Genetic and epigenetic targets of natural dietary compounds as anti-Alzheimer's agents

Alzheimer’s disease is a progressive neurodegenerative disorder and the most common cause of dementia that principally affects older adults.Pathogenic factors,such as oxidative stress,an increase in acetylcholinesterase activity,mitochondrial dysfunction,genotoxicity,and neuroinflammation are present in this syndrome,which leads to neurodegeneration.Neurodegenerative pathologies such as Alzheimer’s disease are considered late-onset diseases caused by the complex combination of genetic,epigenetic,and environmental factors.There are two main types of Alzheimer’s disease,known as familial Alzheimer’s disease(onset<65 years)and late-onset or sporadic Alzheimer’s disease(onset≥65 years).Patients with familial Alzheimer’s disease inherit the disease due to rare mutations on the amyloid precursor protein(APP),presenilin 1 and 2(PSEN1 and PSEN2)genes in an autosomaldominantly fashion with closely 100%penetrance.In contrast,a different picture seems to emerge for sporadic Alzheimer’s disease,which exhibits numerous non-Mendelian anomalies suggesting an epigenetic component in its etiology.Importantly,the fundamental pathophysiological mechanisms driving Alzheimer’s disease are interfaced with epigenetic dysregulation.However,the dynamic nature of epigenetics seems to open up new avenues and hope in regenerative neurogenesis to improve brain repair in Alzheimer’s disease or following injury or stroke in humans.In recent years,there has been an increase in interest in using natural products for the treatment of neurodegenerative illnesses such as Alzheimer’s disease.Through epigenetic mechanisms,such as DNA methylation,non-coding RNAs,histone modification,and chromatin conformation regulation,natural compounds appear to exert neuroprotective effects.While we do not purport to cover every in this work,we do attempt to illustrate how various phytochemical compounds regulate the epigenetic effects of a few Alzheimer’s disease-related genes.

The “Dead Universe” Theory: Natural Separation of Galaxies Driven by the Remnants of a Supermassive Dead Universe

This article explores the dead universe theory as a novel interpretation for the origin and evolution of the universe, suggesting that our cosmos may have originated from the remnants of a preceding universe. This perspective challenges the conventional Big Bang theory, particularly concerning dark matter, the expansion of the universe, and the interpretation of phenomena such as gravitational waves.

Natural history and long-term clinical course of Crohn's disease

Crohn’s disease is a chronic inflammatory disease process involving different sites in the gastrointestinal tract.Occasionally,so-called metastatic disease occurs in extra-intestinal sites.Granulomatous inflammation may be detected in endoscopic biopsies or resected tissues.Genetic,epigenetic and environmental factors appear to play a role.Multiple susceptibility genes have been described in both familial and non-familial forms while the disease is phenotypically heterogeneous with a female predominance.The disorder occurs over a broad age spectrum,from early childhood to late adulthood.More than 80%are diagnosed before age 40 years usually with terminal ileal and colonic involvement.Pediatric-onset disease is more severe and more extensive,usually with a higher chance of upper gastrointestinal tract disease,compared to adult-onset disease.Long-term studies have shown that the disorder may evolve with time into more complex disease with stricture formation and penetrating disease complications(i.e.,fistula,abscess).Although prolonged remission may occur,discrete periods of symptomatic disease may re-appear over many decades suggesting recurrence or re-activation of this inflammatory process.Eventual development of a cure will likely depend on identification of an etiologic cause and a fundamental understanding of its pathogenesis.Until now,treatment has focused on removing risk factors,particularly cigarette smoking,and improving symptoms.In clinical trials,clinical remission is largely defined as improved numerical and endoscopic indices for"mucosal healing"."Deep remission"is a conceptual,more"extended"goal that may or may not alter the long-term natural history of the disease in selected patients,albeit at a significant risk for treatment complications,including serious and unusual opportunistic infections.

Analysis of the supply-demand status of China's natural gas to 2020

The reserves, distribution, production and utilization of natural gas resources in China are introduced in this paper which leads a point of view that China＇s natural gas resources are relatively rich while distributed unevenly. The future production and consumption of China＇s natural gas are predicted using the Generalized Weng model and the Gray prediction model. The prediction suggests that with the increasing gas consumption China＇s natural gas production will not meet demand after 2010. In order to ease the supply-demand gap and realize rational development and utilization of China＇s natural gas resources, this paper puts forward some measures, such as using advanced technologies for natural gas development, establishing a long-distance pipeline network to rationalize the availability of natural gas across China and importing foreign natural gas and liquid natural gas （LNG）.

