BACKGROUND L-type calcium channels are the only protein channels sensitive to calcium channel blockers,and are expressed in various cancer types.The Cancer Genome Atlas database shows that the mRNA levels of multiple ...BACKGROUND L-type calcium channels are the only protein channels sensitive to calcium channel blockers,and are expressed in various cancer types.The Cancer Genome Atlas database shows that the mRNA levels of multiple L-type calcium channel subunits in esophageal squamous cell carcinoma tumor tissue are significantly higher than those in normal esophageal epithelial tissue.Therefore,we hypothesized that amlodipine,a long-acting dihydropyridine L-type calcium channel blocker,may inhibit the occurrence and development of esophageal cancer(EC).AIM To investigate the inhibitory effects of amlodipine on EC through endoplasmic reticulum(ER)stress.METHODS Cav1.3 protein expression levels in 50 pairs of EC tissues and corresponding paracancerous tissues were examined.Subsequently,the inhibitory effects of amlodipine on proliferation and migration of EC cells in vitro were detected using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide and Transwell assays.In vivo experiments were performed using murine xenograft model.To elucidate the underlying mechanisms,in vitro cell studies were performed to confirm that ER stress plays a role in inhibition proliferation and migration of EC cells treated with amlodipine.RESULTS The expression level of Cav1.3 in esophageal carcinoma was 1.6 times higher than that in paracancerous tissues.Amlodipine treatment decreased the viability of esophageal carcinoma cells in a dose-and time-dependent manner.In vivo animal experiments also clearly indicated that amlodipine inhibited the growth of EC tumors in mice.Additionally,amlodipine reduces the migration of tumor cells by inhibiting epithelial-mesenchymal transition(EMT).Mechanistic studies have demonstrated that amlodipine induces ER stress-mediated apoptosis and suppresses EMT.Moreover,amlodipine-induced autophagy was characterized by an increase in autophagy lysosomes and the accumulation of light chain 3B protein.The combination of amlodipine with the ER stress inhibitor 4-phenylbutyric acid further confirmed the role of the ER stress response in amlodipine-induced apoptosis,EMT,and autophagy.Furthermore,blocking autophagy increases the ratio of apoptosis and migration.CONCLUSION Collectively,we demonstrate for the first time that amlodipine promotes apoptosis,induces autophagy,and inhibits migration through ER stress,thereby exerting anti-tumor effects in EC.展开更多
In Kuwait, the scarcity and irregularity of rainfall, the availability of areas of sand supply and the prevalence of strong north westerly winds significantly influence the stability of the fragile ecosystem. Naturall...In Kuwait, the scarcity and irregularity of rainfall, the availability of areas of sand supply and the prevalence of strong north westerly winds significantly influence the stability of the fragile ecosystem. Naturally, grown native shrubs and trees can provide potential shelter to soil surface in desert areas. To study the environmental indicators provided by native plant and their ability to improve quality of life, the morphological properties of the vegetated nabkhas within different areas in Kuwait desert and within protected area were assessed. The vegetated dunes can trap maximum mobile sediments from 10.5 to 0.45 ton thus cost saving per plant estimated to be from 5.5 to 0.24 USD. The arrangements of the native plant from highest efficiency in absorbing carbon dioxides to the least were as follows: Nitraria retusa, Haloxylon salicornicum, Citrullus colocynthis, Tamarix aucheriana, Lycium shawii, Convolvolus oxyphyllus, Rhanterium epapposum, Panicum turgidum, Calligonum polygonoides, Astragalus spinosus, Cyperus conglomerates. The cost saving of CO_(2) per year estimated to be from 0.95 to 1,542.1 USD. The revegetation enhanced physical and chemical quality of soil and created microenvironments for the flora and fauna. The aim of this paper is to identify the environmental indicators related to native plants for the assessment of quality of life.展开更多
Bacterial blight(BB),caused by Xanthomonas oryzae pathovar oryzae(Xoo),poses a significant threat to rice production,particularly in Asia and West Africa.Breeding resistance against BB in elite rice varieties is cruci...Bacterial blight(BB),caused by Xanthomonas oryzae pathovar oryzae(Xoo),poses a significant threat to rice production,particularly in Asia and West Africa.Breeding resistance against BB in elite rice varieties is crucial to advancing rice breeding program and supporting smallholder farmers.Transcription Activator-Like effectors(TALes)are key virulence factors in Xoo,with some targeting the susceptibility(S)genes such as the sugar transporter SWEET genes in rice.Among these,SWEET14 is an important S gene,with its promoter bound by the TALe TalC which exists across all sequenced African Xoo isolates.In the present study,we utilized CRISPR/Cas9-based cytidine and adenine base editors to alter the effector binding element(EBE)of TalC in the promoter of SWEET14 in rice cultivars Kitaake,IR24,and Zhonghua 11.Mutations with C to T changes in EBE led to reduced SWEET14 induction by TalC-containing Xoo strains,resulting in resistance to African Xoo isolates reliant on TalC for virulence.Conversely,A to G changes retained SWEET14 inducibility and susceptibility to Xoo in edited lines.Importantly,no off-target mutations were detected at predicted sites,and the edited lines exhibited no obvious defects in major agronomic traits in Kitaake.These results underscore the effectiveness of base editing systems for both molecular biology research and crop improvement endeavors.展开更多
