Muscle fibers are multinucleated,and muscle fiber nuclei(myonuclei)are believed to be post-mitotic and are typically situated near the periphery of the myofiber.Due to the unique organization of muscle fibers and thei...Muscle fibers are multinucleated,and muscle fiber nuclei(myonuclei)are believed to be post-mitotic and are typically situated near the periphery of the myofiber.Due to the unique organization of muscle fibers and their nuclei,the cellular and molecular mechanisms regulating myofiber homeostasis in unstressed and stressed conditions(e.g.,exercise)are unique.A key role myonuclei play in regulating muscle during exercise is gene transcription.Only recently have investigators had the capability to identify molecular changes at high resolution exclusively in myonuclei in response to perturbations in vivo.The purpose of this review is to describe how myonuclei modulate their transcriptome,epigenetic status,mobility and shape,and microRNA expression in response to exercise in vivo.Given the relative paucity of high-fidelity information on myonucleus-specific contributions to exercise adaptation,we identify specific gaps in knowledge and provide perspectives on future directions of research.展开更多
The internal structures of cells as the basic units of life are a major wonder of the microscopic world.Cellular images provide an intriguing window to help explore and understand the composition and function of these...The internal structures of cells as the basic units of life are a major wonder of the microscopic world.Cellular images provide an intriguing window to help explore and understand the composition and function of these structures.Scientific imagery combined with artistic expression can further expand the potential of imaging in educational dissemination and interdisciplinary applications.展开更多
BACKGROUND Cirrhosis is an important health problem characterized by a significant change in liver parenchyma.In animals,this can be reproduced by an experimental model of bile duct ligation(BDL).Melatonin(MLT)is a ph...BACKGROUND Cirrhosis is an important health problem characterized by a significant change in liver parenchyma.In animals,this can be reproduced by an experimental model of bile duct ligation(BDL).Melatonin(MLT)is a physiological hormone synthesized from serotonin that has been studied for its beneficial properties,including its antioxidant potential.AIM To evaluate MLT’s effects on oxidative stress,the inflammatory process,and DNA damage in an experimental model of secondary biliary cirrhosis.METHODS Male Wistar rats were divided into 4 groups:Control(CO),CO+MLT,BDL,and BDL+MLT.MLT was administered(20 mg/kg)daily beginning on day 15 after biliary obstruction.On day 29 the animals were killed.Blood samples,liver tissue,and bone marrow were collected for further analysis.RESULTS BDL caused changes in biochemical and histological parameters and markers of inflammatory process.Thiobarbituric acid(0.46±0.01)reactive substance levels,superoxide dismutase activity(2.30±0.07)and nitric oxide levels(2.48±0.36)were significantly lower(P<0.001)n the groups that received MLT.DNA damage was also lower(P<0.001)in MLT-treated groups(171.6±32.9)than the BDL-only group(295.5±34.8).Tissue damage and the expression of nuclear factor kappa B,interleukin-1β,Nrf2,NQO1 and Hsp70 were significantly lower in animals treated with MLT(P<0.001).CONCLUSION When administered to rats with BDL-induced secondary biliary cirrhosis,MLT effectively restored the evaluated parameters.展开更多
AIM: To examine the ability of cyclin-dependent kinase inhibitor (CDKI) roscovitine (Rosco) to enhance the antitumor effects of conventional chemotherapeutic agents acting by different mechanisms against human colorec...AIM: To examine the ability of cyclin-dependent kinase inhibitor (CDKI) roscovitine (Rosco) to enhance the antitumor effects of conventional chemotherapeutic agents acting by different mechanisms against human colorectal cancer. METHODS: Human colorectal cancer cells were treat-ed, individually and in combination, with Rosco, taxol, 5-Fluorouracil (5-FU), doxorubicine or vinblastine. The antiproliferative effects and the type of interaction of Rosco with tested chemotherapeutic drugs were de-termined. Cell cycle alterations were investigated by fluorescence-activated cell sorter FACS analysis. Apop-tosis was determined by DNA fragmentation assay. RESULTS: Rosco inhibited the proliferation of tumor cells in a time-and dose-dependent manner. The ef-ficacies of all tested chemotherapeutic drugs were markedly enhanced 3.0-8.42 × 103 and 130-5.28 × 103 fold in combination with 5 and 10 μg/mL Rosco, re-spectively. The combination of Rosco and chemothera-peutic drugs inhibited the growth of human colorectal cancer cells in an additive or synergistic fashion, and in a time and dose dependent manner. Rosco induced apoptosis and synergized with tested chemothera-peutic drugs to induce efficient apoptosis in human colorectal cancer cells. Sequential, inverted sequential and simultaneous treatment of cancer cells with combi-nations of chemotherapeutic drugs and Rosco arrested the growth of human colorectal cancer cells at various phases of the cell cycle as follows: Taxol/Rosco (G2/M-and S-phases), 5-FU/Rosco (S-phase), Dox/Rosco (S-phase) and Vinb/Rosco (G2/M-and S-phases). CONCLUSION: Since the eff icacy of many anticancer drugs depends on their ability to induce apoptotic cell death, modulation of this parameter by cell cycle inhibi-tors may provide a novel chemo-preventive and chemo-therapeutic strategy for human colorectal cancer.展开更多
There has been a need for rapid detection of Avian Influenza virus (AIV) H5N1 due to it being a potential pandemic threat. Most of the current methods, including culture isolation and PCR, are very sensitive and speci...There has been a need for rapid detection of Avian Influenza virus (AIV) H5N1 due to it being a potential pandemic threat. Most of the current methods, including culture isolation and PCR, are very sensitive and specific but require specialized laboratories and trained personnel in order to complete the tests and are time-consuming. The goal of this study was to design a biosensor that would be able to rapidly detect AIV H5N1 using aptamers as biosensing material and a quartz crystal microbalance (QCM) for transducing method. Specific DNA aptamers against AIV H5N1 were immobilized, through biotin and streptavidin conjugation, onto the gold surface of QCM sensor to capture the target virus. Magnetic nanobeads (150 nm in diameter) were then added as amplifiers considering its large surface/volume ratio which allows for faster movement and a higher target molecule binding rate. The result showed that the captured AIV caused frequency change, and more change was observed when the AIV concentration increased. The nanobead amplification was effective at the lower concentrations of AIV, however, it was not significant when the AIV concentration was 1 HA or higher. The detection limit of the aptasensor was 1 HAU with a detection time of 1 h. The capture of the target virus on to the surface of QCM sensor and the binding of magnetic nanobeads with the virus was confirmed with electron microscopy. Aptamers have unlimited shelf life and are temperature stable which allows this aptasensor to give much more consistent results specifically for in field applications.展开更多
