Neurodegenerative disorders affect millions of people worldwide,and the prevalence of these disorders is only projected to rise as the number of people over 65 will drastically increase in the coming years.While thera...Neurodegenerative disorders affect millions of people worldwide,and the prevalence of these disorders is only projected to rise as the number of people over 65 will drastically increase in the coming years.While therapies exist to aid in symptomatic relief,effective treatments that can stop or reve rse the progress of each neurodegenerative disease are lacking.Recently,research on the role of extracellular vesicles as disease markers and therapeutics has been intensively studied.Exosomes,30-150 nm in diameter,are one type of extracellular vesicles facilitating cell-to-cell communication.Exosomes are thought to play a role in disease propagation in a variety of neurodegenerative diseases,such as Alzheimer's disease,Parkinson s disease,and amyotrophic lateral sclerosis.Accordingly,the exosomes derived from the patients are an invaluable source of disease biomarkers.On the other hand,exosomes,especially those derived from stem cells,could serve as a therapeutic for these disorders,as seen by a rapid increase in clinical trials investigating the therapeutic efficacy of exosomes in different neurological diseases.This review summarizes the pathological burden and therapeutic approach of exosomes in neurodegenerative disorders.We also highlight how heat shock increases the yield of exosomes while still maintaining their therapeutic efficacy.Finally,this review concludes with outstanding questions that remain to be addressed in exosomal research.展开更多
Objective:To investigate whether the ethanol extract of Chondracanthus tenellus(Harvey)Hommersand,a type of red algae,could exhibit anti-inflammatory potential in lipopolysaccharide(LPS)-stimulated macrophages.Methods...Objective:To investigate whether the ethanol extract of Chondracanthus tenellus(Harvey)Hommersand,a type of red algae,could exhibit anti-inflammatory potential in lipopolysaccharide(LPS)-stimulated macrophages.Methods:The ethanol extract of Chondracanthus tenellus was applied to 100 ng/mL LPS-stimulated RAW 264.7 cells,and cell viability,phagocytic ability,levels of pro-inflammatory factors,and the production of reactive oxygen species were measured.To identify the underlying mechanism of the ethanol extract of Chondracanthus tenellus,the expression of inflammation-regulated genes was estimated.Results:The ethanol extract of Chondracanthus tenellus had no cytotoxic effect at concentrations below 300μg/mL,and reduced the LPS-induced production of inflammatory mediators including nitric oxide(NO)and prostaglandin E2.Furthermore,the extract markedly suppressed the expression of inducible NO synthase and cyclooxygenase-2,as well as the production of reactive oxygen species.The LPS-induced up-regulation of pro-inflammatory cytokines was attenuated by treatment with the ethanol extract of Chondracanthus tenellus,reducing their extracellular secretion.The Chondracanthus tenellus extract also inhibited LPS-mediated activation of nuclear factor-kappa B(NF-κB).In addition,the phosphorylation of mitogen activated protein kinases(MAPKs)and phosphatidylinositol 3 kinase(PI3K)/Akt was markedly increased by LPS,which was significantly abolished by the Chondracanthus tenellus extract.Conclusions:Our findings indicate that the ethanol extract of Chondracanthus tenellus exhibited potential anti-inflammatory and antioxidant effects through downregulating the NF-κB,MAPKs,and PI3K/Akt signaling pathways in LPS stimulated RAW 264.7 macrophages.tenellus extract.Conclusions:Our findings indicate that the ethanol extract of Chondracanthus tenellus exhibited potential anti-inflammatory and antioxidant effects through downregulating the NF-κB,MAPKs,and PI3K/Akt signaling pathways in LPS stimulated RAW 264.7 macrophages.展开更多
Intracellular protein degradation by the ubiquitin-proteasome system is ATP dependent, and the optimal ATP concentration to activate proteasome function in vitro is -100 μM. IntraceUular ATP levels are generally in t...Intracellular protein degradation by the ubiquitin-proteasome system is ATP dependent, and the optimal ATP concentration to activate proteasome function in vitro is -100 μM. IntraceUular ATP levels are generally in the low millimolar range, but ATP at a level within this range was shown to inhibit proteasome peptidase activities in vitro. Here, we report new evidence that supports a hypothesis that intracellular ATP at the physiological levels bidirectionally regulates 26S proteasome proteolytic function in the cell. First, we confirmed that ATP exerted bidirectional regulation on the 26S proteasome in vitro, with the optimal ATP concentration （between 50 and 100μM） stimulating proteasome chymotrypsin-like activities. Second, we found that manipulating intracellular ATP levels also led to bidirectional changes in the levels of proteasome-specific protein substrates in cultured cells. Finally, measures to increase intracellular ATP enhanced, while decreasing intraceHular ATP attenuated the ability of proteasome inhibition to induce cell death. These data strongly suggest that endogenous ATP within the physiological concentration range can exert a negative impact on proteasome activities, allowing the cell to rapidly upregulate proteasome activity on ATP reduction under stress conditions.展开更多
Pancreatic cancer is highly aggressive and lethal.Due to the lack of effective methods for detecting the disease at an early stage,pancreatic cancer is frequently diagnosed late.Gemcitabine has been the standard chemo...Pancreatic cancer is highly aggressive and lethal.Due to the lack of effective methods for detecting the disease at an early stage,pancreatic cancer is frequently diagnosed late.Gemcitabine has been the standard chemotherapy drug for patients with pancreatic cancer for over 20 years,but its anti-tumor effect is limited.Therefore,FOLFIRINOX(leucovorin,fluorouracil,irinotecan,oxaliplatin)as well as combination therapies using gemcitabine and conventional agents,such as cisplatin and capecitabine,has also been administered;however,these have not resulted in complete remission.Therefore,there is a need to develop novel and effective therapies for pancreatic cancer.Recently,some studies have reported that combinations of gemcitabine and targeted drugs have had significant antitumor effects on pancreatic cancer cells.As gemcitabine induced DNA damage response,the proteins related to DNA damage response can be suitable additional targets for novel gemcitabine-based combination therapy.Furthermore,KRAS/RAF/MEK/ERK signaling triggered by oncogenic mutated KRAS and autophagy are frequently activated in pancreatic cancer.Therefore,these characteristics of pancreatic cancer are potential targets for developing effective novel therapies.In this minireview,combinations of gemcitabine and targeted drugs to these characteristics,combinations of targeted drugs,combinations of natural products and anti-cancer agents,including gemcitabine,and combinations among natural products are discussed.展开更多