Liver cancer is the sixth most common cancer and the third leading cause of cancer death worldwide.The predominant type of primary liver cancer is hepatocellular carcinoma(HCC).Tumor vascular endothelial cells(VECs),a...Liver cancer is the sixth most common cancer and the third leading cause of cancer death worldwide.The predominant type of primary liver cancer is hepatocellular carcinoma(HCC).Tumor vascular endothelial cells(VECs),a major component of cells in the microenvironment of HCC,play multifaceted roles in contributing to tumor angiogenesis,proliferation,and migration,as well as therapeutic resistance by attracting myeloid-derived suppressor cells and suppressing cytotoxic CD8 T cell differentiation and function.Recently,Wu et al reported that apatinib,an inhibitor of vascular endothelial growth factor receptor 2,can inhibit tumor VEC glycolysis by regulating phosphatidylinositol 3-kinase/protein kinase B/6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 signaling pathway to suppress HCC progression.With great interest,this editorial paper aims to review the function and key molecular signaling pathways of tumor VECs in HCC initiation and progression and summarize potential treatment options in clinical trials.展开更多
Metabolic dysfunction-associated steatotic liver disease(MASLD)is featured by the accumulation of excessive fat in the liver.It is caused by many factors,such as overweight,obesity,diabetes,and high plasma levels of s...Metabolic dysfunction-associated steatotic liver disease(MASLD)is featured by the accumulation of excessive fat in the liver.It is caused by many factors,such as overweight,obesity,diabetes,and high plasma levels of sugar,cholesterol,and triglycerides.MASLD is commonly associated with type 2 diabetes(T2D),which is characterized by a pathophysiological deficiency of insulin secretion due to impaired function of pancreatic βcells and insulin resistance.T2D has become a global pandemic that influences more than 21.7 million people worldwide.Preclinical and clinical studies have been performed to investigate molecular crosslinks between T2D and MASLD and their therapeutic strategies.Accumulating evidence has demonstrated that macrophages are cellular mediators that contribute to the progression of MASLD and T2D by impacting the resolution of inflammation.Different types of macrophages are involved in the pathogenesis of MASLD and T2D,including liver-resident macrophages or Kupffer cells,monocyte-derived macrophages,and adipose tissue macrophages.These macrophages secrete enzymes,chemokines,cytokines,as well as exosomes,to induce metabolic inflammation and insulin resistance,immune cell infiltration,and tissue injury.In this review,we provide a comprehensive summary of the molecular and cellular interactions between MASLD and T2D with a specific discussion of the critical roles of macrophages and inflammation.The underlying molecular mechanisms and the associated therapeutic targets and strategies are also reviewed.展开更多
Metabolic dysfunction-associated steatotic liver disease(MASLD)is the most common chronic liver disease,affecting more than 30%of adults and 7%-14%of youths globally.MASLD and its advanced form of metabolic dysfunctio...Metabolic dysfunction-associated steatotic liver disease(MASLD)is the most common chronic liver disease,affecting more than 30%of adults and 7%-14%of youths globally.MASLD and its advanced form of metabolic dysfunctionassociated steatohepatitis(MASH)can progress to liver cirrhosis and hepatocellular carcinoma.Despite its growing burden,effective therapies for MASLD and MASH remain limited.Accumulating evidence indicates that short-chain fatty acids(SCFAs)modulate the activation of hepatic innate and adaptive immune cells,influencing liver inflammation and fibrosis.Moreover,SCFAs modulate liver lipid and glucose metabolism and insulin sensitivity,affecting MASLD progression.This review summarizes the cellular and molecular mechanisms through which SCFAs impact liver inflammation,fibrosis,and energy metabolism.Several key molecular signaling pathways are discussed.Clinical trials aiming to modulate SCFA production through different treatments are reviewed.Collectively,emerging evidence supports that targeting SCFA-mediated function represents a promising therapeutic strategy for MASLD and MASH.展开更多