In this study,we hypothesized that Piezo 1 channels mediate the compression-enhanced invasive phenotype of cancer cells via a caveolae-dependent mechanism.To test this hypothesis,we examined in vitro cultured human br...In this study,we hypothesized that Piezo 1 channels mediate the compression-enhanced invasive phenotype of cancer cells via a caveolae-dependent mechanism.To test this hypothesis,we examined in vitro cultured human breast cancer cells for their ability to invade and degrade extracellular matrix in the presence or absence of compressive stress,together with corresponding changes in Piezo1 as well as cytoskeletal remodeling and calcium signaling.Here we show that compressive stress enhanced invasion,matrix degradation,and invadopodia formation of breast cancer cells.We further identified Piezo1 as the putative mechanosensitive cellular component that transmits compression to induce calcium influx,which in turn triggers several downstream pathways.Interestingly,for the first time we observed inv-adopodia with matrix degradation ability on the apical side of the cells, similar to those commonly observed at the cell s ventral side.Furthermore,we demonstrate that Piezo1 and caveolae were both involved in mediating the compressive stress-induced cancer cell invasive phenotype as Piezo 1 and caveolae were often colocalized,and reduction of Cav-1 expression or disruption of caveolae with methyl-β-cyclodextrin led to not only reduced Piezo1 expression but also attenuation of the invasive phenotypes promoted by compressive stress.Taken together,we first observed that in breast cancer cells,simulating uncontrolled growth-induced compressive stress enhanced cancer cell invasion,matrix degradation,and invadopodia and stress fiber formation.Our study also confirmed that Piezo1 channels are highly expressed in breast cancer cells compared to normal breast cells,and is consistent with the data that compressive stress regulates cell migration of breast cancer cells but not normal breast cells.Additionally,we identified that Piezol mediated these processes and the invasive phenotypes also depended on the integrity of caveolae.These findings provide the first demonstration that compressive stress enhances matrix degradation by breast cancer cells and Piezo1 is an essential mechanosensor and transducer for such stress in breast cancer.Additionally,our data supports the model where caveolae might be the'mechanical force foci'which concentrates Piezol to facilitate force sensing and transduction in mammalian cells.Our work may have relevance to human tumors in vivo.As solid tumor experiences high compressive stress due to uncontrolled proliferation and confinement by the stiff extracellular matrix environment,this microenvironment facilitates compression-enhanced cell invasion.The identification of Piezo1’s crucial role in this process provides the first demonstration of the dependence of Piezo1 channels on the response of breast cancer cells to physiological compressive stress.The functional dependence of Piezo1 on caveolae further highlights the importance of membrane organization and composition on forcegated ion channels.Both of these findings underscore the cardinal role that Piezo1 channels play in regulating cell invasion and may inspire further development targeting Piezol as a potential cancer therapeutic target.展开更多
Laryngeal squamous cell carcinoma(LSCC) remains a highly morbid and fatal disease. Historically, it has been a model example for organ preservation and treatment stratification paradigms. Unfortunately, survival for L...Laryngeal squamous cell carcinoma(LSCC) remains a highly morbid and fatal disease. Historically, it has been a model example for organ preservation and treatment stratification paradigms. Unfortunately, survival for LSCC has stagnated over the past few decades. As the era of next-generation sequencing and personalized treatment for cancer approaches, LSCC may be an ideal disease for consideration of further treatment stratification and personalization. Here, we will discuss the important history of LSCC as a model system for organ preservation, unique and potentially targetable genetic signatures of LSCC, and methods for bringing stratified, personalized treatment strategies to the 21^(st) century.展开更多
Objective:To study the inhibitory effect of rice bran extracts of Thai black Kam Muang and red Hawm Dawk Mali Deang on oxidative stress factors including superoxide(O2·-),nitric oxide(NO·),and inducible nitr...Objective:To study the inhibitory effect of rice bran extracts of Thai black Kam Muang and red Hawm Dawk Mali Deang on oxidative stress factors including superoxide(O2·-),nitric oxide(NO·),and inducible nitric oxide synthase(iNOS).Methods:Bran extracts(40%ethanol)of Kam Muang and Hawm Dawk Mali Deang were obtained and evaluated for in vitro 2-2′-azino-di-(3-ethylbenzthiazoline sulfonate)(ABTS)and NO·scavenging activity.Their inhibitory effects on cellular O2·-and NO·were measured in phorbol 12-myristate 13-acetate-stimulated neutrophil-like HL-60 cells and lipopolysaccharidestimulated RAW264.7 macrophages,respectively,and their viability was monitored using the MTT assay.The effect on iNOS expression was also assessed by the Western blotting assay.Total contents of phenolics,flavonoids,and subtypes were also determined.Results:Hawm Dawk Mali Deang exhibited about 3.5-fold greater cellular O2·-inhibitory activity than Kam Muang[EC50 values of(23.57±4.54)and(81.98±1.45)μg/mL,respectively]in phorbol 12-myristate 13-acetate-stimulated HL-60 cells.Hawm Dawk Mali Deang exhibited about 2-fold higher in vitro ABTS·+and NO·scavenging activity than Kam Muang,but it exerted cellular NO·inhibitory activity of only about 26%(undetermined EC50 value)in lipopolysaccharide-stimulated RAW264.7 cells.Conversely,Kam Muang exerted potent cellular NO·inhibitory activity[EC50 value:(281.13±59.18)μg/mL]and dose-dependently decreased iNOS levels.No cytotoxicity of both extracts was detected in both cell types.As for corresponding contents,Hawm Dawk Mali Deang contained higher contents of phenolics and flavonoids than Kam Muang.Moreover,Kam Muang and Hawm Dawk Mali Deang had a high content of total anthocyanins[(14.73±0.52)mg C3GE/g of extract]and total proanthocyanidins[(115.13±1.47)mg CE/g of extract],respectively.Conclusions:Based on these data,bran extracts of Thai black Kam Muang and red rice Hawm Dawk Mali Deang can help lower oxidative stress and inflammation attributed partly to O2·-and NO·.展开更多
Pluripotent cellular models have shown great promise in the study of a number of neurological disorders. Several advantages of using a stem cell model include the potential for cells to derive disease relevant neurona...Pluripotent cellular models have shown great promise in the study of a number of neurological disorders. Several advantages of using a stem cell model include the potential for cells to derive disease relevant neuronal cell types, providing a system for researchers to monitor disease progression during neurogenesis, along with serving as a platform for drug discovery. A number of stem cell derived models have been employed to establish in ~,itro research models of Huntington＇s disease that can be used to investigate cellular pathology and screen lk^r drug and cell-based therapies. Although some progress has been made, there are a number of challenges and limitations that must be overcome before the true potential of this research strategy is achieved. In this article we review current stem cell models that have been reported, as well as discuss the issues that impair these studies. We also highlight the prospective application of Huntington＇s disease stem cell models in the development of novel therapeutic strategies and advancement of personalized medicine.展开更多
Therapy resistance is a significant challenge for prostate cancer treatment in clinic. Although targeted therapies such as androgen deprivation and androgen receptor (AR) inhibition are effective initially, tumor cell...Therapy resistance is a significant challenge for prostate cancer treatment in clinic. Although targeted therapies such as androgen deprivation and androgen receptor (AR) inhibition are effective initially, tumor cells eventually evade these strategies through multiple mechanisms. Lineage reprogramming in response to hormone therapy represents a key mechanism that is increasingly observed. The studies in this area have revealed specific combinations of alterations present in adenocarcinomas that provide cells with the ability to transdifferentiate and perpetuate AR-independent tumor growth after androgen-based therapies. Interestingly, several master regulators have been identified that drive plasticity, some of which also play key roles during development and differentiation of the cell lineages in the normal prostate. Thus, further study of each AR-independent tumor type and understanding underlying mechanisms are warranted to develop combinational therapies that combat lineage plasticity in prostate cancer.展开更多