Gastric cancer(GC)is a primary cause of cancer-related mortality worldwide,and even after therapeutic gastrectomy,survival rates remain poor.The presence of gastric cancer stem cells(GCSCs)is thought to be the major r...Gastric cancer(GC)is a primary cause of cancer-related mortality worldwide,and even after therapeutic gastrectomy,survival rates remain poor.The presence of gastric cancer stem cells(GCSCs)is thought to be the major reason for resistance to anticancer treatment(chemotherapy or radiotherapy),and for the development of tumor recurrence,epithelial–mesenchymal transition,and metastases.Additionally,GCSCs have the capacity for self-renewal,differentiation,and tumor initiation.They also synthesize antiapoptotic factors,demonstrate higher performance of drug efflux pumps,and display cell plasticity abilities.Moreover,the tumor microenvironment(TME;tumor niche)that surrounds GCSCs contains secreted growth factors and supports angiogenesis and is thus responsible for the maintenance of the growing tumor.However,the genesis of GCSCs is unclear and exploration of the source of GCSCs is essential.In this review,we provide up-todate information about GCSC-surface/intracellular markers and GCSC-mediated pathways and their role in tumor development.This information will support improved diagnosis,novel therapeutic approaches,and better prognosis using GCSC-targeting agents as a potentially effective treatment choice following surgical resection or in combination with chemotherapy and radiotherapy.To date,most anti-GCSC blockers when used alone have been reported as unsatisfactory anticancer agents.However,when used in combination with adjuvant therapy,treatment can improve.By providing insights into the molecular mechanisms of GCSCs associated with tumors in GC,the aim is to optimize anti-GCSCs molecular approaches for GC therapy in combination with chemotherapy,radiotherapy,or other adjuvant treatment.展开更多
Anesthetics evoke a stress-response, upregulating heat shock genes. This neuroprotective response to proteotoxic stress represents preconditioning, a process by which neuronal tissue, previously exposed to anesthetics...Anesthetics evoke a stress-response, upregulating heat shock genes. This neuroprotective response to proteotoxic stress represents preconditioning, a process by which neuronal tissue, previously exposed to anesthetics, is protected against future insult. It presumes a sub-lethal injury, affecting protein unfolding. Our hypothesis is: preconditioning evokes molecular events that result in downstream changes that offer a selective advantage in terms of neuronal function. We focused on the neurobehavioral aspects which we neurophenotyped. Larval zebrafish were exposed to trifluoroethanol (TFE), an anesthetic mimetic, and tested for both individual and group behavioral markers of neuronal function. In bright/dark tests, we observed that TFE-exposed larvae spent more time in the dark area (typically an adult-like response) than control larvae. The response of TFE larvae to noise startle was directly opposite to that of controls. TFE larvae swam towards the source of the startle (into the bright zone), whereas control larvae swam away from the source of the startle (into the dark), typical of fear-response. The larvae also exhibited several differences in social behaviors, including synchronized schooling and shoaling behaviors. The TFE-group showed a greater number of synchronized events versus controls. The TFE-group also exhibited more shoaling events compared with controls. While the long-term effects have yet to be determined, these results shed light on the mechanism of anesthetic preconditioning. These complex zebrafish behaviors normally develop with age and therefore represent, in the TFE-exposed group, a pattern of accelerated maturation of neuronal function, which is the neurophenotype attributed to preconditioning.展开更多
Objective:To investigate whether ethanol extracts of Chondracanthus tenellus(EECT)could improve immunomodulatory property of murine monocyte/macrophage RAW 264.7 cells.Methods:Cell viability,phagocytic ability,and nit...Objective:To investigate whether ethanol extracts of Chondracanthus tenellus(EECT)could improve immunomodulatory property of murine monocyte/macrophage RAW 264.7 cells.Methods:Cell viability,phagocytic ability,and nitric oxide were measured.The levels of prostaglandin E2 and cytokines were determined using enzyme-linked immunosorbent assay kits.Expression of immunoregulatory response protein was detected by Western blotting assay.Results:As the concentration of EECT increased,the morphology of the cells changed to a typical active macrophage shape,and the phagocytic activity increased significantly.EECT also effectively enhanced the production and secretion of immunomodulatory mediators,such as nitric oxide and prostaglandin E2,and cytokines.In addition,compared with the control group,EECT markedly stimulated the expression of Toll-like receptor 4(TLR4)and myeloid differentiation factor 88,one of the TLR4 adapter molecules.Furthermore,EECT promoted the nucleus translocation of nuclear factor-kappa B(NF-κB)by increasing the phosphorylation and degradation of the inhibitor of NF-κB-α,indicating activation of the NF-κB signaling pathway.Meanwhile,similar trends were found in cells treated with lipopolysaccharide as a positive control.Conclusions:Taken together,the results indicate that EECT has an immunomodulatory effect by increasing the production of immunomodulatory mediators and cytokines through activation of the TLR4/NF-κB signaling pathway.EECT could be used as a potential candidate for medication or dietary supplements to increase immune activity.展开更多
The problem of contamination of Lerma River in the State of Mexico, México, has been studied in an integral way, since it is one of the rivers of importance due to its geographical situation in the country. Jos&#...The problem of contamination of Lerma River in the State of Mexico, México, has been studied in an integral way, since it is one of the rivers of importance due to its geographical situation in the country. José Antonio Dam is the main receiving body of this river that is being contaminated by, industrial wastewater, of which about 70% is inorganic, as well as discharges municipal and agricultural, driving a lot of material in suspension. This dam acts as a regulator of avenues and its water is used for agricultural irrigation and its sediments are used as sludge to improve agricultural soil in the surroundings. One of the studies that have been carried out is to determine the geochemical distribution of heavy metals in the sediments of this dam, as well as its adsorptive capacity towards different metals. It has been observed that these sediments acts as metal contaminants sequester. Knowing the composition and morphology of these sediments can provide information to understand the mobility of different heavy metals it contains, and potential health risk, which can finally lead to the establishment of purification capacity of this sludge.展开更多