Inflammatory bowel disease course in Crohn's disease:Is the natural history changing?

Crohn’s disease(CD)is a multifactorial potentially debilitating disease.It has a variable disease course,but the majority of patients eventually develop penetrating or stricturing complications leading to repeated surgeries and disability.Studies on the natural history of CD provide invaluable data on its course and clinical predictors,and may help to identify patient subsets based on clinical phenotype.Most data are available from referral centers,however these outcomes may be different from those in population-based cohorts.New data suggest the possibility of a change in the natural history in Crohn’s disease,with an increasing percentage of patients diagnosed with inflammatory disease behavior.Hospitalization rates remain high,while surgery rates seem to have decreased in the last decade.In addition,mortality rates still exceed that of the general population.The impact of changes in treatment strategy,including increased,earlier use of immunosuppressives,biological therapy,and patient monitoring on the natural history of the disease are still conflictive.In this review article,the authors summarize the available evidence on the natural history,current trends,and predictive factors for evaluating the disease course of CD.

Natural polyphenols effects on protein aggregates in Alzheimer＇s and Parkinson＇s prion-like diseases

Alzheimer＇s and Parkinson＇s diseases are the most common neurodegenerative diseases. They are characterized by protein aggregates and so can be considered as prion-like disease. The major components of these deposits are amyloid peptide and tau for Alzheimer＇s disease, α-synuclein and synphilin-1 for Parkinson＇s disease. Drugs currently proposed to treat these pathologies do not prevent neurodegenerative processes and are mainly symptomatic therapies. Molecules inducing inhibition of aggregation or disaggregation of these proteins could have beneficial effects, especially if they have other beneficial effects for these diseases. Thus, several natural polyphenols, which have antioxidative, anti-inflammatory and neuroprotective properties, have been largely studied, for their effects on protein aggregates found in these diseases, notably in vitro. In this article, we propose to review the significant papers concerning the role of polyphenols on aggregation and disaggregation of amyloid peptide, tau, α-synuclein, synphilin-1, suggesting that these compounds could be useful in the treatments in Alzheimer＇s and Parkinson＇s diseases.

Interventions of natural and synthetic agents in inflammatory bowel disease, modulation of nitric oxide pathways

Inflammatory bowel disease(IBD)refers to a group of disorders characterized by chronic inflammation of the gastrointestinal(GI)tract.The elevated levels of nitric oxide(NO)in serum and affected tissues;mainly synthesized by the inducible nitric oxide synthase(iNOS)enzyme;can exacerbate GI inflammation and is one of the major biomarkers of GI inflammation.Various natural and synthetic agents are able to ameliorate GI inflammation and decrease iNOS expression to the extent comparable with some IBD drugs.Thereby,the purpose of this study was to gather a list of natural or synthetic mediators capable of modulating IBD through the NO pathway.Electronic databases including Google Scholar and PubMed were searched from 1980 to May 2018.We found that polyphenols and particularly flavonoids are able to markedly attenuate NO production and iNOS expression through the nuclear factorκB(NF-κB)and JAK/STAT signaling pathways.Prebiotics and probiotics can also alter the GI microbiota and reduce NO expression in IBD models through a broad array of mechanisms.A number of synthetic molecules have been found to suppress NO expression either dependent on the NF-κB signaling pathway(i.e.,dexamethasone,pioglitazone,tropisetron)or independent from this pathway(i.e.,nicotine,prednisolone,celecoxib,β-adrenoceptor antagonists).Co-administration of natural and synthetic agents can affect the tissue level of NO and may improve IBD symptoms mainly by modulating the Toll like receptor-4 and NF-κB signaling pathways.

Neuroglobin and neuroprotection:the role of natural and synthetic compounds in neuroglobin pharmacological induction

Neuroglobin(Ngb)is a 17 kDa monomeric hexa-coordinated heme protein belonging to the globin family.Ngb is mainly expressed in neurons of the central and peripheral nervous system,although moderate levels of Ngb have been detected in non-nervous tissues.In the past decade,Ngb has been studied for its neuroprotective role in a large number of neurological disorders such as Alzheimer’s disease,Huntington’s disease,brain ischemia and hypoxia.This review discusses and summarizes the natural compounds and the small synthetic molecules capable of modulating Ngb expression that exhibits a protective role against various neurodegenerative diseases.