Promoting better protein digestibility through exogenous enzymes in the diet is essential in the nutrition of companion animals, mainly for better performance and maintenance of the animals’ physiological and metabol...Promoting better protein digestibility through exogenous enzymes in the diet is essential in the nutrition of companion animals, mainly for better performance and maintenance of the animals’ physiological and metabolic systems, promoting health and adequate growth. In addition, it reduces the cost of the diet by possibly reducing protein in the diet, which is the main and most expensive ingredient for dogs and cats. The objective of this study was to verify whether the addition of protease to dog and cat food can improve the protein digestibility of the food, thus facilitating greater absorption of amino acids and influencing metabolic biomarkers and immune response. To this end, two experiments were carried out to evaluate the protease from the fermentation of Aspergillus niger and Bacillus subtilis. Experiment 1 was carried out with ten male, non-castrated beagles divided into two groups of five animals: the control group (without enzyme) and the test group (with 250 g of protease/ton). The animals underwent two 45-day experimental periods, and in the second period, after a 15-day interval, the dogs in the control group became part of the treatment group (crossover model). Adding this enzyme to the dogs’ diet had no adverse effects on the animals’ health besides improving the digestibility of dry matter and crude protein consumed by the dogs. Experiment 2 was carried out with sixteen female cats of no defined breed, non-castrated, divided into four groups with four animals per group, namely: Treatment A (without enzyme), Treatment B (with protease at a dose of 100 g/ton), Treatment C (with protease at a dose of 200 g/ton) and Treatment D (with protease at a dose of 400 g/ton). The cats underwent two 30-day experimental periods, and in the second period, after a 15-day interval, the animals switched between treatments (crossover model) to increase the power of the statistical test. The enzyme consumption did not affect the felines’ metabolism and health but improved the digestibility of crude protein at doses of 200 and 400 g/ton. The results allow us to conclude that the protease used in this study can improve the digestibility of crude protein for dogs and cats.展开更多
AIM： To study the effects of adeno-associated virus （AAV） delivered short hairpin RNAs （shRNAs） on adult CD-1 mouse cochlea damaged by aminoglycoside anti-biotic kanamycin. METHODS： Three different shRNAs were d...AIM： To study the effects of adeno-associated virus （AAV） delivered short hairpin RNAs （shRNAs） on adult CD-1 mouse cochlea damaged by aminoglycoside anti-biotic kanamycin. METHODS： Three different shRNAs were designed （p27^Kip1, p53 and p27^Kip1＋p53） and tested in COS cells. A total of 20 adult CD-1 mice were used in the experiment. Mice were divided into fve different groups （four animals/group） depending on the AAV-shRNA construct they received and whether they received kanamycin or not. Saline and AAV-EGFP injected animals were used as controls. All constructs were injected through the round window membrane （RWM） into the cochlea. Cochleae were harvested after 1 mo. Apoptosis was detected with Tunel labeling from paraffin-embedded cochlear tissue sections.RESULTS： AAV2/2-p27^Kip1-shRNA and AAV2/2-p53-shRNA were tested in COS cells. Western blotting analysis confirmed that both constructs silenced their target genes effectively in the cell culture. AAV2/2-shRNA constructs were injected into the cochlea of CD-1 mice through the intact RWM. Cotransductionof Cotransduction of individual AAV2/2-shRNAs with AAV2/2-EGFP resulted in EGFP expression in the organ of Corti.Kanamycin Kanamycin treatment had no effect on the expression pattern of the EGFP. AAV2/2-shRNA treated mice （either with p53 or p27Kip1and p53 together） showed fewer apop-totic hair cells in the cochlea than the control group （P 〈 0.05; AAV2/2-p53-shRNA vs saline P = 0.00014; AAV2/2-p27＋p53-shRNA vs saline P = 0.0011）. AAV2/2-p27-shRNA injected cochleae showed no significant difference in the number of apoptotic cells when compared to the saline injected cochleae.CONCLUSION： Silencing of p53 protein in the kana-mycin treated ears may decrease cell death in the organ of Corti.展开更多
Background:Rods and cones are critical for light detection.Although there has been considerable work done in elucidating the molecular mechanisms involved in rod development,not much is known about how the cone cell f...Background:Rods and cones are critical for light detection.Although there has been considerable work done in elucidating the molecular mechanisms involved in rod development,not much is known about how the cone cell fate decision is made by the multipotent retinal progenitor cells during development.Analysis of the promoter regions of Nrl and trβ2,rod and cone differentiation factors respectively,revealed DNA binding motifs of two POU-domain containing transcription factors,Pou2f1 and Pou2f2.Preliminary experiments showed that Pou2f1/2 are expressed during the peak of cone genesis in the embryonic retina.Therefore,we hypothesize that Pou2f1/2 specify cone cell fate in the developing retina.Methods:We used immunofluorescence and in situ hybridization to establish the spatiotemporal expression of Pou2f1/2 during retinogenesis.We performed in vivo electroporation in post-natal mice to misexpress Pou2f1/2 and used antibodies specific to proteins expressed in cones such as Rxrγand S-opsin to count cones.Using ex vivo electroporation of embryonic retinal explants,we knocked out Pou2f1 and Pou2f2 using CRISPR/Cas9 gRNAs at the peak of cone production window.Finally,we transfected post-natal retinal explants with a combination of regulatory elements of Nrl or thrb with control backbone vector,Pou2f1 or Pou2f2 using electroporation.Results:We found that Pou2f1/2 are expressed in retinal progenitor cells in the developing retina and subsequently in the differentiated cones.Pou2f1/2 misexpression outside the cone genesis window led to an increase in cones at the expense of rods.Pou2f1/2 indel knockouts generated by CRISPR/Cas9 gRNAs led to a decrease in cones and a converse increase in rods.Finally,we found that Pou2f1/2 activate the cis-regulatory module(CRM)of the thrb gene and repress the activity of the CRM of Nrl.Conclusions:These results uncover novel players that establish the complex gene regulatory network for cone photoreceptor fate specification in the retinal progenitor cells.We anticipate that this work should help us devise improved replacement therapies in the future utilizing stem cells for retinal degenerative diseases such as aged-related macular degeneration(AMD)and Stargardt’s disease.展开更多
