effect of ZrO 2 -based nanofluids on the wettability alteration of a carbonate reservoir rock was experimentally studied. Several nanofluids were made composed of ZrO 2 nanoparticles and mixtures of nonionic surfactants. The effect of nanofluids on the wettability of carbonate samples were investigated by measuring the contact angles, and it was shown that designed nanofluids could significantly change the wettability of the rock from a strongly oil-wet to a strongly water-wet condition. Scanning electron microscopy (SEM) images and X-ray Diffraction (XRD) data verify adsorption of nanoparticles on the rock and formation of nanotextured surfaces. Moreover, this paper reports the quick imbibitions of ZrO 2 nanofluids into oil-wet core plugs saturated with stock tank oil. The results show that a considerable amount of oil can be quickly recovered by free imbibitions of the nanofluids into the core plugs. A theoretical approach is also presented to explain the wettability alteration by formation of composite nanotextured surfaces.

BACKGROUND: Breast cancer still is a topic. This overview of the literature aimed to update the current knowledge on quality of life in breast cancer patients. METHODS: A review of literature in MEDLINE, Cochrane Database of Systematic Reviews and Google Scholar were carried out to identify review papers on health-related quality of life in breast cancer during the 2008 to 2018. All publications were screened using the PRISMA guideline. The methodological quality of reviews was assessed using the AMSTAR. The findings were summarized and tabulated accordingly. RESULTS: Within over a decade, a total of 974 review papers were identified which according to the study selection criteria finally we have evaluated 82 reviews. Of these about 85% had a reasonable methodological quality. The findings were mainly summarized on several headings including instruments used to measure quality of life, treatment, supportive care, psychological distress, and symptoms. Questionnaires had a good performance to quantify quality of life in breast cancer patients. Most reviews were focused on the impact of treatment including endocrine therapy as well as integrating complementary and alternative medicine into the current practice. According to the reviews, yoga was the most recommended exercise to improve quality of life in breast cancer patients. CONCLUSION: Overall, the findings from this overview indicated that quality of life in breast cancer patients enhanced during the last decade. Several simple but effective interventions such as physical activity and psychosocial interventions proved to be effective in improving quality of life in this population. However, management of symptoms such as pain, and lymphedema, issues related to worry, sexual function especially for young patients, and the future outlooks all are among topics that deserve further consideration. Also, this overview indicated that methodological issues in measuring quality of life in breast cancer patients improved greatly, but still there is a long way to go to understand what really matter to patients.

Colorectal cancer (CRC) is the fourth leading cause of the worldwide cancer mortality. Different molecular mechanisms have been attributed to the development and progress of CRC. In this review, we will focus on the mitogen-activated protein kinase (MAPK) cascades downstream of the epidermal growth factor receptor (EGFR), Notch, PI3K/AKT pathway, transforming growth factor-β (TGF-β), and Wnt signaling pathways. Various mutations in the components of these signaling pathways have been linked to the development of CRC. Accordingly, numerous efforts have been carried out to target the signaling pathways to develop novel therapeutic approaches. Herein, we review the signaling pathways involved in the incidence and progression of CRC, and the strategies for the therapy targeting components of signaling pathways in CRC.

Release and distribution of heavy metals through industrial wastewaters has adverse affects on the environment via contamination of surface- and ground-water resources. Biosorption of heavy metals from aqueous solutions has been proved to be very promising, offering significant advantages such as low cost, availability, profitability, ease of operation, and high efficiency, especially when dealing with low concentrations. Residual biomasses of industrial microorganisms including bacteria, algae, fungi, and yeast have been found to be capable of efficiently accumulating heavy metals as biosorbent. This paper presents and investigates major mechanisms of biosorption and most of the functional groups involved. The biosorption process includes the following mechanisms: transport across cell membrane, complexation, ion exchange, precipitation, and physical adsorption. In order to understand how metals bind to the biomass, it is essential to identify the functional groups responsible for metal binding. Most of these groups have been characterized on the cell walls. The biosorbent contains a variety of functional sites including carboxyl, imidazole, sulfydryl, amino, phosphate, sulfate, thioether, phenol, carbonyl, amide, and hydroxyl moieties that are responsible for metal adsorption. These could be helpful to improve biosorbents through modification of surface reactive sites via surface grafting and/or exchange of functional groups.

Reports of the increasing incidence of male infertility paired with decreasing semen quality have triggered studies on the effects of lifestyle and environmental factors on the male reproductive potential. There are numerous exogenous and endogenous factors that are able to induce excessive production of reactive oxygen species (ROS) beyond that of cellular antioxidant capacity, thus causing oxidative stress. In turn, oxidative stress negatively affects male reproductive functions and may induce infertility either directly or indirectly by affecting the hypothalamus-pituitary-gonadal (HPG) axis and/or disrupting its crosstalk with other hormonal axes. This review discusses the important exogenous and endogenous factors leading to the generation of ROS in different parts of the male reproductive tract. It also highlights the negative impact of oxidative stress on the regulation and cross-talk between the reproductive hormones. It further describes the mechanism of ROS-induced derangement of male reproductive hormonal profiles that could ultimately lead to male infertility. An understanding of the disruptive effects of ROS on male reproductive hormones would encourage further investigations directed towards the prevention of ROS-mediated hormonal imbalances, which in turn could help in the management of male infertility.