The nucleotide-binding domain,leucine-rich repeat,and pyrin domain-containing protein 3(NLRP3)inflammasome is a critical modulator in inflammatory disease.Activation and mutation of NLRP3 can cause severe inflammation...The nucleotide-binding domain,leucine-rich repeat,and pyrin domain-containing protein 3(NLRP3)inflammasome is a critical modulator in inflammatory disease.Activation and mutation of NLRP3 can cause severe inflammation in diseases such as chronic infantile neurologic cutaneous and articular syndrome,Muckle-Wells syndrome,and familial cold autoinflammatory syndrome 1.To date,a great effort has been made to decode the underlying mechanisms of NLRP3 activation.The priming and activation of NLRP3 drive the maturation and release of active interleukin(IL)-18 and IL-1βto cause inflammation and pyroptosis,which can significantly trigger many diseases including inflammatory diseases,immune disorders,metabolic diseases,and neurodegenerative diseases.The investigation of NLRP3 as a therapeutic target for disease treatment is a hot topic in both preclinical studies and clinical trials.Developing potent NLRP3 inhibitors and downstream IL-1 inhibitors attracts wide-spectrum attention in both research and pharmaceutical fields.In this minireview,we first updated the molecular mechanisms involved in NLRP3 inflammasome activation and the associated downstream signaling pathways.We then reviewed the molecular and cellular pathways of NLRP3 in many diseases,including obesity,diabetes,and other metabolic diseases.In addition,we briefly reviewed the roles of NLRP3 in cancer growth and relative immune checkpoint therapy.Finally,clinical trials with treatments targeting NLRP3 and its downstream signaling pathways were summarized.展开更多
This study aims to uncover the hormetic process of luteolin,a common dietary flavone,in neuronal cells through its role in inducing mitochondrial stress.In rat pheochromocytoma PC12 cells,luteolin at low concentration...This study aims to uncover the hormetic process of luteolin,a common dietary flavone,in neuronal cells through its role in inducing mitochondrial stress.In rat pheochromocytoma PC12 cells,luteolin at low concentrations caused a mild and reversible loss of mitochondrial membrane potential(MMP),while high concentrations of luteolin triggered intense and sustained depolarization of MMP.The MMP disturbance was shown to have a close association with the trophic and/or toxic effects triggered by luteolin;because the common mitochondrial uncouplers shared similar bi-phase dose-response on cell viability,as that of luteolin.Along with the induced MMP pertubation,luteolin triggered the development of autophagy and mitophagy,as determined by m Cherry-GFP-LC3B tandem protein,and by the co-localization of mitochondrial/lysosomal staining.Subsequent application of autophagy inhibitors in the cultures blocked the luteolin-induced neurotrophic activities and sensitized the cells to be less resistant to luteolin-mediated cytotoxicity.Other flavonoids also displayed similar properties in the cultures,indicating that these compounds act as hormetic pharmacological inducers that stimulate cells to become more resilient and adapt to threats.This study provides a unifying mechanistic explanation for the neuro-beneficial effects of luteolin and other flavonoids.展开更多
Chromosomal rearrangements(CRs)often cause phenotypic variations.Although several major rearrangements have been identified in Triticeae,a comprehensive study of the order,timing,and breakpoints of CRs has not been co...Chromosomal rearrangements(CRs)often cause phenotypic variations.Although several major rearrangements have been identified in Triticeae,a comprehensive study of the order,timing,and breakpoints of CRs has not been conducted.Here,we reconstruct high-quality ancestral genomes for the most recent common ancestor(MRCA)of the Triticeae,and the MRCA of the wheat lineage(Triticum and Aegilops).The protogenes of MRCA of the Triticeae and the wheat lineage are 22,894 and 29,060,respectively,which were arranged in their ancestral order.By partitioning modern Triticeae chromosomes into sets of syntenic regions and linking each to the corresponding protochromosomes,we revisit the rye chromosome structural evolution and propose alternative evolutionary routes.The previously identified 4L/5L reciprocal translocation in rye and Triticum urartu is found to have occurred independently and is unlikely to be the result of chromosomal introgression following distant hybridization.We also clarify that the 4AL/7BS translocation in tetraploid wheat was a bidirectional rather than unidirectional translocation event.Lastly,we identify several breakpoints in protochromosomes that independently reoccur following Triticeae evolution,representing potential CR hotspots.This study demonstrates that these reconstructed ancestral genomes can serve as special comparative references and facilitate a better understanding of the evolution of structural rearrangements in Triticeae.展开更多
BACKGROUND The causes of death in patients with advanced esophageal cancer are multi-factorial,with tumor metastasis being one of the important factors.Histone acetylation promotes the migration of esophageal squamous...BACKGROUND The causes of death in patients with advanced esophageal cancer are multi-factorial,with tumor metastasis being one of the important factors.Histone acetylation promotes the migration of esophageal squamous cell carcinoma(ESCC)cells,while the histone deacetylase inhibitor(HDACi)shows complex effects on tumor functions.AIM To comprehensively elucidate the impact and molecular mechanisms of trichostatin A(TSA),an HDACi,on cell migration in ESCC through bromodomain-containing protein(BRD4)/cellular myelocytomatosis oncogene(c-Myc)/endoplasmic reticulum(ER)-stress.METHODS The effects of TSA on ESCC cell lines Eca109 and EC9706 migration were evaluated using Transwell assays,with small interfering transfection and pathway-specific inhibitors to elucidate underlying mechanisms.The mRNA levels involved were examined by quantitative real-time polymerase chain reaction.Protein levels of acetylated histones H3(acH3)and acetylated histones H4,BRD4,c-Myc,as