The somatic epigenome can be reprogrammed to a pluri-potent state by a combination of transcription factors.Altering cell fate involves transcription factors coopera-tion,epigenetic reconfi guration,such as DNA methyl...The somatic epigenome can be reprogrammed to a pluri-potent state by a combination of transcription factors.Altering cell fate involves transcription factors coopera-tion,epigenetic reconfi guration,such as DNA methylation and histone modification,posttranscriptional regulation by microRNAs,and so on.Nevertheless,such reprogram-ming is inefficient.Evidence suggests that during the early stage of reprogramming,the process is stochastic,but by the late stage,it is deterministic.In addition to con-ventional reprogramming methods,dozens of small mol-ecules have been identifi ed that can functionally replace reprogramming factors and signifi cantly improve induced pluripotent stem cell(iPSC)reprogramming.Indeed,iPS cells have been created recently using chemical com-pounds only.iPSCs are thought to display subtle genetic and epigenetic variability;this variability is not random,but occurs at hotspots across the genome.Here we dis-cuss the progress and current perspectives in the fi eld.Research into the reprogramming process today will pave the way for great advances in regenerative medicine in the future.展开更多
The immune system is the body's main cancer surveillance system.Unlike surgery,radiation,and chemotherapy,which are typically nonspecific,cancer immunotherapy holds tremendous promise as it harnesses the high spec...The immune system is the body's main cancer surveillance system.Unlike surgery,radiation,and chemotherapy,which are typically nonspecific,cancer immunotherapy holds tremendous promise as it harnesses the high specificity of a person's immune system to kill cancer cells selectively.This promising approach includes checkpoint inhibitors,chimeric antigen receptor (CAR)-T cell therapy,cancer vaccines,cytokines,and monoclonal antibodies,among others.Cancer immunotherapy has progressed tremendously,resulting from basic science discoveries in the molecular and cellular biology of T cells.展开更多
Background Patients intoxicated at the time of burn experience increased rates of sepsis and death compared with that observed in similarly sized burns alone.We sought to characterise changes in the intestinal microbi...Background Patients intoxicated at the time of burn experience increased rates of sepsis and death compared with that observed in similarly sized burns alone.We sought to characterise changes in the intestinal microbiome and short-chain fatty acids(SCFAs)following alcohol intoxication and burn injury and to determine whether these changes are associated with intestinal inflammation.Methods 10–12-week-old C57BL/6 male and female mice were subjected to ethanol intoxication and a 12.5%total body surface area scald burn injury.The following day,mice were euthanised and faecal contents from the caecum and small intestine(SI)were harvested for 16S sequencing for microbial analysis and caecum contents underwent high-performance liquid chromatography mass spectroscopy to assess SCFAs.Results The intestinal microbiome of ethanol burn(EB)mice exhibited decreased alpha diversity and distinct beta diversity compared with sham vehicle(SV).EB faeces were marked by increased Proteobacteria and many pathobionts.EB caecum faeces exhibited a significant decrease in butyrate and a downward trend in acetate and total SCFAs.SCFA changes correlated with microbial changes particularly in the SI.Treatment of murine duodenal cell clone-K(MODE-K)cells with faecal slurries led to upregulation of interleukin-6(IL-6)from EB faeces compared with SV faeces which correlated with levels of Enterobacteriaceae.However,supplementation of butyrate reduced faecal slurry-induced MODE-K cells IL-6 release.Conclusion Together,these findings suggest that alcohol and burn injury induce bacterial dysbiosis and a decrease in SCFAs,which together can promote intestinal inflammation and barrier disruption,predisposing to postinjury pathology.展开更多
为了探索包含SH-2功能域的蛋白酪氨酸磷酸酶(SH-2-containing protein tyrosine phosphatase1,SHP-1)在IL-4诱导的IL-4受体(IL-4receptor,IL-4R)表达中的作用,用Na3VO4处理野生型(wildtype,WT)实验小鼠的脾脏细胞以及用IL-4刺激可育Moth...为了探索包含SH-2功能域的蛋白酪氨酸磷酸酶(SH-2-containing protein tyrosine phosphatase1,SHP-1)在IL-4诱导的IL-4受体(IL-4receptor,IL-4R)表达中的作用,用Na3VO4处理野生型(wildtype,WT)实验小鼠的脾脏细胞以及用IL-4刺激可育Motheaten小鼠(viable motheatenmice,mev/mev)的脾脏细胞,并检测IL-4RαmRNA的表达.我们发现IL-4诱导的IL-4RαmRNA表达在经Na3VO4处理后野生型小鼠的脾脏细胞以及用IL-4刺激的mev/mev小鼠的脾脏细胞中降低了.结果表明,IL-4诱导的IL-4RαmRNA表达的降低是由于IL-4R的低水平表达导致的STAT6信号转导缺陷.实验进一步证实,在mev/mev小鼠的脾脏细胞中IL-4Rα蛋白表达的降低是由于细胞组成的改变.在mev/mev小鼠脾脏组织中,表达相对高水平IL-4R的CD4+,CD8+和CD19+的细胞比例显著下降,相反表达低水平IL-4R的Mac-1+和Gr-1+细胞比例明显升高.尽管IL-4R蛋白表达是明显下降的,但在同窝对照小鼠(+/?)和mev/mev小鼠的脾脏细胞中IL-4RαmRNA的表达未发现明显的差异.在B细胞、T细胞和巨噬细胞中也没有显著差异.这提示在巨噬细胞中IL-4R表达细胞类型特异性下调是通过转录后水平的调控来实现的.研究结果提示,在脾脏细胞中SHP-1对于IL-4诱导的IL-4R表达是必需的,并且通过影响血细胞生成而间接地调控相应的功能.展开更多
Growth-defense tradeoffs are thought to occur in plants due to resource restrictions, which demand prior- itization towards either growth or defense, depending on external and internal factors. These tradeoffs have pr...Growth-defense tradeoffs are thought to occur in plants due to resource restrictions, which demand prior- itization towards either growth or defense, depending on external and internal factors. These tradeoffs have profound implications in agriculture and natural ecosystems, as both processes are vital for plant survival, reproduction, and, ulti- mately, plant fitness. While many of the molecular mechanisms underlying growth and defense tradeoffs remain to be elucidated, hormone crosstalk has emerged as a major player in regulating tradeoffs needed to achieve a balance. In this review, we cover recent advances in understanding growth-defense tradeoffs in plants as well as what is known regard- ing the underlying molecular mechanisms. Specifically, we address evidence supporting the growth-defense tradeoff concept, as well as known interactions between defense signaling and growth signaling. Understanding the molecular basis of these tradeoffs in plants should provide a foundation for the development of breeding strategies that optimize the growth-defense balance to maximize crop yield to meet rising global food and biofuel demands.展开更多
The TP53 gene is well known to be the most frequently mutated gene in human cancer.In addition to mutations,there are > 20 different coding region single-nucleotide polymorphisms (SNPs) in the TP53 gene,as well as ...The TP53 gene is well known to be the most frequently mutated gene in human cancer.In addition to mutations,there are > 20 different coding region single-nucleotide polymorphisms (SNPs) in the TP53 gene,as well as SNPs in MDM2,the negative regulator of p53.Several of these SNPs are known to alter p53 pathway function.This makes p53 rather unique among cancer-critical genes,e.g.the coding regions of other cancer-critical genes like Ha-Ras,RB,and PI3KCA do not have non-synonymous coding region SNPs that alter their function in cancer.The next frontier in p53 biology will consist of probing which of these coding region SNPs are moderately or strongly pathogenic and whether they influence cancer risk and the efficacy of cancer therapy.The challenge after that will consist of determining whether we can tailor chemotherapy to correct the defects for each ofthese variants.Here we review the SNPs in TP53 and MDM2 that show the most significant impact on cancer and other diseases.We also propose avenues for how this information can be used to better inform personalized medicine approaches to cancer and other diseases.展开更多
文摘Muscle fibers are multinucleated,and muscle fiber nuclei(myonuclei)are believed to be post-mitotic and are typically situated near the periphery of the myofiber.Due to the unique organization of muscle fibers and their nuclei,the cellular and molecular mechanisms regulating myofiber homeostasis in unstressed and stressed conditions(e.g.,exercise)are unique.A key role myonuclei play in regulating muscle during exercise is gene transcription.Only recently have investigators had the capability to identify molecular changes at high resolution exclusively in myonuclei in response to perturbations in vivo.The purpose of this review is to describe how myonuclei modulate their transcriptome,epigenetic status,mobility and shape,and microRNA expression in response to exercise in vivo.Given the relative paucity of high-fidelity information on myonucleus-specific contributions to exercise adaptation,we identify specific gaps in knowledge and provide perspectives on future directions of research.