The objective of this project was to search for consensus in differential gene expression data and in regulation of differentially expressed genes among DNA microarray studies of atherosclerotic vessels and plaque. Se...The objective of this project was to search for consensus in differential gene expression data and in regulation of differentially expressed genes among DNA microarray studies of atherosclerotic vessels and plaque. Seventeen DNA microarray studies of atherosclerosis were analyzed. Only 19 genes were found to be differentially expressed in 3 or more of the studies. The nineteen genes belong to classic gene ontologies known to be involved in atherosclerosis: immunity and defense, metabolism, proteases, receptors, and signal transduction. Four bioinformatics programs (TRED, rVISTA, JASPAR, and Ariadne Pathways) were used to further analyze the promoter regions and common upstream regulators of the 19 genes. Twelve of the genes shared nine common upstream regulators, many of them known to affect atherosclerosis, and one possible new pathway was identified that may be involved in this disease.展开更多
Anatomy, a foremost basic medical science (BMS) has evolved in content and context, while remaining the most fundamental BMS subject. Stakeholders have continually made efforts especially in recent time to achieve an ...Anatomy, a foremost basic medical science (BMS) has evolved in content and context, while remaining the most fundamental BMS subject. Stakeholders have continually made efforts especially in recent time to achieve an evolution of this subject. The primary aim of this work was to study the perceptions and experiences of Anatomists towards contributing to programme and career advancements. Following ethical approval, structured questionnaire was administered to Nigerian anatomists using a Google form. It is a total population study. The questionnaire had 13 sections, with each section addressing a theme that was integral to the subject of research interest. The last section collected free responses as qualitative information. After indicating informed consent, 106 anatomists properly completed and returned the questionnaires. Statistical and quantitative analyses of results were done. The most popular field amongst respondents was Neuroscience (60.9%);followed by Histology or Microscopic Anatomy (53.6%), Embryology or developmental anatomy (35.5%), Gross anatomy (34.5%) and Histochemistry (30.9%). About half of Nigerian anatomists involved in the study had a PhD degree. Training emphasized the cognitive domains the most. Consequently, emphasis should be laid on the psychomotor (skills) and the affective domain (attitude) to improve capacity, competences, and the job prospects of trainees. The consensus was that the programme trained students and prepared graduates as medical educators, scientists, and researchers. Anatomy has significant potential to contribute to development with proper programme design, emphasis on research, teaching and applied services competencies, effective policy formulation and implementation and adherence to best practices.展开更多
Tuberculosis (TB) remains a public health challenge and one of the leading causes of death worldwide. TB is preventable and curable. However, treatment of tuberculosis has continued to be difficult as a result of rapi...Tuberculosis (TB) remains a public health challenge and one of the leading causes of death worldwide. TB is preventable and curable. However, treatment of tuberculosis has continued to be difficult as a result of rapid increase of multidrug and extensively drug resistant strains of Mycobacterium tuberculosis. Medicinal plants have for centuries been traditionally used in treatment of tuberculosis and similar ailments. They possess antimicrobial properties which render them a new hope as a source of novel bioactive leads in the development of antimycobacterial agents. In this study, 2 plant species commonly used traditionally in Uganda for treatment of tuberculosis, Zanthoxylum leprieurii and Rubia cordifolia were screened for in vitro antimycobacterial activity against Mycobacterium tuberculosis strains;pan sensitive MTB H37Rv, Rifampicin resistant TMC 331 strain and two wild strains (one rifampicin resistant and another one rifampicin susceptible). Antimycobacterial activity of aqueous, ethanolic and methanolic plant extracts was determined using Resazurin Microtiter Assay (REMA). Both plant extracts exhibited significant in vitro antimycobacterial activity against all strains of Mycobacterium tuberculosis. Minimum inhibitory concentrations (MIC) of methanolic crude extracts of both plants ranged from 23.4 μg/mL to 187.5 μg/mL. Comparatively, methanol extracts of both plants possessed superior antimycobacterial activity against all Mycobacterium tuberculosis strains. Our findings indicated that both plants exhibited activity against susceptible and resistant strains of Mycobacterium tuberculosis. While antimycobacterial activity of Z. leprieurii confirms results from previous studies, activity of the extracts of R. cordifolia is reported for the first time in East Africa. Further studies aimed at determining the effects of combination of these plant extracts and standard anti-TB drugs should be carried out.展开更多
Semi-large scale liquid cultivation of transformed Escherichia coli (E. coli) in medium (100-200 ml) has been widely used for the acquisition of relatively large amounts of plasmid DNA (50-300 μg). However, this meth...Semi-large scale liquid cultivation of transformed Escherichia coli (E. coli) in medium (100-200 ml) has been widely used for the acquisition of relatively large amounts of plasmid DNA (50-300 μg). However, this method requires an expensive high-speed centrifugation apparatus to precipitate E. coli before lysis, which is both laborious and time-consuming. Here, we demonstrate a method for agar plate-based cultivation of bacteria that does not employ a high-speed centrifugation apparatus. This procedure proves to be simple and reproducible, yielding an average of 82 μg of plasmid DNA per experiment. It may therefore be valuable for cloning/transfection experiments under limited financial backgrounds.展开更多
OBJECTIVE:To examine whether specific stimulation of Shenshu(BL23)affects sympathetic nervous activity(SNA)-associated plasma renin concentration(PRC).METHODS:Eight healthy volunteers participated in three pattern con...OBJECTIVE:To examine whether specific stimulation of Shenshu(BL23)affects sympathetic nervous activity(SNA)-associated plasma renin concentration(PRC).METHODS:Eight healthy volunteers participated in three pattern conditions in random order:control(Cont),stimulation of Shenshu(BL23),and stimulation of sham point(Sham).All participants were initially in the supine position for>60 min,and then remained in the standing position during the experimental procedure to increase SNA.An electrocardiogram was used to calculate low frequency/high frequency(LF/HF)ratio;blood was collected to analyze PRC.RESULTS:The LF/HF ratio was significantly increased in the standing position when compared with the supine position(P<0.01).There was no difference in LF/HF ratio during or after stimulation of Shenshu(BL23)in the standing position when compared with before the stimulation in the supine position;however,the LF/HF ratio was significantly increased in Cont and Sham conditions(P<0.01).There was no difference in PRC after stimulation of Shenshu(BL23)in the standing position when compared with before the stimulation in the supine position;however,there was a significant increase in PRC in the Cont and Sham conditions(Cont P<0.05,Sham P<0.01).CONCLUSION:Our results demonstrated that specific acupuncture stimulation of Shenshu(BL23)in the standing position decreased SNA-associated PRC,which was not observed during acupuncture stimulation of the sham point.展开更多