well as markers of ER stress and epithelial-mesenchymal transition(EMT),were analyzed using western blot.Additionally,this method was also used to examine acH3 levels in esophageal cancer tissues and adjacent tissues.Patient outcomes were subsequently tracked to identify prognostic indicators using Log-Rank tests and Cox multivariate analysis.RESULTS TSA promoted the migration of ESCC cells by stimulating the EMT process.TSA-mediated histone acetylation facilitated the recruitment of BRD4,a bromodomain-containing protein,triggering the expression of c-Myc.This cascade induced ER stress and enhanced EMT in ESCC cells.To further elucidate the underlying mechanism,we employed various interventions including the ER stress inhibitor 4-phenylbutyric acid,knockdown of c-Myc and BRD4 expression,and utilization of the BRD4 inhibitor carboxylic acid as well as the inhibitor of TSA 1.Mechanist-ically,these studies revealed that TSA-mediated histone acetylation facilitated the recruitment of BRD4,which in turn triggered the expression of c-Myc.This sequential activation induced ER stress and subsequently enhanced EMT,thereby promoting the migration of ESCC cells.Additionally,we examined histone acetylation levels in specimens from 43 patients with ESCC,including both tumor tissues and paired adjacent tissues.Statistical analysis unveiled a negative correlation between the level of histone acetylation and the long-term prognosis of patients with ESCC.CONCLUSION TSA promoted ESCC cell migration through the BRD4/c-Myc/ER stress pathway.Moreover,elevated histone acetylation in ESCC tissues correlated with poor ESCC prognosis.These findings enhance our understanding of ESCC migration and HDACi therapy.展开更多
MicroRNAs are short regulatory RNAs that negatively modulate gene expression at the post-transcriptional level, and are deeply involved in the pathogenesis of several types of cancers. To investigate whether specific ...MicroRNAs are short regulatory RNAs that negatively modulate gene expression at the post-transcriptional level, and are deeply involved in the pathogenesis of several types of cancers. To investigate whether specific miRNAs and their target genes participate in the molecular pathogenesis of laryngeal carcinoma, oligonucleotide microarrays were used to assess the differential expression profiles of microRNAs and mRNAs in laryngeal carcinoma tissues compared with normal tissues. The oncogeuic miRNA, microRNA-21 （miR-21）, was found to he npregulated in laryngeal carcinoma tissues. Knockdown of miR-21 by specific antisense oligonucleotides inhibited the proliferation potential of HEp-2 cells, whereas overexpression of miR-21 elevated growth activity of the cells, as detected by the colony formation assay. The cell number reduction caused by miR-21 inhibition was due to the loss of control of the G1-S phase transition, instead of a noticeable increase in apoptosis. Subsequently, a new target gene of miR- 21, BTG2, was found to be downregulated in laryngeal carcinoma tissues. BTG2 is known to act as a pan-cell cycle regulator and tumor suppressor. These findings indicate that aberrant expression of miR-21 may contribute to the malignant phenotype of laryngeal carcinoma by maintaining a low level of BTG2. The identification of the oneogenic miR-21 and its target gene, BTG2, in laryngeal carcinoma is potentially valuable for cancer diagnosis and therapy.展开更多
Oxidative stress and mitochondrial damage have been implicated in the pathogenesis of several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Oxidati...Oxidative stress and mitochondrial damage have been implicated in the pathogenesis of several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Oxidative stress is characterized by the overproduction of reactive oxygen species, which can induce mitochondrial DNA mutations, damage the mitochondrial respiratory chain, alter membrane permeability, and influence Ca2＋ homeostasis and mitochondrial defense systems. All these changes are implicated in the development of these neurodegenerative diseases, mediating or amplifying neuronal dysfunction and triggering neurodegeneration. This paper summarizes the contribution of oxidative stress and mitochondrial damage to the onset of neurodegenerative diseases and discusses strategies to modify mitochondrial dysfunction that may be attractive therapeutic interventions for the treatment of various neurodegenerative diseases.展开更多
In multiloci-based genetic association studies of complex diseases, a powerful and high efficient tool for analyses oflinkage disequilibrium (LD) between markers, haplotype distributions and many chi-square/p values w...In multiloci-based genetic association studies of complex diseases, a powerful and high efficient tool for analyses oflinkage disequilibrium (LD) between markers, haplotype distributions and many chi-square/p values with a large numberof samples has been sought for long. In order to achieve the goal of obtaining meaningful results directly from raw data,we developed a robust and user-friendly software platform with a series of tools for analysis in association study withhigh efficiency. The platform has been well evaluated by several sets of real data.展开更多