基金supported by the Fundamental Research Funds for the Central Universities(No.226-2024-00038),China.
文摘The internal structures of cells as the basic units of life are a major wonder of the microscopic world.Cellular images provide an intriguing window to help explore and understand the composition and function of these structures.Scientific imagery combined with artistic expression can further expand the potential of imaging in educational dissemination and interdisciplinary applications.
基金supported by USDA-ARS National Program NP301 project "Response of Diverse Rice Germplasm to Biotic and Abiotic Stresses Project No. 6225-21000-008-00D"
基金Supported by Fundo de IncentivoàPesquisa e Eventos(FIPE).
文摘BACKGROUND Cirrhosis is an important health problem characterized by a significant change in liver parenchyma.In animals,this can be reproduced by an experimental model of bile duct ligation(BDL).Melatonin(MLT)is a physiological hormone synthesized from serotonin that has been studied for its beneficial properties,including its antioxidant potential.AIM To evaluate MLT’s effects on oxidative stress,the inflammatory process,and DNA damage in an experimental model of secondary biliary cirrhosis.METHODS Male Wistar rats were divided into 4 groups:Control(CO),CO+MLT,BDL,and BDL+MLT.MLT was administered(20 mg/kg)daily beginning on day 15 after biliary obstruction.On day 29 the animals were killed.Blood samples,liver tissue,and bone marrow were collected for further analysis.RESULTS BDL caused changes in biochemical and histological parameters and markers of inflammatory process.Thiobarbituric acid(0.46±0.01)reactive substance levels,superoxide dismutase activity(2.30±0.07)and nitric oxide levels(2.48±0.36)were significantly lower(P<0.001)n the groups that received MLT.DNA damage was also lower(P<0.001)in MLT-treated groups(171.6±32.9)than the BDL-only group(295.5±34.8).Tissue damage and the expression of nuclear factor kappa B,interleukin-1β,Nrf2,NQO1 and Hsp70 were significantly lower in animals treated with MLT(P<0.001).CONCLUSION When administered to rats with BDL-induced secondary biliary cirrhosis,MLT effectively restored the evaluated parameters.
文摘AIM: To examine the ability of cyclin-dependent kinase inhibitor (CDKI) roscovitine (Rosco) to enhance the antitumor effects of conventional chemotherapeutic agents acting by different mechanisms against human colorectal cancer. METHODS: Human colorectal cancer cells were treat-ed, individually and in combination, with Rosco, taxol, 5-Fluorouracil (5-FU), doxorubicine or vinblastine. The antiproliferative effects and the type of interaction of Rosco with tested chemotherapeutic drugs were de-termined. Cell cycle alterations were investigated by fluorescence-activated cell sorter FACS analysis. Apop-tosis was determined by DNA fragmentation assay. RESULTS: Rosco inhibited the proliferation of tumor cells in a time-and dose-dependent manner. The ef-ficacies of all tested chemotherapeutic drugs were markedly enhanced 3.0-8.42 × 103 and 130-5.28 × 103 fold in combination with 5 and 10 μg/mL Rosco, re-spectively. The combination of Rosco and chemothera-peutic drugs inhibited the growth of human colorectal cancer cells in an additive or synergistic fashion, and in a time and dose dependent manner. Rosco induced apoptosis and synergized with tested chemothera-peutic drugs to induce efficient apoptosis in human colorectal cancer cells. Sequential, inverted sequential and simultaneous treatment of cancer cells with combi-nations of chemotherapeutic drugs and Rosco arrested the growth of human colorectal cancer cells at various phases of the cell cycle as follows: Taxol/Rosco (G2/M-and S-phases), 5-FU/Rosco (S-phase), Dox/Rosco (S-phase) and Vinb/Rosco (G2/M-and S-phases). CONCLUSION: Since the eff icacy of many anticancer drugs depends on their ability to induce apoptotic cell death, modulation of this parameter by cell cycle inhibi-tors may provide a novel chemo-preventive and chemo-therapeutic strategy for human colorectal cancer.
文摘There has been a need for rapid detection of Avian Influenza virus (AIV) H5N1 due to it being a potential pandemic threat. Most of the current methods, including culture isolation and PCR, are very sensitive and specific but require specialized laboratories and trained personnel in order to complete the tests and are time-consuming. The goal of this study was to design a biosensor that would be able to rapidly detect AIV H5N1 using aptamers as biosensing material and a quartz crystal microbalance (QCM) for transducing method. Specific DNA aptamers against AIV H5N1 were immobilized, through biotin and streptavidin conjugation, onto the gold surface of QCM sensor to capture the target virus. Magnetic nanobeads (150 nm in diameter) were then added as amplifiers considering its large surface/volume ratio which allows for faster movement and a higher target molecule binding rate. The result showed that the captured AIV caused frequency change, and more change was observed when the AIV concentration increased. The nanobead amplification was effective at the lower concentrations of AIV, however, it was not significant when the AIV concentration was 1 HA or higher. The detection limit of the aptasensor was 1 HAU with a detection time of 1 h. The capture of the target virus on to the surface of QCM sensor and the binding of magnetic nanobeads with the virus was confirmed with electron microscopy. Aptamers have unlimited shelf life and are temperature stable which allows this aptasensor to give much more consistent results specifically for in field applications.