There is a constant growth in the demand of data information transmission capacity, that is, more and more people send data, voice, video signals, among others, through communications networks. Due to the above there ...There is a constant growth in the demand of data information transmission capacity, that is, more and more people send data, voice, video signals, among others, through communications networks. Due to the above there is great interest in improving network devices, such as optical amplifiers, which must cover a large bandwidth and generate greater gain than those currently available. For this reason in this work a computational simulation for a Quasi-system was carried out</span></span><span><span><span style="font-family:""> </span></span></span><span><span><span style="font-family:"">three energy levels of Erbium and Ytterbium varying their concentrations and proving that they are optimal candidates in a zinc phosphate matrix as this type of glass contains properties such as, high transparency, low melting point, high thermal stability, high gain density due to high solubility, low refractive index and low dispersion, which makes them optimal as signal amplifiers. The results confirm that by increasing the doping of the Erbium ion the gain of the amplifier decreases, contrary to the Ytterbium ion that by increasing the doping the gain of the amplifier increases.展开更多
Long gap peripheral nerve injuries usually reulting in life-changing problems for patients. Skeletal muscle derived-multipotent stem cells （Sk-MSCs） can differentiate into Schwann and perineurial/endoneurial cells, ...Long gap peripheral nerve injuries usually reulting in life-changing problems for patients. Skeletal muscle derived-multipotent stem cells （Sk-MSCs） can differentiate into Schwann and perineurial/endoneurial cells, vascular relating pericytes, and endothelial and smooth muscle cells in the damaged peripheral nerve niche. Application of the Sk-MSCs in the bridging conduit for repairing long nerve gap injury resulted favorable axonal regeneration, which showing superior effects than gold standard therapy--healthy nerve autograft. This means that it does not need to sacrifice of healthy nerves or loss of related functions for repairing peripheral nerve injury.展开更多
Ischemic stroke is a global epidemic condition due to an inadequate supply of blood and oxygen to a specific area of brain either by arterial blockage or by narrowing of blood vessels.Despite having advancement in the...Ischemic stroke is a global epidemic condition due to an inadequate supply of blood and oxygen to a specific area of brain either by arterial blockage or by narrowing of blood vessels.Despite having advancement in the use of thrombolytic and clot removal medicine,significant numbers of stroke patients are still left out without option for treatment.In this review,we summarize recent research work on the activation ofδ-opioid receptor as a strategy for treating ischemic stroke-caused neuronal injury.Moreover,as activation ofδ-opioid receptor by a non-peptidicδ-opioid receptor agonist also modulates the expression,maturation and processing of amyloid precursor protein andβ-secretase activity,the potential role of these effects on ischemic stroke caused dementia or Alzheimer’s disease are also discussed.展开更多
Pesticides are an integral part in maintaining agriculture and horticultural productivity and play a vital role in meeting the increasing food, fiber, and fuel needs of the growing population. Globally, organophosphat...Pesticides are an integral part in maintaining agriculture and horticultural productivity and play a vital role in meeting the increasing food, fiber, and fuel needs of the growing population. Globally, organophosphate pesticides(OPPs) are among the most common pesticides used due to their high proficiency and relatively low persistence in the environment. However, recent studies have reported problems due to pesticide use, e.g., phorate contamination of aquatic ecosystems(fresh and groundwater), sediments, fruits and vegetables, and forage crops. This review highlights many cases where phorate has been detected above its respective maximum residue limit values. Organophosphate pesticides, including phorate, have negative impacts on both the environment and human health. The ecological and public health concerns of recurrent pesticide utilization have encouraged the research related to environmental fate of pesticides.Bioremediation is an effective, eco-friendly, and financially viable approach for the decontamination and degradation of toxic OPPs from the environment,compared to the costly, unecological, and time-consuming physicochemical approaches, which lead to the generation of byproducts of higher toxicity.Researchers have recognized that a wide range of microbes, mainly bacteria, can degrade this extremely hazardous pesticide. Therefore, this review discusses the present pesticide scenarios, especially phorate contamination, its toxicity, biodegradation, and metabolic products via bacterial communities, both in India and globally. The latest and up-to-date literatures on the use, contamination, and bacterial application of phorate degradation are also summarized. This article offers national and international food safety organizations and public health authorities the ability to be involved in preventing the risks associated with the use of food and nutrition products contaminated with extremely toxic phorate pesticide. This article would also enable researchers to develop comprehensive and sustainable methods to effectively remediate pesticide-contaminated environments. In conclusion, it is envisaged that the successful application of bacterial communities for degradation of phorate would help in understanding the fate and persistence of such toxic pollutants in a better way.展开更多