MicroRNAs(miRNAs) are a class of small noncoding RNAs that post-transcriptionally regulate the expression of many target genes via mRNA degradation or translation inhibition. Many studies have shown that miRNAs are in...MicroRNAs(miRNAs) are a class of small noncoding RNAs that post-transcriptionally regulate the expression of many target genes via mRNA degradation or translation inhibition. Many studies have shown that miRNAs are involved in the modulation of gene expression and replication of hepatitis B virus(HBV) and hepatitis C virus(HCV) and play a pivotal role in host-virus interactions. Increasing evidence also demonstrates that viral infection leads to alteration of the miRNA expression profile in hepatic tissues or circulation. The deregulated miRNAs participate in hepatocellular carcinoma(HCC)initiation and progression by functioning as oncogenes or tumor suppressor genes by targeting various genes involved in cancer-related signaling pathways. The distinct expression pattern of miRNAs may be a useful marker for the diagnosis and prognosis of virus-related diseases considering the limitation of currently used biomarkers. Moreover, the role of deregulated miRNA in host-virus interactions and HCC development suggested that miRNAs may serve as therapeutic targets or astools. In this review, we summarize the recent findings about the deregulation and the role of miRNAs during HBV/HCV infection and HCC development, and we discuss the possible mechanism of action of miRNAs in the pathogenesis of virus-related diseases. Furthermore, we discuss the potential of using miRNAs as markers for diagnosis and prognosis as well as therapeutic targets and drugs.展开更多
Objective:To evaluate the antioxidant activity of aqueous extract of Atoringa oleifeta M.oleifera) young leaves by in vivo as well as in vitro assays.Methods:In vitro study included estimation of total phenolic,total ...Objective:To evaluate the antioxidant activity of aqueous extract of Atoringa oleifeta M.oleifera) young leaves by in vivo as well as in vitro assays.Methods:In vitro study included estimation of total phenolic,total ilavonol,total flavonoid and total antioxidant power(FRAP assay).Tn addition, in vivo study was done with the identified most effective dose of 200 nig/kg of its lyophilized powder on normal and diabetic rats.Its effect on different oxidative free radical scavenging enzymes,viz,superoxide dismutase(SOD),catalase(CAT),glutathione-S-transferase(GST),lipid peroxide(LPO) contents were measured.Results:Significant increase in activities of SOD.CAT, GST while,a decrease in LPO content was observed.Whereas,total phenolic,flavonoid and ilavonol contents in the extract were found to be 120 mg/g of CAK,40.5 mg/g of QEK and 12.12 mg/g of QE,respectively.On the other hand.FRAP assay results of M.oleifera leaves was(85.00±5.00)μM of Fe^+/g of extract powder.Conclusions:The significant antioxidant activities of M.oleifera leaves from both in vivo as well as in vitro studies suggests that the regular intake of its leaves through diet can protect normal as well as diabetic patients against oxidative damage.展开更多
Liver fibrosis accompanies the progression of chronic liver diseases independent of etiologies,such as hepatitis viral infection,alcohol consumption,and metabolicassociated fatty liver disease.It is commonly associate...Liver fibrosis accompanies the progression of chronic liver diseases independent of etiologies,such as hepatitis viral infection,alcohol consumption,and metabolicassociated fatty liver disease.It is commonly associated with liver injury,inflammation,and cell death.Liver fibrosis is characterized by abnormal accumulation of extracellular matrix components that are expressed by liver myofibroblasts such as collagens and alpha-smooth actin proteins.Activated hepatic stellate cells contribute to the major population of myofibroblasts.Many treatments for liver fibrosis have been investigated in clinical trials,including dietary supplementation(e.g.,vitamin C),biological treatment(e.g.,simtuzumab),drug(e.g.,pegbelfermin and natural herbs),genetic regulation(e.g.,non-coding RNAs),and transplantation of stem cells(e.g.,hematopoietic stem cells).However,none of these treatments has been approved by Food and Drug Administration.The treatment efficacy can be evaluated by histological staining methods,imaging methods,and serum biomarkers,as well as fibrosis scoring systems,such as fibrosis-4 index,aspartate aminotransferase to platelet ratio,and non-alcoholic fatty liver disease fibrosis score.Furthermore,the reverse of liver fibrosis is slowly and frequently impossible for advanced fibrosis or cirrhosis.To avoid the lifethreatening stage of liver fibrosis,anti-fibrotic treatments,especially for combined behavior prevention,biological treatment,drugs or herb medicines,and dietary regulation are needed.This review summarizes the past studies and current and future treatments for liver fibrosis.展开更多