NANOMECHANICAL MAPPING OF CARBON BLACK REINFORCED NATURAL RUBBER BY ATOMIC FORCE MICROSCOPY

Atomic force microscopy （AFM） has the advantage of obtaining mechanical properties as well as topographic information at the same time. By analyzing force-distance curves measured over two-dimensional area using Hertzian contact mechanics, Young＇s modulus mapping was obtained with nanometer-scale resolution. Furthermore, the sample deformation by the force exerted was also estimated from the force-distance curve analyses. We could thus reconstruct a real topographic image by incorporating apparent topographic image with deformation image. We applied this method to carbon black reinforced natural rubber to obtain Young＇s modulus distribution image together with reconstructed real topographic image. Then we were able to recognize three regions; rubber matrix, carbon black （or bound rubber） and intermediate regions. Though the existence of these regions had been investigated by pulsed nuclear magnetic resonance, this paper would be the first to report on the quantitative evaluation of the interfacial region in real space.

Effects of natural cerebrolysin on protective proteins and pro-apoptotic molecules in mesenchymal stem cells following beta-amyloid peptide1-40-induced endoplasmic reticulum stress

BACKGROUND： Studies have demonstrated that β-amyloid peptide （Aβ）, a characteristic pathological product of Alzheimer＇s disease （AD）, results in neuronal endoplasmic reticulum stress （ERS）. However, the mechanisms of traditional Chinese medicine against ERS in AD are poorly understood. OBJECTIVE： To measure expression levels of protective proteins （GRP78 and GRP94） of ER molecular partners and pro-apoptotic Caspase-12 ER membrane expression following application of traditional Chinese medicine natural cerebrolysin （NC） to treat Aβ1-40-induced ERS. DESIGN, TIME AND SETTING： A parallel-controlled study was performed at the Institute of Integrated Western and Traditional Chinese Medicine, Shenzhen Hospital of Southern Medical University between September 2006 and November 2008. MATERIALS： Sprague Dawley male rats, 6-8 weeks old, were used to harvest tibial and femoral bone marrow. Isolation and purification of mesenchymal stem cells （MSCs） were established from the whole bone marrow by removing non-adherent cells in primary and passage cultures. Aβ1-40 was provided by Sigma, USA. NC was provided by Shenzhen Institute of Integrated Chinese and Western Medicine, China. NC was predominantly composed of Renshen （Radix Ginseng）, Tianma （Rhizoma Gastrodiae）, and Yinxingye （Ginkgo Leaf） in a proportion of 1 ： 2： 2. Following conventional water extraction technology, an extract （1 ： 20） was prepared. Six adult, male, New Zealand rabbits underwent intragastric administration of NC extract （0.976 g/kg per day） for 1 month to prepare NC-positive serum, and the remaining 6 rabbits received intragastric administration of physiological saline to prepare normal blank serum. METHODS： A total of 500 nmol/L Aβ1-40 was used to establish ERS models of primary cultured MSCs. AD cell models were incubated with different doses of NC-positive serum （2.5%, 5%, and 10%）. MSCs treated with normal blank serum served as normal blank controls. MAIN OUTCOME MEASURES： Reverse transcription-polymerase chain reaction and fluorescent immunocytochemistry were respectively used to measure mRNA and protein expression levels of GRP78, GRP94, and Caspase-12 in MSCs. RESULTS： Following Aβ1-40 exposure, mRNA and protein expression levels of GRP78 and GRP94, as well as Caspase-12, significantly increased （P 〈 0.05）, suggesting successful establishment of ERS models. Following NC-positive serum application, mRNA and protein expression levels of GRP78 and GRP94 in MSCs significantly increased （P 〈 0.05 or P 〈 0.01）. However, mRNA and protein expression levels of Caspase-12 significantly decreased （P 〈 0.05, or P 〈 0.01） compared with the ERS model group. These effects were dose-dependent. CONCLUSION： NC downregulated Caspase-12 expression and upregulated GRP78 and GRP94 expression in MSCs in a dose-dependent manner under the state of Aβ1-40-induced ERS.

Quality of healing of gastric ulcers: Natural products beyond acid suppression

Gastric ulcer is a chronic disease featured with unexpected complications, including bleeding, stenosis and perforation, as well as a high incidence of recurrence. Clinical treatments for gastric ulcer have allowed the rapid development of potent anti-ulcer drugs during the last several decades. Gastric ulcer healing is successful with conventional treatments including H2-receptor antagonists, and proton pump inhibitors(PPIs) have been essential for ulcer healing and prevention of complications. Additionally, Helicobacter pylori eradication therapy is effective in reducing ulcer recurrence and leads to physiological changes in the gastric mucosa which affect the ulcer healing process. However, in spite of these advancements, some patients have suf-fered from recurrence or intractability in spite of continuous anti-ulcer therapy. A new concept of the quality of ulcer healing(QOUH) was initiated that considers the reconstruction of the mucosal structure and its function for preventing ulcer recurrence. Although several gastroprotection provided these achievements of the QOUH, which PPI or other acid suppressants did not accomplish, we found that gastroprotection that originated from natural products, such as a newer formulation from either Artemisia or S-allyl cysteine from garlic, were very effective in the QOUH, as well as improving clinical symptoms with fewer side effects. In this review, we will introduce the importance of the QOUH in ulcer healing and the achievements from natural products.