Despite improvements in the early diagnosis,prognosis and therapeutic strategies for gastric cancer(GC),human GC remains one of the most frequently diagnosed malignant tumors in the world,and the survival rate of GC p...Despite improvements in the early diagnosis,prognosis and therapeutic strategies for gastric cancer(GC),human GC remains one of the most frequently diagnosed malignant tumors in the world,and the survival rate of GC patients remains very poor.Thus,a suitable therapeutic strategy for GC is important for prolonging survival.Both tumor cells themselves and the tumor microenvironment play an important role in tumorigenesis,including angiogenesis,inflammation,immunosuppression and metastasis.Importantly,these cells contribute to gastric carcinogenesis by altering the angiogenic phenotype switch.The development,relapse and spreading of tumors depend on new vessels that provide the nutrition,growth factors and oxygen required for continuous tumor growth.Therefore,a state of tumor dormancy could be induced by blocking tumor-associated angiogenesis.Recently,several antiangiogenic agents have been identified,and their potential for the clinical management of GC has been tested.Here,we provide an up-to-date summary of angiogenesis and the angiogenic factors associated with tumor progression in GC.We also review antiangiogenic agents with a focus on the anti-vascular endothelial growth factor receptor(VEGFR)-mediated pathway for endothelial cell growth and their angiogenesis ability in GC.However,most antiangiogenic agents have reported no benefit to overall survival(OS)compared to chemotherapy alone in local or advanced GC.In phase III clinical trials,only ramucirumab(anti-VEGFR blocker)and apatinib(VEGFR-TKI blocker)have reported an improved median overall response rate and prolonged OS and progression-free survival outcomes as a 2 nd-line agent combined with chemotherapy treatment in advanced GC.By providing insights into the molecular mechanisms of angiogenesis associated with tumor progression in GC,this review will hopefully aid the optimization of antiangiogenesis strategies for GC therapy in combination with chemotherapy and adjuvant treatment.展开更多
基金supported by the National Institute on Aging of NIH(No.RF1AG072510 to HW)the National Institute of General Medical Sciences(NINGM)of NIH(No.P20GM103443 to HW via Dr.Victor Huber)+1 种基金the National Science Foundation(NSF)(No.DGE-1633213 to CCH via Dr.Brian Burrell)the NIH/NIGMS(No.T32GM-136503 to CCH via Dr.Brian Burrell)。
文摘Neurodegenerative disorders affect millions of people worldwide,and the prevalence of these disorders is only projected to rise as the number of people over 65 will drastically increase in the coming years.While therapies exist to aid in symptomatic relief,effective treatments that can stop or reve rse the progress of each neurodegenerative disease are lacking.Recently,research on the role of extracellular vesicles as disease markers and therapeutics has been intensively studied.Exosomes,30-150 nm in diameter,are one type of extracellular vesicles facilitating cell-to-cell communication.Exosomes are thought to play a role in disease propagation in a variety of neurodegenerative diseases,such as Alzheimer's disease,Parkinson s disease,and amyotrophic lateral sclerosis.Accordingly,the exosomes derived from the patients are an invaluable source of disease biomarkers.On the other hand,exosomes,especially those derived from stem cells,could serve as a therapeutic for these disorders,as seen by a rapid increase in clinical trials investigating the therapeutic efficacy of exosomes in different neurological diseases.This review summarizes the pathological burden and therapeutic approach of exosomes in neurodegenerative disorders.We also highlight how heat shock increases the yield of exosomes while still maintaining their therapeutic efficacy.Finally,this review concludes with outstanding questions that remain to be addressed in exosomal research.
基金This research was a part of the project titled‘Omics based on fishery disease control technology development and industrialization(20150242)’,funded by the Ministry of Oceans and Fisheries,Republic of Korea。
文摘Objective:To investigate whether the ethanol extract of Chondracanthus tenellus(Harvey)Hommersand,a type of red algae,could exhibit anti-inflammatory potential in lipopolysaccharide(LPS)-stimulated macrophages.Methods:The ethanol extract of Chondracanthus tenellus was applied to 100 ng/mL LPS-stimulated RAW 264.7 cells,and cell viability,phagocytic ability,levels of pro-inflammatory factors,and the production of reactive oxygen species were measured.To identify the underlying mechanism of the ethanol extract of Chondracanthus tenellus,the expression of inflammation-regulated genes was estimated.Results:The ethanol extract of Chondracanthus tenellus had no cytotoxic effect at concentrations below 300μg/mL,and reduced the LPS-induced production of inflammatory mediators including nitric oxide(NO)and prostaglandin E2.Furthermore,the extract markedly suppressed the expression of inducible NO synthase and cyclooxygenase-2,as well as the production of reactive oxygen species.The LPS-induced up-regulation of pro-inflammatory cytokines was attenuated by treatment with the ethanol extract of Chondracanthus tenellus,reducing their extracellular secretion.The Chondracanthus tenellus extract also inhibited LPS-mediated activation of nuclear factor-kappa B(NF-κB).In addition,the phosphorylation of mitogen activated protein kinases(MAPKs)and phosphatidylinositol 3 kinase(PI3K)/Akt was markedly increased by LPS,which was significantly abolished by the Chondracanthus tenellus extract.Conclusions:Our findings indicate that the ethanol extract of Chondracanthus tenellus exhibited potential anti-inflammatory and antioxidant effects through downregulating the NF-κB,MAPKs,and PI3K/Akt signaling pathways in LPS stimulated RAW 264.7 macrophages.tenellus extract.Conclusions:Our findings indicate that the ethanol extract of Chondracanthus tenellus exhibited potential anti-inflammatory and antioxidant effects through downregulating the NF-κB,MAPKs,and PI3K/Akt signaling pathways in LPS stimulated RAW 264.7 macrophages.
基金Acknowledgments This work was supported by the National High Technol- ogy Research and Development Program of China （Project 2006AA02Z4B5）, the National Natural Science Foundation of China （Project 2010）, and a Key Project （9251018201002） of Guangdong Province Natural Science Foundation （to JL）. It was also supported in part by Grants HL072166, HL085629, and HL068936 of the NIH and an Established Investigator Award （0740025N） of the American Heart Association （to XW）.
文摘Intracellular protein degradation by the ubiquitin-proteasome system is ATP dependent, and the optimal ATP concentration to activate proteasome function in vitro is -100 μM. IntraceUular ATP levels are generally in the low millimolar range, but ATP at a level within this range was shown to inhibit proteasome peptidase activities in vitro. Here, we report new evidence that supports a hypothesis that intracellular ATP at the physiological levels bidirectionally regulates 26S proteasome proteolytic function in the cell. First, we confirmed that ATP exerted bidirectional regulation on the 26S proteasome in vitro, with the optimal ATP concentration （between 50 and 100μM） stimulating proteasome chymotrypsin-like activities. Second, we found that manipulating intracellular ATP levels also led to bidirectional changes in the levels of proteasome-specific protein substrates in cultured cells. Finally, measures to increase intracellular ATP enhanced, while decreasing intraceHular ATP attenuated the ability of proteasome inhibition to induce cell death. These data strongly suggest that endogenous ATP within the physiological concentration range can exert a negative impact on proteasome activities, allowing the cell to rapidly upregulate proteasome activity on ATP reduction under stress conditions.