Objective：Previous studies have identified that kazrin is a constituent of desmosome and influences intercellular adhesion,growing development and morphology.We previously cloned another new isoform,kazrin F and foun...Objective：Previous studies have identified that kazrin is a constituent of desmosome and influences intercellular adhesion,growing development and morphology.We previously cloned another new isoform,kazrin F and found that it has anti-apoptotic effects on human glioma cell line.To further explore whether kazrin F is involved in tumorigenesis,we investigated its expression and role in cervical cancer（CC） cells.Methods：The role of kazrin F and miR-186 in CC was determined by 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide（MTT） assay,colony formation,transwell,and apoptosis assays.Using enhanced green fluorescent protein（EGFP） reporter assays,reverse transcription-quantitative polymerase chain reaction（RT-qPCR） and western blot analysis,we identified kazrin F post-transcriptional regulation by miR-186.Results：We demonstrate that kazrin F is highly expressed in CC tissues compared with the adjacent noncancerous tissues and promotes cell proliferation,colony formation,migration and invasion in HeLa and C33 A cells by suppressing apoptosis and facilitating epithelial-to-mesenchymal transition（EMT）.Furthermore,miR-186 was confirmed as a regulator of kazrin F dysregulation.An EGFP reporter assay proved that miR-186 directly targets the 3＇-untranslated region（3＇UTR） of kazrin F and downregulates its expression,and miR-186 expression showed an inverse correlation with kazrin F levels in CC tissues.In addition,overexpression of miR-186 suppressed the malignant behaviors of CC cells.The ectopic expression of kazrin F rescued the inhibitory effects of miR-186.Conclusions：Our findings indicate that the upregulation of kazrin F due to downregulated miR-186 levels contributes to malignancy,and highlight the significance of kazrin F in CC tumorigenesis.展开更多
Hepatocellular carcinoma(HCC) is the leading cause of cancer-related death worldwide. Diabetes mellitus, a risk factor for cancer, is also globally endemic. The clinical link between these two diseases has been the su...Hepatocellular carcinoma(HCC) is the leading cause of cancer-related death worldwide. Diabetes mellitus, a risk factor for cancer, is also globally endemic. The clinical link between these two diseases has been the subject of investigation for a century, and diabetes mellitus has been established as a risk factor for HCC. Accordingly, metformin, a first-line oral anti-diabetic, was first proposed as a candidate anti-cancer agent in 2005 in a cohort study in Scotland. Several subsequent large cohort studies and randomized controlled trials have not demonstrated significant efficacy for metformin in suppressing HCC incidence and mortality in diabetic patients; however, two recent randomized controlled trials have reported positive data for the tumor-preventive potential of metformin in non-diabetic subjects. The search for biological links between cancer and diabetes has revealed intracellular pathways that are shared by cancer and diabetes. The signal transduction mechanisms by which metformin suppresses carcinogenesis in cell lines or xenograft tissues and improves chemoresistance in cancer stem cells have also been elucidated. This review addresses the clinical and biological links between HCC and diabetes mellitus and the anti-cancer activity of metformin in clinical studies and basic experiments.展开更多
基金Supported by the Key Medical Scientific and Technological Project of Henan Province,No.SBGJ202102188Henan Provincial Medical Science and Technology Project,No.LHGJ20221012the Key Project of Science and Technology of Xinxiang,No.GG2020027.
文摘BACKGROUND L-type calcium channels are the only protein channels sensitive to calcium channel blockers,and are expressed in various cancer types.The Cancer Genome Atlas database shows that the mRNA levels of multiple L-type calcium channel subunits in esophageal squamous cell carcinoma tumor tissue are significantly higher than those in normal esophageal epithelial tissue.Therefore,we hypothesized that amlodipine,a long-acting dihydropyridine L-type calcium channel blocker,may inhibit the occurrence and development of esophageal cancer(EC).AIM To investigate the inhibitory effects of amlodipine on EC through endoplasmic reticulum(ER)stress.METHODS Cav1.3 protein expression levels in 50 pairs of EC tissues and corresponding paracancerous tissues were examined.Subsequently,the inhibitory effects of amlodipine on proliferation and migration of EC cells in vitro were detected using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide and Transwell assays.In vivo experiments were performed using murine xenograft model.To elucidate the underlying mechanisms,in vitro cell studies were performed to confirm that ER stress plays a role in inhibition proliferation and migration of EC cells treated with amlodipine.RESULTS The expression level of Cav1.3 in esophageal carcinoma was 1.6 times higher than that in paracancerous tissues.Amlodipine treatment decreased the viability of esophageal carcinoma cells in a dose-and time-dependent manner.In vivo animal experiments also clearly indicated that amlodipine inhibited the growth of EC tumors in mice.Additionally,amlodipine reduces the migration of tumor cells by inhibiting epithelial-mesenchymal transition(EMT).Mechanistic studies have demonstrated that amlodipine induces ER stress-mediated apoptosis and suppresses EMT.Moreover,amlodipine-induced autophagy was characterized by an increase in autophagy lysosomes and the accumulation of light chain 3B protein.The combination of amlodipine with the ER stress inhibitor 4-phenylbutyric acid further confirmed the role of the ER stress response in amlodipine-induced apoptosis,EMT,and autophagy.Furthermore,blocking autophagy increases the ratio of apoptosis and migration.CONCLUSION Collectively,we demonstrate for the first time that amlodipine promotes apoptosis,induces autophagy,and inhibits migration through ER stress,thereby exerting anti-tumor effects in EC.