基金supported by Key Program of NSF of China ( 11532003) to L.D.NSF-MCB 1561794 to A.P.L.
文摘In this study,we hypothesized that Piezo 1 channels mediate the compression-enhanced invasive phenotype of cancer cells via a caveolae-dependent mechanism.To test this hypothesis,we examined in vitro cultured human breast cancer cells for their ability to invade and degrade extracellular matrix in the presence or absence of compressive stress,together with corresponding changes in Piezo1 as well as cytoskeletal remodeling and calcium signaling.Here we show that compressive stress enhanced invasion,matrix degradation,and invadopodia formation of breast cancer cells.We further identified Piezo1 as the putative mechanosensitive cellular component that transmits compression to induce calcium influx,which in turn triggers several downstream pathways.Interestingly,for the first time we observed inv-adopodia with matrix degradation ability on the apical side of the cells, similar to those commonly observed at the cell s ventral side.Furthermore,we demonstrate that Piezo1 and caveolae were both involved in mediating the compressive stress-induced cancer cell invasive phenotype as Piezo 1 and caveolae were often colocalized,and reduction of Cav-1 expression or disruption of caveolae with methyl-β-cyclodextrin led to not only reduced Piezo1 expression but also attenuation of the invasive phenotypes promoted by compressive stress.Taken together,we first observed that in breast cancer cells,simulating uncontrolled growth-induced compressive stress enhanced cancer cell invasion,matrix degradation,and invadopodia and stress fiber formation.Our study also confirmed that Piezo1 channels are highly expressed in breast cancer cells compared to normal breast cells,and is consistent with the data that compressive stress regulates cell migration of breast cancer cells but not normal breast cells.Additionally,we identified that Piezol mediated these processes and the invasive phenotypes also depended on the integrity of caveolae.These findings provide the first demonstration that compressive stress enhances matrix degradation by breast cancer cells and Piezo1 is an essential mechanosensor and transducer for such stress in breast cancer.Additionally,our data supports the model where caveolae might be the'mechanical force foci'which concentrates Piezol to facilitate force sensing and transduction in mammalian cells.Our work may have relevance to human tumors in vivo.As solid tumor experiences high compressive stress due to uncontrolled proliferation and confinement by the stiff extracellular matrix environment,this microenvironment facilitates compression-enhanced cell invasion.The identification of Piezo1’s crucial role in this process provides the first demonstration of the dependence of Piezo1 channels on the response of breast cancer cells to physiological compressive stress.The functional dependence of Piezo1 on caveolae further highlights the importance of membrane organization and composition on forcegated ion channels.Both of these findings underscore the cardinal role that Piezo1 channels play in regulating cell invasion and may inspire further development targeting Piezol as a potential cancer therapeutic target.
基金J. Chad Brenner received funding from NIH (Grants No. U01DE025184 and P30: CA046592 S1)Andrew C. Birkeland and Rebecca Hoesli received support from University of Michigan Otolaryngology Resident Research (Grant No. T32DC005356)Megan L. Ludwig was supported by NIH (Grant No. T-32-GM007315)
文摘Laryngeal squamous cell carcinoma(LSCC) remains a highly morbid and fatal disease. Historically, it has been a model example for organ preservation and treatment stratification paradigms. Unfortunately, survival for LSCC has stagnated over the past few decades. As the era of next-generation sequencing and personalized treatment for cancer approaches, LSCC may be an ideal disease for consideration of further treatment stratification and personalization. Here, we will discuss the important history of LSCC as a model system for organ preservation, unique and potentially targetable genetic signatures of LSCC, and methods for bringing stratified, personalized treatment strategies to the 21^(st) century.
基金supported by the National Research Council of Thailand and the Faculty of Medicine,Thammasat University
文摘Objective:To study the inhibitory effect of rice bran extracts of Thai black Kam Muang and red Hawm Dawk Mali Deang on oxidative stress factors including superoxide(O2·-),nitric oxide(NO·),and inducible nitric oxide synthase(iNOS).Methods:Bran extracts(40%ethanol)of Kam Muang and Hawm Dawk Mali Deang were obtained and evaluated for in vitro 2-2′-azino-di-(3-ethylbenzthiazoline sulfonate)(ABTS)and NO·scavenging activity.Their inhibitory effects on cellular O2·-and NO·were measured in phorbol 12-myristate 13-acetate-stimulated neutrophil-like HL-60 cells and lipopolysaccharidestimulated RAW264.7 macrophages,respectively,and their viability was monitored using the MTT assay.The effect on iNOS expression was also assessed by the Western blotting assay.Total contents of phenolics,flavonoids,and subtypes were also determined.Results:Hawm Dawk Mali Deang exhibited about 3.5-fold greater cellular O2·-inhibitory activity than Kam Muang[EC50 values of(23.57±4.54)and(81.98±1.45)μg/mL,respectively]in phorbol 12-myristate 13-acetate-stimulated HL-60 cells.Hawm Dawk Mali Deang exhibited about 2-fold higher in vitro ABTS·+and NO·scavenging activity than Kam Muang,but it exerted cellular NO·inhibitory activity of only about 26%(undetermined EC50 value)in lipopolysaccharide-stimulated RAW264.7 cells.Conversely,Kam Muang exerted potent cellular NO·inhibitory activity[EC50 value:(281.13±59.18)μg/mL]and dose-dependently decreased iNOS levels.No cytotoxicity of both extracts was detected in both cell types.As for corresponding contents,Hawm Dawk Mali Deang contained higher contents of phenolics and flavonoids than Kam Muang.Moreover,Kam Muang and Hawm Dawk Mali Deang had a high content of total anthocyanins[(14.73±0.52)mg C3GE/g of extract]and total proanthocyanidins[(115.13±1.47)mg CE/g of extract],respectively.Conclusions:Based on these data,bran extracts of Thai black Kam Muang and red rice Hawm Dawk Mali Deang can help lower oxidative stress and inflammation attributed partly to O2·-and NO·.
基金supported by the National Center for Research Resources P51RR165supported by the Office of Research and Infrastructure Program(ORIP)/OD P510D11132+1 种基金supported by the grant awarded by the ORIP/NIH(RR018827)the Atlanta Clinical and Translational Science Institute to AWSC
文摘Pluripotent cellular models have shown great promise in the study of a number of neurological disorders. Several advantages of using a stem cell model include the potential for cells to derive disease relevant neuronal cell types, providing a system for researchers to monitor disease progression during neurogenesis, along with serving as a platform for drug discovery. A number of stem cell derived models have been employed to establish in ~,itro research models of Huntington＇s disease that can be used to investigate cellular pathology and screen lk^r drug and cell-based therapies. Although some progress has been made, there are a number of challenges and limitations that must be overcome before the true potential of this research strategy is achieved. In this article we review current stem cell models that have been reported, as well as discuss the issues that impair these studies. We also highlight the prospective application of Huntington＇s disease stem cell models in the development of novel therapeutic strategies and advancement of personalized medicine.