文摘Pancreatic cancer is highly aggressive and lethal.Due to the lack of effective methods for detecting the disease at an early stage,pancreatic cancer is frequently diagnosed late.Gemcitabine has been the standard chemotherapy drug for patients with pancreatic cancer for over 20 years,but its anti-tumor effect is limited.Therefore,FOLFIRINOX(leucovorin,fluorouracil,irinotecan,oxaliplatin)as well as combination therapies using gemcitabine and conventional agents,such as cisplatin and capecitabine,has also been administered;however,these have not resulted in complete remission.Therefore,there is a need to develop novel and effective therapies for pancreatic cancer.Recently,some studies have reported that combinations of gemcitabine and targeted drugs have had significant antitumor effects on pancreatic cancer cells.As gemcitabine induced DNA damage response,the proteins related to DNA damage response can be suitable additional targets for novel gemcitabine-based combination therapy.Furthermore,KRAS/RAF/MEK/ERK signaling triggered by oncogenic mutated KRAS and autophagy are frequently activated in pancreatic cancer.Therefore,these characteristics of pancreatic cancer are potential targets for developing effective novel therapies.In this minireview,combinations of gemcitabine and targeted drugs to these characteristics,combinations of targeted drugs,combinations of natural products and anti-cancer agents,including gemcitabine,and combinations among natural products are discussed.
基金the Ministry of Science and Technology,Taiwan,No.MOST 108-2320-B-255-002-MY3Chang Gung Medical Research Foundation,Taoyuan,Taiwan No.CMRPF1I0031,No.CMRPF1I0041,No.CMRPF1I0041-2,and No.CMRPF1L0021and Chang Gung University of Science and Technology,Taoyuan,Taiwan,No.ZRRPF3J0081,No.ZRRPF3K0111,and No.ZRRPF3L0091.
文摘Gastric cancer(GC)is a primary cause of cancer-related mortality worldwide,and even after therapeutic gastrectomy,survival rates remain poor.The presence of gastric cancer stem cells(GCSCs)is thought to be the major reason for resistance to anticancer treatment(chemotherapy or radiotherapy),and for the development of tumor recurrence,epithelial–mesenchymal transition,and metastases.Additionally,GCSCs have the capacity for self-renewal,differentiation,and tumor initiation.They also synthesize antiapoptotic factors,demonstrate higher performance of drug efflux pumps,and display cell plasticity abilities.Moreover,the tumor microenvironment(TME;tumor niche)that surrounds GCSCs contains secreted growth factors and supports angiogenesis and is thus responsible for the maintenance of the growing tumor.However,the genesis of GCSCs is unclear and exploration of the source of GCSCs is essential.In this review,we provide up-todate information about GCSC-surface/intracellular markers and GCSC-mediated pathways and their role in tumor development.This information will support improved diagnosis,novel therapeutic approaches,and better prognosis using GCSC-targeting agents as a potentially effective treatment choice following surgical resection or in combination with chemotherapy and radiotherapy.To date,most anti-GCSC blockers when used alone have been reported as unsatisfactory anticancer agents.However,when used in combination with adjuvant therapy,treatment can improve.By providing insights into the molecular mechanisms of GCSCs associated with tumors in GC,the aim is to optimize anti-GCSCs molecular approaches for GC therapy in combination with chemotherapy,radiotherapy,or other adjuvant treatment.
文摘Anesthetics evoke a stress-response, upregulating heat shock genes. This neuroprotective response to proteotoxic stress represents preconditioning, a process by which neuronal tissue, previously exposed to anesthetics, is protected against future insult. It presumes a sub-lethal injury, affecting protein unfolding. Our hypothesis is: preconditioning evokes molecular events that result in downstream changes that offer a selective advantage in terms of neuronal function. We focused on the neurobehavioral aspects which we neurophenotyped. Larval zebrafish were exposed to trifluoroethanol (TFE), an anesthetic mimetic, and tested for both individual and group behavioral markers of neuronal function. In bright/dark tests, we observed that TFE-exposed larvae spent more time in the dark area (typically an adult-like response) than control larvae. The response of TFE larvae to noise startle was directly opposite to that of controls. TFE larvae swam towards the source of the startle (into the bright zone), whereas control larvae swam away from the source of the startle (into the dark), typical of fear-response. The larvae also exhibited several differences in social behaviors, including synchronized schooling and shoaling behaviors. The TFE-group showed a greater number of synchronized events versus controls. The TFE-group also exhibited more shoaling events compared with controls. While the long-term effects have yet to be determined, these results shed light on the mechanism of anesthetic preconditioning. These complex zebrafish behaviors normally develop with age and therefore represent, in the TFE-exposed group, a pattern of accelerated maturation of neuronal function, which is the neurophenotype attributed to preconditioning.
基金This research was a part of the project titled‘Omics based on fishery disease control technology development and industrialization(20150242)’funded by the Ministry of Oceans and Fisheries,Republic of Korea.
文摘Objective:To investigate whether ethanol extracts of Chondracanthus tenellus(EECT)could improve immunomodulatory property of murine monocyte/macrophage RAW 264.7 cells.Methods:Cell viability,phagocytic ability,and nitric oxide were measured.The levels of prostaglandin E2 and cytokines were determined using enzyme-linked immunosorbent assay kits.Expression of immunoregulatory response protein was detected by Western blotting assay.Results:As the concentration of EECT increased,the morphology of the cells changed to a typical active macrophage shape,and the phagocytic activity increased significantly.EECT also effectively enhanced the production and secretion of immunomodulatory mediators,such as nitric oxide and prostaglandin E2,and cytokines.In addition,compared with the control group,EECT markedly stimulated the expression of Toll-like receptor 4(TLR4)and myeloid differentiation factor 88,one of the TLR4 adapter molecules.Furthermore,EECT promoted the nucleus translocation of nuclear factor-kappa B(NF-κB)by increasing the phosphorylation and degradation of the inhibitor of NF-κB-α,indicating activation of the NF-κB signaling pathway.Meanwhile,similar trends were found in cells treated with lipopolysaccharide as a positive control.Conclusions:Taken together,the results indicate that EECT has an immunomodulatory effect by increasing the production of immunomodulatory mediators and cytokines through activation of the TLR4/NF-κB signaling pathway.EECT could be used as a potential candidate for medication or dietary supplements to increase immune activity.