Healing and regeneration of bone injuries, particularly those that are associated with large bone defects, are a complicated process. There is growing interest in the application of osteoinductive and osteogenic growth factors and mesenchymal stem cells (MSCs) in order to significantly improve bone repair and regeneration. MSCs are multipotent stromal stem cells that can be harvested from many different sources and differentiated into a variety of cell types, such as preosteogenic chondroblasts and osteoblasts. The effectiveness of MSC therapy is dependent on several factors, including the differentiating state of the MSCs at the time of application, the method of their delivery, the concentration of MSCs per injection, the vehicle used, and the nature and extent of injury, for example. Tissue engineering and regenerative medicine, together with genetic engineering and gene therapy, are advanced options that may have the potential to improve the outcome of cell therapy. Although several in vitro and in vivo investigations have suggested the potential roles of MSCs in bone repair and regeneration, the mechanism of MSC therapy in bone repair has not been fully elucidated, the efficacy of MSC therapy has not been strongly proven in clinical trials, and several controversies exist, making it difficult to draw conclusions from the results. In this review, we update the recent advances in the mechanisms of MSC action and the delivery approaches in bone regenerative medicine. We will also review the most recent clinical trials to find out how MSCs may be beneficial for treating bone defects.

BACKGROUND: The 12-item Short Form Health Survey (SF-12) as a shorter alternative of the SF-36 is largely used in health outcomes surveys. The aim of this study was to validate the SF-12 in Iran. METHODS: A random sample of the general population aged 15 years and over living in Tehran, Iran completed the SF-12. Reliability was estimated using internal consistency and validity was assessed using known groups comparison and convergent validity. In addition, the factor structure of the questionnaire was extracted by performing both exploratory factor analysis (EFA) and confirmatory factor analysis (CFA). RESULTS: In all, 5587 individuals were studied (2721 male and 2866 female). The mean age and formal education of the respondents were 35.1 (SD = 15.4) and 10.2 (SD = 4.4) years respectively. The results showed satisfactory internal consistency for both summary measures, that are the Physical Component Summary (PCS) and the Mental Component Summary (MCS); Cronbach's alpha for PCS-12 and MCS-12 was 0.73 and 0.72, respectively. Known-groups comparison showed that the SF-12 discriminated well between men and women and those who differed in age and educational status (P < 0.001). In addition, correlations between the SF-12 scales and single items showed that the physical functioning, role physical, bodily pain and general health subscales correlated higher with the PCS-12 score, while the vitality, social functioning, role emotional and mental health subscales more correlated with the MCS-12 score lending support to its good convergent validity. Finally the principal component analysis indicated a two-factor structure (physical and mental health) that jointly accounted for 57.8% of the variance. The confirmatory factory analysis also indicated a good fit to the data for the two-latent structure (physical and mental health). CONCLUSION: In general the findings suggest that the SF-12 is a reliable and valid measure of health related quality of life among Iranian population. However, further studies are needed to establish stronger psychometric properties for this alternative form of the SF-36 Health Survey in Iran.

Advanced glycation end products (AGEs) and their receptor have been implicated in the progressions of many intractable diseases, such as diabetes and atherosclerosis, and are also critical for pathologic changes in chronic degenerative diseases, such as Alzheimer's disease, Parkinson's disease, and alcoholic brain damage. Recently activated macrophages were found to be a source of AGEs, and the most abundant form of AGEs, AGE-albumin excreted by macrophages has been implicated in these diseases and to act through common pathways. AGEs inhibition has been shown to prevent the pathogenesis of AGEs-related diseases in human, and therapeutic advances have resulted in several agents that prevent their adverse effects. Recently, anti-inflammatory molecules that inhibit AGEs have been shown to be good candidates for ameliorating diabetic complications as well as degenerative diseases. This review was undertaken to present, discuss, and clarify current understanding regarding AGEs formation in association with macrophages, different diseases, therapeutic and diagnostic strategy and links with RAGE inhibition.

BACKGROUND: Alzheimer's disease is characterized by a slow, progressive decline in cognitive function and behaviour. Acetylcholine esterase inhibitors are the only agents approved by the Food and Drug Administration for the treatment of Alzheimer's disease. All other agents prescribed for the treatment of Alzheimer's disease are used on an off-label basis. Current research into new drugs is focused on agents that will prevent, slow down and/or halt the progress of the disease process. Salvia officinalis has been used in herbal medicine for many centuries. It has been suggested, on the basis of traditional medicine, its in vitro cholinergic binding properties and modulation of mood and cognitive performance in humans, that Salvia officinalis might potentially provide a novel natural treatment for Alzheimer's disease. The objective of this study was to assess the efficacy and safety of Salvia officinalis extract using a fixed dose (60 drops/day), in patients with mild to moderate Alzheimer's disease, over a 4-month period. METHODS: This was a 4-month, parallel group, placebo-controlled trial undertaken in three centres in Tehran, Iran. Patients with mild to moderate Alzheimer's disease aged between 65 and 80 years (n = 42, 18 women) with a score of > or = 12 on the cognitive subscale of Alzheimer's Disease Assessment Scale (ADAS-cog) and < or = 2 on the Clinical Dementia Rating (CDR) were randomized to placebo or fixed dose of S. officinalis extract. Over the 16 weeks, the main efficacy measures were the change in the ADAS-cog and CDR-Sum of Boxes scores compared with baseline. In addition, side-effects were systematically recorded throughout the study using a checklist. RESULTS: At 4 months, S. officinalis extract produced a significant better outcome on cognitive functions than placebo (ADAS-cog: F = 4.77, d.f. = 1, P = 0.03) (CDR-SB: F = 10.84, d.f. = 1, P < 0.003). There were no significant differences in the two groups in terms of observed side-effects except agitation that appears to be more frequent in the placebo group (P = 0.09). CONCLUSIONS: The results of this study indicate the efficacy of S. officinalis extract in the management of mild to moderate Alzheimer's disease. Moreover, S. officinalis may well reduce agitation of patients but this needs to be confirmed.