文摘In Kuwait, the scarcity and irregularity of rainfall, the availability of areas of sand supply and the prevalence of strong north westerly winds significantly influence the stability of the fragile ecosystem. Naturally, grown native shrubs and trees can provide potential shelter to soil surface in desert areas. To study the environmental indicators provided by native plant and their ability to improve quality of life, the morphological properties of the vegetated nabkhas within different areas in Kuwait desert and within protected area were assessed. The vegetated dunes can trap maximum mobile sediments from 10.5 to 0.45 ton thus cost saving per plant estimated to be from 5.5 to 0.24 USD. The arrangements of the native plant from highest efficiency in absorbing carbon dioxides to the least were as follows: Nitraria retusa, Haloxylon salicornicum, Citrullus colocynthis, Tamarix aucheriana, Lycium shawii, Convolvolus oxyphyllus, Rhanterium epapposum, Panicum turgidum, Calligonum polygonoides, Astragalus spinosus, Cyperus conglomerates. The cost saving of CO_(2) per year estimated to be from 0.95 to 1,542.1 USD. The revegetation enhanced physical and chemical quality of soil and created microenvironments for the flora and fauna. The aim of this paper is to identify the environmental indicators related to native plants for the assessment of quality of life.
基金supported by a sub-award to the University of Missouri from the Heinrich Heine University of Dusseldorf funded by the Bill&Melinda Gates Foundation(OPP1155704)(Bing Yang)and the China Scholar Council(Chenhao Li,as a joint Ph.D.student).
文摘Bacterial blight(BB),caused by Xanthomonas oryzae pathovar oryzae(Xoo),poses a significant threat to rice production,particularly in Asia and West Africa.Breeding resistance against BB in elite rice varieties is crucial to advancing rice breeding program and supporting smallholder farmers.Transcription Activator-Like effectors(TALes)are key virulence factors in Xoo,with some targeting the susceptibility(S)genes such as the sugar transporter SWEET genes in rice.Among these,SWEET14 is an important S gene,with its promoter bound by the TALe TalC which exists across all sequenced African Xoo isolates.In the present study,we utilized CRISPR/Cas9-based cytidine and adenine base editors to alter the effector binding element(EBE)of TalC in the promoter of SWEET14 in rice cultivars Kitaake,IR24,and Zhonghua 11.Mutations with C to T changes in EBE led to reduced SWEET14 induction by TalC-containing Xoo strains,resulting in resistance to African Xoo isolates reliant on TalC for virulence.Conversely,A to G changes retained SWEET14 inducibility and susceptibility to Xoo in edited lines.Importantly,no off-target mutations were detected at predicted sites,and the edited lines exhibited no obvious defects in major agronomic traits in Kitaake.These results underscore the effectiveness of base editing systems for both molecular biology research and crop improvement endeavors.
文摘Liver cancer is the sixth most common cancer and the third leading cause of cancer death worldwide.The predominant type of primary liver cancer is hepatocellular carcinoma(HCC).Tumor vascular endothelial cells(VECs),a major component of cells in the microenvironment of HCC,play multifaceted roles in contributing to tumor angiogenesis,proliferation,and migration,as well as therapeutic resistance by attracting myeloid-derived suppressor cells and suppressing cytotoxic CD8 T cell differentiation and function.Recently,Wu et al reported that apatinib,an inhibitor of vascular endothelial growth factor receptor 2,can inhibit tumor VEC glycolysis by regulating phosphatidylinositol 3-kinase/protein kinase B/6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 signaling pathway to suppress HCC progression.With great interest,this editorial paper aims to review the function and key molecular signaling pathways of tumor VECs in HCC initiation and progression and summarize potential treatment options in clinical trials.