文摘The problem of contamination of Lerma River in the State of Mexico, México, has been studied in an integral way, since it is one of the rivers of importance due to its geographical situation in the country. José Antonio Dam is the main receiving body of this river that is being contaminated by, industrial wastewater, of which about 70% is inorganic, as well as discharges municipal and agricultural, driving a lot of material in suspension. This dam acts as a regulator of avenues and its water is used for agricultural irrigation and its sediments are used as sludge to improve agricultural soil in the surroundings. One of the studies that have been carried out is to determine the geochemical distribution of heavy metals in the sediments of this dam, as well as its adsorptive capacity towards different metals. It has been observed that these sediments acts as metal contaminants sequester. Knowing the composition and morphology of these sediments can provide information to understand the mobility of different heavy metals it contains, and potential health risk, which can finally lead to the establishment of purification capacity of this sludge.
文摘The objective of this project was to search for consensus in differential gene expression data and in regulation of differentially expressed genes among DNA microarray studies of atherosclerotic vessels and plaque. Seventeen DNA microarray studies of atherosclerosis were analyzed. Only 19 genes were found to be differentially expressed in 3 or more of the studies. The nineteen genes belong to classic gene ontologies known to be involved in atherosclerosis: immunity and defense, metabolism, proteases, receptors, and signal transduction. Four bioinformatics programs (TRED, rVISTA, JASPAR, and Ariadne Pathways) were used to further analyze the promoter regions and common upstream regulators of the 19 genes. Twelve of the genes shared nine common upstream regulators, many of them known to affect atherosclerosis, and one possible new pathway was identified that may be involved in this disease.
文摘Anatomy, a foremost basic medical science (BMS) has evolved in content and context, while remaining the most fundamental BMS subject. Stakeholders have continually made efforts especially in recent time to achieve an evolution of this subject. The primary aim of this work was to study the perceptions and experiences of Anatomists towards contributing to programme and career advancements. Following ethical approval, structured questionnaire was administered to Nigerian anatomists using a Google form. It is a total population study. The questionnaire had 13 sections, with each section addressing a theme that was integral to the subject of research interest. The last section collected free responses as qualitative information. After indicating informed consent, 106 anatomists properly completed and returned the questionnaires. Statistical and quantitative analyses of results were done. The most popular field amongst respondents was Neuroscience (60.9%);followed by Histology or Microscopic Anatomy (53.6%), Embryology or developmental anatomy (35.5%), Gross anatomy (34.5%) and Histochemistry (30.9%). About half of Nigerian anatomists involved in the study had a PhD degree. Training emphasized the cognitive domains the most. Consequently, emphasis should be laid on the psychomotor (skills) and the affective domain (attitude) to improve capacity, competences, and the job prospects of trainees. The consensus was that the programme trained students and prepared graduates as medical educators, scientists, and researchers. Anatomy has significant potential to contribute to development with proper programme design, emphasis on research, teaching and applied services competencies, effective policy formulation and implementation and adherence to best practices.
文摘Tuberculosis (TB) remains a public health challenge and one of the leading causes of death worldwide. TB is preventable and curable. However, treatment of tuberculosis has continued to be difficult as a result of rapid increase of multidrug and extensively drug resistant strains of Mycobacterium tuberculosis. Medicinal plants have for centuries been traditionally used in treatment of tuberculosis and similar ailments. They possess antimicrobial properties which render them a new hope as a source of novel bioactive leads in the development of antimycobacterial agents. In this study, 2 plant species commonly used traditionally in Uganda for treatment of tuberculosis, Zanthoxylum leprieurii and Rubia cordifolia were screened for in vitro antimycobacterial activity against Mycobacterium tuberculosis strains;pan sensitive MTB H37Rv, Rifampicin resistant TMC 331 strain and two wild strains (one rifampicin resistant and another one rifampicin susceptible). Antimycobacterial activity of aqueous, ethanolic and methanolic plant extracts was determined using Resazurin Microtiter Assay (REMA). Both plant extracts exhibited significant in vitro antimycobacterial activity against all strains of Mycobacterium tuberculosis. Minimum inhibitory concentrations (MIC) of methanolic crude extracts of both plants ranged from 23.4 μg/mL to 187.5 μg/mL. Comparatively, methanol extracts of both plants possessed superior antimycobacterial activity against all Mycobacterium tuberculosis strains. Our findings indicated that both plants exhibited activity against susceptible and resistant strains of Mycobacterium tuberculosis. While antimycobacterial activity of Z. leprieurii confirms results from previous studies, activity of the extracts of R. cordifolia is reported for the first time in East Africa. Further studies aimed at determining the effects of combination of these plant extracts and standard anti-TB drugs should be carried out.
文摘Semi-large scale liquid cultivation of transformed Escherichia coli (E. coli) in medium (100-200 ml) has been widely used for the acquisition of relatively large amounts of plasmid DNA (50-300 μg). However, this method requires an expensive high-speed centrifugation apparatus to precipitate E. coli before lysis, which is both laborious and time-consuming. Here, we demonstrate a method for agar plate-based cultivation of bacteria that does not employ a high-speed centrifugation apparatus. This procedure proves to be simple and reproducible, yielding an average of 82 μg of plasmid DNA per experiment. It may therefore be valuable for cloning/transfection experiments under limited financial backgrounds.
文摘OBJECTIVE:To examine whether specific stimulation of Shenshu(BL23)affects sympathetic nervous activity(SNA)-associated plasma renin concentration(PRC).METHODS:Eight healthy volunteers participated in three pattern conditions in random order:control(Cont),stimulation of Shenshu(BL23),and stimulation of sham point(Sham).All participants were initially in the supine position for>60 min,and then remained in the standing position during the experimental procedure to increase SNA.An electrocardiogram was used to calculate low frequency/high frequency(LF/HF)ratio;blood was collected to analyze PRC.RESULTS:The LF/HF ratio was significantly increased in the standing position when compared with the supine position(P<0.01).There was no difference in LF/HF ratio during or after stimulation of Shenshu(BL23)in the standing position when compared with before the stimulation in the supine position;however,the LF/HF ratio was significantly increased in Cont and Sham conditions(P<0.01).There was no difference in PRC after stimulation of Shenshu(BL23)in the standing position when compared with before the stimulation in the supine position;however,there was a significant increase in PRC in the Cont and Sham conditions(Cont P<0.05,Sham P<0.01).CONCLUSION:Our results demonstrated that specific acupuncture stimulation of Shenshu(BL23)in the standing position decreased SNA-associated PRC,which was not observed during acupuncture stimulation of the sham point.