文摘Therapy resistance is a significant challenge for prostate cancer treatment in clinic. Although targeted therapies such as androgen deprivation and androgen receptor (AR) inhibition are effective initially, tumor cells eventually evade these strategies through multiple mechanisms. Lineage reprogramming in response to hormone therapy represents a key mechanism that is increasingly observed. The studies in this area have revealed specific combinations of alterations present in adenocarcinomas that provide cells with the ability to transdifferentiate and perpetuate AR-independent tumor growth after androgen-based therapies. Interestingly, several master regulators have been identified that drive plasticity, some of which also play key roles during development and differentiation of the cell lineages in the normal prostate. Thus, further study of each AR-independent tumor type and understanding underlying mechanisms are warranted to develop combinational therapies that combat lineage plasticity in prostate cancer.
文摘Promoting better protein digestibility through exogenous enzymes in the diet is essential in the nutrition of companion animals, mainly for better performance and maintenance of the animals’ physiological and metabolic systems, promoting health and adequate growth. In addition, it reduces the cost of the diet by possibly reducing protein in the diet, which is the main and most expensive ingredient for dogs and cats. The objective of this study was to verify whether the addition of protease to dog and cat food can improve the protein digestibility of the food, thus facilitating greater absorption of amino acids and influencing metabolic biomarkers and immune response. To this end, two experiments were carried out to evaluate the protease from the fermentation of Aspergillus niger and Bacillus subtilis. Experiment 1 was carried out with ten male, non-castrated beagles divided into two groups of five animals: the control group (without enzyme) and the test group (with 250 g of protease/ton). The animals underwent two 45-day experimental periods, and in the second period, after a 15-day interval, the dogs in the control group became part of the treatment group (crossover model). Adding this enzyme to the dogs’ diet had no adverse effects on the animals’ health besides improving the digestibility of dry matter and crude protein consumed by the dogs. Experiment 2 was carried out with sixteen female cats of no defined breed, non-castrated, divided into four groups with four animals per group, namely: Treatment A (without enzyme), Treatment B (with protease at a dose of 100 g/ton), Treatment C (with protease at a dose of 200 g/ton) and Treatment D (with protease at a dose of 400 g/ton). The cats underwent two 30-day experimental periods, and in the second period, after a 15-day interval, the animals switched between treatments (crossover model) to increase the power of the statistical test. The enzyme consumption did not affect the felines’ metabolism and health but improved the digestibility of crude protein at doses of 200 and 400 g/ton. The results allow us to conclude that the protease used in this study can improve the digestibility of crude protein for dogs and cats.
基金Supported by grants fromm a Helsinki University Central Hospital Research Fundsthe Sigrid Jusélius Foundation+1 种基金the Instrumentarium Research Foundationthe Finnish Medical Foundation
文摘AIM： To study the effects of adeno-associated virus （AAV） delivered short hairpin RNAs （shRNAs） on adult CD-1 mouse cochlea damaged by aminoglycoside anti-biotic kanamycin. METHODS： Three different shRNAs were designed （p27^Kip1, p53 and p27^Kip1＋p53） and tested in COS cells. A total of 20 adult CD-1 mice were used in the experiment. Mice were divided into fve different groups （four animals/group） depending on the AAV-shRNA construct they received and whether they received kanamycin or not. Saline and AAV-EGFP injected animals were used as controls. All constructs were injected through the round window membrane （RWM） into the cochlea. Cochleae were harvested after 1 mo. Apoptosis was detected with Tunel labeling from paraffin-embedded cochlear tissue sections.RESULTS： AAV2/2-p27^Kip1-shRNA and AAV2/2-p53-shRNA were tested in COS cells. Western blotting analysis confirmed that both constructs silenced their target genes effectively in the cell culture. AAV2/2-shRNA constructs were injected into the cochlea of CD-1 mice through the intact RWM. Cotransductionof Cotransduction of individual AAV2/2-shRNAs with AAV2/2-EGFP resulted in EGFP expression in the organ of Corti.Kanamycin Kanamycin treatment had no effect on the expression pattern of the EGFP. AAV2/2-shRNA treated mice （either with p53 or p27Kip1and p53 together） showed fewer apop-totic hair cells in the cochlea than the control group （P 〈 0.05; AAV2/2-p53-shRNA vs saline P = 0.00014; AAV2/2-p27＋p53-shRNA vs saline P = 0.0011）. AAV2/2-p27-shRNA injected cochleae showed no significant difference in the number of apoptotic cells when compared to the saline injected cochleae.CONCLUSION： Silencing of p53 protein in the kana-mycin treated ears may decrease cell death in the organ of Corti.
文摘Background:Rods and cones are critical for light detection.Although there has been considerable work done in elucidating the molecular mechanisms involved in rod development,not much is known about how the cone cell fate decision is made by the multipotent retinal progenitor cells during development.Analysis of the promoter regions of Nrl and trβ2,rod and cone differentiation factors respectively,revealed DNA binding motifs of two POU-domain containing transcription factors,Pou2f1 and Pou2f2.Preliminary experiments showed that Pou2f1/2 are expressed during the peak of cone genesis in the embryonic retina.Therefore,we hypothesize that Pou2f1/2 specify cone cell fate in the developing retina.Methods:We used immunofluorescence and in situ hybridization to establish the spatiotemporal expression of Pou2f1/2 during retinogenesis.We performed in vivo electroporation in post-natal mice to misexpress Pou2f1/2 and used antibodies specific to proteins expressed in cones such as Rxrγand S-opsin to count cones.Using ex vivo electroporation of embryonic retinal explants,we knocked out Pou2f1 and Pou2f2 using CRISPR/Cas9 gRNAs at the peak of cone production window.Finally,we transfected post-natal retinal explants with a combination of regulatory elements of Nrl or thrb with control backbone vector,Pou2f1 or Pou2f2 using electroporation.Results:We found that Pou2f1/2 are expressed in retinal progenitor cells in the developing retina and subsequently in the differentiated cones.Pou2f1/2 misexpression outside the cone genesis window led to an increase in cones at the expense of rods.Pou2f1/2 indel knockouts generated by CRISPR/Cas9 gRNAs led to a decrease in cones and a converse increase in rods.Finally,we found that Pou2f1/2 activate the cis-regulatory module(CRM)of the thrb gene and repress the activity of the CRM of Nrl.Conclusions:These results uncover novel players that establish the complex gene regulatory network for cone photoreceptor fate specification in the retinal progenitor cells.We anticipate that this work should help us devise improved replacement therapies in the future utilizing stem cells for retinal degenerative diseases such as aged-related macular degeneration(AMD)and Stargardt’s disease.