Proximity to corridors benefits bird communities in vegetated interrow vineyards in Mendoza, Argentina

Management under ecological schemes and increasing habitat heterogeneity,are essential for enhancing biodiversity in vineyards.Birds provide several contributions to agriculture,for example pest control,recreation and enhancing human mental health,and have intrinsic value.Birds are also ideal model organisms because they are easy to survey,and species respond differently to agricultural land use at different scales.Vegetated borders of crops are key for many species of birds,and distance to the border have been found to be an important factor in vineyard-dominated agroecosystems.We evaluate if there are differences in the bird assemblage,between the interior compared to borders within vineyards,using a hierarchical community occupancy model.We hypoth-esized that occupancy of birds is greater in environments with greater heterogeneity,which in this study was considered to be contributed by the proximity to vegetated corridors.We expected that vineyard borders close to corridors will have higher bird occupancy than the center of the vineyard.The research was conducted in three vineyards with biodiversity-friendly management practices,in Gualtallary,Mendoza,Argentina.Bird surveys were conducted over three breeding seasons from 2018 to 2020.Occupancy and richness of the bird community was more closely associated with the borders adjacent to the corridors than with the interior of the vineyards,as we initially predicted,although the assemblage of birds did not differ much.More than 75%of the registered species consume exclusively or partially invertebrates.Biodiversity-friendly management and ecological schemes,together with vegetated corridors provide multiple benefits for biodiversity conservation.These ap-proaches not only minimize the use of agrochemicals but also prioritize soil cover with spontaneous vegetation,which supports a diverse community of insectivorous bird species,potentially contributing to pest control.

Design of Natural Children’s Recreational Spaces and Facilities in Urban Neighborhood Parks

Taking into account problems existing in urban children’s recreational spaces, this paper mainly discussed the method to design natural children’s recreational spaces and facilities, analyzed the characteristics and influencing factors of natural children’s recreational spaces and facilities based on the characteristics of behavioral and psychological cognition of preschool children, and concluded that children’s recreational spaces consist of five parts, namely, the border, entrance, internal activity space, viewing space and supporting space and that the design of recreational facilities should meet the four points of naturalness, appropriate fuzziness, appropriate scale and size, and diversities and opportunities, with a view to providing a reference for the design of children’s recreational spaces and facilities.

Towards the Development of Mechanical Systems Entirely Based on Natural Materials

In order to mitigate the risks stemming from the utilization of mineral and synthetic organic substances,consensus exists in the literature that additional efforts should be devoted to the identification of adequate equivalent natural(ecological)materials.This work presents the outcomes of a preliminary study where the physical,mechanical,chemical and thermal properties of natural fibers have been considered.Initially,areca,and materials such as Moroccan doum and jute are considered.As a case study,a brake pad based on natural fibers is critically assessed.

Characterization of FeCo Nanoparticles Reinforced Natural Rubber using Nanomechanical Mapping

The morphology, nanomechanical properties and interfacial regions of natural rubber（NR） and FeCo nanoparticles composite were determined by AFM nanomechanical mapping. The results showed that the size of FeCo particles was mostly from 40 to 100 nm and the FeCo nanoparticles were homogeneously dispersed in the NR bulk. The strength of NR composite increased with the FeCo nanoparticles loading. Young＇s modulus of NR region, FeCo region and interfacial region was measured by AFM nanomechanical tapping as 1.6 ± 0.6, 16.7 ±4.2 and 5.8 ± 1.5 MPa, respectively. The width of the interface for NR5, NR10 and NR15 was determined to be 15±8.1, 26±14.3 and 32±16.4 nm, respectively.