文摘There is a constant growth in the demand of data information transmission capacity, that is, more and more people send data, voice, video signals, among others, through communications networks. Due to the above there is great interest in improving network devices, such as optical amplifiers, which must cover a large bandwidth and generate greater gain than those currently available. For this reason in this work a computational simulation for a Quasi-system was carried out</span></span><span><span><span style="font-family:""> </span></span></span><span><span><span style="font-family:"">three energy levels of Erbium and Ytterbium varying their concentrations and proving that they are optimal candidates in a zinc phosphate matrix as this type of glass contains properties such as, high transparency, low melting point, high thermal stability, high gain density due to high solubility, low refractive index and low dispersion, which makes them optimal as signal amplifiers. The results confirm that by increasing the doping of the Erbium ion the gain of the amplifier decreases, contrary to the Ytterbium ion that by increasing the doping the gain of the amplifier increases.
基金supported by a 2013 Tokai University School of Medicine,Project Research Grant
文摘Long gap peripheral nerve injuries usually reulting in life-changing problems for patients. Skeletal muscle derived-multipotent stem cells （Sk-MSCs） can differentiate into Schwann and perineurial/endoneurial cells, vascular relating pericytes, and endothelial and smooth muscle cells in the damaged peripheral nerve niche. Application of the Sk-MSCs in the bridging conduit for repairing long nerve gap injury resulted favorable axonal regeneration, which showing superior effects than gold standard therapy--healthy nerve autograft. This means that it does not need to sacrifice of healthy nerves or loss of related functions for repairing peripheral nerve injury.
基金supported by the National Institute of Neurological Disorders and Stroke under research grant NS088084(to HW)
文摘Ischemic stroke is a global epidemic condition due to an inadequate supply of blood and oxygen to a specific area of brain either by arterial blockage or by narrowing of blood vessels.Despite having advancement in the use of thrombolytic and clot removal medicine,significant numbers of stroke patients are still left out without option for treatment.In this review,we summarize recent research work on the activation ofδ-opioid receptor as a strategy for treating ischemic stroke-caused neuronal injury.Moreover,as activation ofδ-opioid receptor by a non-peptidicδ-opioid receptor agonist also modulates the expression,maturation and processing of amyloid precursor protein andβ-secretase activity,the potential role of these effects on ischemic stroke caused dementia or Alzheimer’s disease are also discussed.
文摘Pesticides are an integral part in maintaining agriculture and horticultural productivity and play a vital role in meeting the increasing food, fiber, and fuel needs of the growing population. Globally, organophosphate pesticides(OPPs) are among the most common pesticides used due to their high proficiency and relatively low persistence in the environment. However, recent studies have reported problems due to pesticide use, e.g., phorate contamination of aquatic ecosystems(fresh and groundwater), sediments, fruits and vegetables, and forage crops. This review highlights many cases where phorate has been detected above its respective maximum residue limit values. Organophosphate pesticides, including phorate, have negative impacts on both the environment and human health. The ecological and public health concerns of recurrent pesticide utilization have encouraged the research related to environmental fate of pesticides.Bioremediation is an effective, eco-friendly, and financially viable approach for the decontamination and degradation of toxic OPPs from the environment,compared to the costly, unecological, and time-consuming physicochemical approaches, which lead to the generation of byproducts of higher toxicity.Researchers have recognized that a wide range of microbes, mainly bacteria, can degrade this extremely hazardous pesticide. Therefore, this review discusses the present pesticide scenarios, especially phorate contamination, its toxicity, biodegradation, and metabolic products via bacterial communities, both in India and globally. The latest and up-to-date literatures on the use, contamination, and bacterial application of phorate degradation are also summarized. This article offers national and international food safety organizations and public health authorities the ability to be involved in preventing the risks associated with the use of food and nutrition products contaminated with extremely toxic phorate pesticide. This article would also enable researchers to develop comprehensive and sustainable methods to effectively remediate pesticide-contaminated environments. In conclusion, it is envisaged that the successful application of bacterial communities for degradation of phorate would help in understanding the fate and persistence of such toxic pollutants in a better way.
基金Supported by the Ministry of Science and Technology,Taiwan,No.MOST 106-2320-B-255-005 and No.MOST 107-2320-B-255-003Chang Gung Medical Research Foundation,Taoyuan,Taiwan,No.CMRPF1G0011,No.CMRPF1G0251,No.CMRPF1I0031,No.CMRPF1H0051,and No.CMRPF1I0041Chang Gung University of Science and Technology,Taoyuan,Taiwan,No.ZRRPF3H0131
文摘Despite improvements in the early diagnosis,prognosis and therapeutic strategies for gastric cancer(GC),human GC remains one of the most frequently diagnosed malignant tumors in the world,and the survival rate of GC patients remains very poor.Thus,a suitable therapeutic strategy for GC is important for prolonging survival.Both tumor cells themselves and the tumor microenvironment play an important role in tumorigenesis,including angiogenesis,inflammation,immunosuppression and metastasis.Importantly,these cells contribute to gastric carcinogenesis by altering the angiogenic phenotype switch.The development,relapse and spreading of tumors depend on new vessels that provide the nutrition,growth factors and oxygen required for continuous tumor growth.Therefore,a state of tumor dormancy could be induced by blocking tumor-associated angiogenesis.Recently,several antiangiogenic agents have been identified,and their potential for the clinical management of GC has been tested.Here,we provide an up-to-date summary of angiogenesis and the angiogenic factors associated with tumor progression in GC.We also review antiangiogenic agents with a focus on the anti-vascular endothelial growth factor receptor(VEGFR)-mediated pathway for endothelial cell growth and their angiogenesis ability in GC.However,most antiangiogenic agents have reported no benefit to overall survival(OS)compared to chemotherapy alone in local or advanced GC.In phase III clinical trials,only ramucirumab(anti-VEGFR blocker)and apatinib(VEGFR-TKI blocker)have reported an improved median overall response rate and prolonged OS and progression-free survival outcomes as a 2 nd-line agent combined with chemotherapy treatment in advanced GC.By providing insights into the molecular mechanisms of angiogenesis associated with tumor progression in GC,this review will hopefully aid the optimization of antiangiogenesis strategies for GC therapy in combination with chemotherapy and adjuvant treatment.