基金the National Institutes of Health(NS079625 and HD073162 to P.J.).
文摘The somatic epigenome can be reprogrammed to a pluri-potent state by a combination of transcription factors.Altering cell fate involves transcription factors coopera-tion,epigenetic reconfi guration,such as DNA methylation and histone modification,posttranscriptional regulation by microRNAs,and so on.Nevertheless,such reprogram-ming is inefficient.Evidence suggests that during the early stage of reprogramming,the process is stochastic,but by the late stage,it is deterministic.In addition to con-ventional reprogramming methods,dozens of small mol-ecules have been identifi ed that can functionally replace reprogramming factors and signifi cantly improve induced pluripotent stem cell(iPSC)reprogramming.Indeed,iPS cells have been created recently using chemical com-pounds only.iPSCs are thought to display subtle genetic and epigenetic variability;this variability is not random,but occurs at hotspots across the genome.Here we dis-cuss the progress and current perspectives in the fi eld.Research into the reprogramming process today will pave the way for great advances in regenerative medicine in the future.
文摘The immune system is the body's main cancer surveillance system.Unlike surgery,radiation,and chemotherapy,which are typically nonspecific,cancer immunotherapy holds tremendous promise as it harnesses the high specificity of a person's immune system to kill cancer cells selectively.This promising approach includes checkpoint inhibitors,chimeric antigen receptor (CAR)-T cell therapy,cancer vaccines,cytokines,and monoclonal antibodies,among others.Cancer immunotherapy has progressed tremendously,resulting from basic science discoveries in the molecular and cellular biology of T cells.
基金National Institutes of Health grants,T32AA013527,R01GM128242,and F30DK123929 supported this work.
文摘Background Patients intoxicated at the time of burn experience increased rates of sepsis and death compared with that observed in similarly sized burns alone.We sought to characterise changes in the intestinal microbiome and short-chain fatty acids(SCFAs)following alcohol intoxication and burn injury and to determine whether these changes are associated with intestinal inflammation.Methods 10–12-week-old C57BL/6 male and female mice were subjected to ethanol intoxication and a 12.5%total body surface area scald burn injury.The following day,mice were euthanised and faecal contents from the caecum and small intestine(SI)were harvested for 16S sequencing for microbial analysis and caecum contents underwent high-performance liquid chromatography mass spectroscopy to assess SCFAs.Results The intestinal microbiome of ethanol burn(EB)mice exhibited decreased alpha diversity and distinct beta diversity compared with sham vehicle(SV).EB faeces were marked by increased Proteobacteria and many pathobionts.EB caecum faeces exhibited a significant decrease in butyrate and a downward trend in acetate and total SCFAs.SCFA changes correlated with microbial changes particularly in the SI.Treatment of murine duodenal cell clone-K(MODE-K)cells with faecal slurries led to upregulation of interleukin-6(IL-6)from EB faeces compared with SV faeces which correlated with levels of Enterobacteriaceae.However,supplementation of butyrate reduced faecal slurry-induced MODE-K cells IL-6 release.Conclusion Together,these findings suggest that alcohol and burn injury induce bacterial dysbiosis and a decrease in SCFAs,which together can promote intestinal inflammation and barrier disruption,predisposing to postinjury pathology.
文摘为了探索包含SH-2功能域的蛋白酪氨酸磷酸酶(SH-2-containing protein tyrosine phosphatase1,SHP-1)在IL-4诱导的IL-4受体(IL-4receptor,IL-4R)表达中的作用,用Na3VO4处理野生型(wildtype,WT)实验小鼠的脾脏细胞以及用IL-4刺激可育Motheaten小鼠(viable motheatenmice,mev/mev)的脾脏细胞,并检测IL-4RαmRNA的表达.我们发现IL-4诱导的IL-4RαmRNA表达在经Na3VO4处理后野生型小鼠的脾脏细胞以及用IL-4刺激的mev/mev小鼠的脾脏细胞中降低了.结果表明,IL-4诱导的IL-4RαmRNA表达的降低是由于IL-4R的低水平表达导致的STAT6信号转导缺陷.实验进一步证实,在mev/mev小鼠的脾脏细胞中IL-4Rα蛋白表达的降低是由于细胞组成的改变.在mev/mev小鼠脾脏组织中,表达相对高水平IL-4R的CD4+,CD8+和CD19+的细胞比例显著下降,相反表达低水平IL-4R的Mac-1+和Gr-1+细胞比例明显升高.尽管IL-4R蛋白表达是明显下降的,但在同窝对照小鼠(+/?)和mev/mev小鼠的脾脏细胞中IL-4RαmRNA的表达未发现明显的差异.在B细胞、T细胞和巨噬细胞中也没有显著差异.这提示在巨噬细胞中IL-4R表达细胞类型特异性下调是通过转录后水平的调控来实现的.研究结果提示,在脾脏细胞中SHP-1对于IL-4诱导的IL-4R表达是必需的,并且通过影响血细胞生成而间接地调控相应的功能.
文摘Growth-defense tradeoffs are thought to occur in plants due to resource restrictions, which demand prior- itization towards either growth or defense, depending on external and internal factors. These tradeoffs have profound implications in agriculture and natural ecosystems, as both processes are vital for plant survival, reproduction, and, ulti- mately, plant fitness. While many of the molecular mechanisms underlying growth and defense tradeoffs remain to be elucidated, hormone crosstalk has emerged as a major player in regulating tradeoffs needed to achieve a balance. In this review, we cover recent advances in understanding growth-defense tradeoffs in plants as well as what is known regard- ing the underlying molecular mechanisms. Specifically, we address evidence supporting the growth-defense tradeoff concept, as well as known interactions between defense signaling and growth signaling. Understanding the molecular basis of these tradeoffs in plants should provide a foundation for the development of breeding strategies that optimize the growth-defense balance to maximize crop yield to meet rising global food and biofuel demands.
文摘The TP53 gene is well known to be the most frequently mutated gene in human cancer.In addition to mutations,there are > 20 different coding region single-nucleotide polymorphisms (SNPs) in the TP53 gene,as well as SNPs in MDM2,the negative regulator of p53.Several of these SNPs are known to alter p53 pathway function.This makes p53 rather unique among cancer-critical genes,e.g.the coding regions of other cancer-critical genes like Ha-Ras,RB,and PI3KCA do not have non-synonymous coding region SNPs that alter their function in cancer.The next frontier in p53 biology will consist of probing which of these coding region SNPs are moderately or strongly pathogenic and whether they influence cancer risk and the efficacy of cancer therapy.The challenge after that will consist of determining whether we can tailor chemotherapy to correct the defects for each ofthese variants.Here we review the SNPs in TP53 and MDM2 that show the most significant impact on cancer and other diseases.We also propose avenues for how this information can be used to better inform personalized medicine approaches to cancer and other diseases.