Barrett’s esophagus:Review of natural history and comparative efficacy of endoscopic and surgical therapies

Barrett's esophagus(BE)is the precursor to esophageal adenocarcinoma(EAC).Progression to cancer typically occurs in a stepwise fashion through worsening dysplasia and ultimately,invasive neoplasia.Established EAC with deep involvement of the esophageal wall and/or metastatic disease is invariably associated with poor long-term survival rates.This guides the rationale of surveillance of Barrett’s in an attempt to treat lesions at an earlier,and potentially curative stage.The last two decades have seen a paradigm shift in management of Barrett’s with rapid expansion in the role of endoscopic eradication therapy(EET)for management of dysplastic and early neoplastic BE,and there have been substantial changes to international consensus guidelines for management of early BE based on evolving evidence.This review aims to assist the physician in the therapeutic decision-making process with patients by comprehensive review and summary of literature surrounding natural history of Barrett’s by histological stage,and the effectiveness of interventions in attenuating the risk posed by its natural history.Key findings were as follows.Non-dysplastic Barrett’s is associated with extremely low risk of progression,and interventions cannot be justified.The annual risk of cancer progression in low grade dysplasia is between 1%-3%;EET can be offered though evidence for its benefit remains confined to highly select settings.High-grade dysplasia progresses to cancer in 5%-10%per year;EET is similarly effective to and less morbid than surgery and should be routinely performed for this indication.Risk of nodal metastases in intramucosal cancer is 2%-4%,which is comparable to operative mortality rate,so EET is usually preferred.Submucosal cancer is associated with nodal metastases in 14%-41%hence surgery remains standard of care,except for select situations.

Gene expression in rat mesenchymal stem cells following treatment with natural cerebrolysin-containing serum Validation of a whole genome microarray technique

BACKGROUND： Natural cerebrolysin （NC）, a Chinese herbal drug for the treatment of Alzheimer＇s disease （AD）, induces mesenchymal stem cell （MSC） differentiation into neuron-like cells, with low toxicity. But the mechanisms involved in NC effects on MSCs remain poorly understood. OBJECTIVE： We used a whole genome microarray technique to further investigate the molecular, genetic, and pharmacodynamic mechanisms of NC on MSC gene expression profiles. DESIGN, TIME AND SETTING： A parallel, controlled, in vitro experiment was performed at the First Affiliated Hospital of Shenzhen University, Shenzhen Institute of Integrated Chinese and Western Medicine, China, between September 2006 and October 2008. MATERIALS： NC was provided by Shenzhen Institute of Integrated Chinese and Western Medicine China. It was predominantly composed of Renshen （Radix Ginseng）, Tianma （Rhizoma Gastrodiae） and Yinxingye （Ginkgo Leaf） and prepared by conventional water extractJon technology. Twelve adult, male, New Zealand rabbits were included, six of which underwent intragastric administration of NC extract for 1 month to create NC-containing serum. METHODS： Bone marrow was collected from the tibia and femur of Sprague Dawley rats, aged 6 8 months old. Rat MSCs were isolated and purified by the whole bone marrow adherence method. After in vitro culture, MSCs from passage 4 were treated with NC-containing serum for 48 hours, and total RNA was extracted. Gene expression in MSCs was analyzed using Affymetrix whole genome microarray analysis. MAIN OUTCOME MEASURES： Differentially expressed genes in NC serum-treated MSCs. RESULTS： NC treated MSCs displayed 46 differentially expressed genes, 22 with upregulated expression （fold change 〉 2） and 24 with downregulated expression （fold change 〈 -2）. Differentially expressed genes participated in neuronal growth, differentiation, and function, cell growth, differentiation, proliferation, apoptosis, signal transduction, substance/energy metabolism, ion transport, and immune responses. NC treatment changed levels of transforming growth factor β/ bone morphogenetic proteins, Hedgehog, Bmp, and Wntsignaling pathways, which regulate nerve cell differentiation, development and function, as well as learning and memory; Ras, G protein- coupled receptor signal pathways that are related to cell growth, proliferation, and apoptosis; and mitogen-activated protein kinase kinase kinase signaling cascades. CONCLUSION： NC can regulate gene expression for many signal transduction pathways related to nerve cell differentiation, development and function, learning and memory function, as well as regulation of cell growth, differentiation, proliferation, or apoptosis to mediate the genetic effects of NC treatment on AD.

LIRR's Project of “Study on Spalling Mechanism Mechanism of Dense Refractory Castables by Rapid Heating-up” Being Obtained the Support from National Natural Natural Science Foundation of China

LIRR＇s Priject of ＂Research on Spalling Mechanism Due to Rapid Heating-up of Dense Refractory Castables＂ declared by Wang Zhanmin,vice-president of LIRR,will gain the fund support from National Natural Science Foundation of China in 2011.

Guizhou's Natural Resources Awaiting Development

Guizhou is one of the concentration provinces for natural resources in China. Most outstanding of these, in particular, are energy resources, mineral resources, biological resources and tourism resources. They occupy a very important position in the country. Guizhou’s natural resources are of multiple categories, high grade, huge re-