文摘Metabolic dysfunction-associated steatotic liver disease(MASLD)is featured by the accumulation of excessive fat in the liver.It is caused by many factors,such as overweight,obesity,diabetes,and high plasma levels of sugar,cholesterol,and triglycerides.MASLD is commonly associated with type 2 diabetes(T2D),which is characterized by a pathophysiological deficiency of insulin secretion due to impaired function of pancreatic βcells and insulin resistance.T2D has become a global pandemic that influences more than 21.7 million people worldwide.Preclinical and clinical studies have been performed to investigate molecular crosslinks between T2D and MASLD and their therapeutic strategies.Accumulating evidence has demonstrated that macrophages are cellular mediators that contribute to the progression of MASLD and T2D by impacting the resolution of inflammation.Different types of macrophages are involved in the pathogenesis of MASLD and T2D,including liver-resident macrophages or Kupffer cells,monocyte-derived macrophages,and adipose tissue macrophages.These macrophages secrete enzymes,chemokines,cytokines,as well as exosomes,to induce metabolic inflammation and insulin resistance,immune cell infiltration,and tissue injury.In this review,we provide a comprehensive summary of the molecular and cellular interactions between MASLD and T2D with a specific discussion of the critical roles of macrophages and inflammation.The underlying molecular mechanisms and the associated therapeutic targets and strategies are also reviewed.
文摘Metabolic dysfunction-associated steatotic liver disease(MASLD)is the most common chronic liver disease,affecting more than 30%of adults and 7%-14%of youths globally.MASLD and its advanced form of metabolic dysfunctionassociated steatohepatitis(MASH)can progress to liver cirrhosis and hepatocellular carcinoma.Despite its growing burden,effective therapies for MASLD and MASH remain limited.Accumulating evidence indicates that short-chain fatty acids(SCFAs)modulate the activation of hepatic innate and adaptive immune cells,influencing liver inflammation and fibrosis.Moreover,SCFAs modulate liver lipid and glucose metabolism and insulin sensitivity,affecting MASLD progression.This review summarizes the cellular and molecular mechanisms through which SCFAs impact liver inflammation,fibrosis,and energy metabolism.Several key molecular signaling pathways are discussed.Clinical trials aiming to modulate SCFA production through different treatments are reviewed.Collectively,emerging evidence supports that targeting SCFA-mediated function represents a promising therapeutic strategy for MASLD and MASH.
文摘The nucleotide-binding domain,leucine-rich repeat,and pyrin domain-containing protein 3(NLRP3)inflammasome is a critical modulator in inflammatory disease.Activation and mutation of NLRP3 can cause severe inflammation in diseases such as chronic infantile neurologic cutaneous and articular syndrome,Muckle-Wells syndrome,and familial cold autoinflammatory syndrome 1.To date,a great effort has been made to decode the underlying mechanisms of NLRP3 activation.The priming and activation of NLRP3 drive the maturation and release of active interleukin(IL)-18 and IL-1βto cause inflammation and pyroptosis,which can significantly trigger many diseases including inflammatory diseases,immune disorders,metabolic diseases,and neurodegenerative diseases.The investigation of NLRP3 as a therapeutic target for disease treatment is a hot topic in both preclinical studies and clinical trials.Developing potent NLRP3 inhibitors and downstream IL-1 inhibitors attracts wide-spectrum attention in both research and pharmaceutical fields.In this minireview,we first updated the molecular mechanisms involved in NLRP3 inflammasome activation and the associated downstream signaling pathways.We then reviewed the molecular and cellular pathways of NLRP3 in many diseases,including obesity,diabetes,and other metabolic diseases.In addition,we briefly reviewed the roles of NLRP3 in cancer growth and relative immune checkpoint therapy.Finally,clinical trials with treatments targeting NLRP3 and its downstream signaling pathways were summarized.
基金supported by Hong Kong RGC-GFC 16100921Hong Kong RGC Theme-based Research Scheme(T13-605/18-W)+3 种基金Hong Kong Innovation Technology Fund(PRP/076/20FXITCPD/17-9,MHP/004/21)PD18SC01 and HMRF18SC06HMRF20SC07,AFD20SC01Shenzhen Science and Technology Innovation Committee(ZDSYS201707281432317)。
文摘This study aims to uncover the hormetic process of luteolin,a common dietary flavone,in neuronal cells through its role in inducing mitochondrial stress.In rat pheochromocytoma PC12 cells,luteolin at low concentrations caused a mild and reversible loss of mitochondrial membrane potential(MMP),while high concentrations of luteolin triggered intense and sustained depolarization of MMP.The MMP disturbance was shown to have a close association with the trophic and/or toxic effects triggered by luteolin;because the common mitochondrial uncouplers shared similar bi-phase dose-response on cell viability,as that of luteolin.Along with the induced MMP pertubation,luteolin triggered the development of autophagy and mitophagy,as determined by m Cherry-GFP-LC3B tandem protein,and by the co-localization of mitochondrial/lysosomal staining.Subsequent application of autophagy inhibitors in the cultures blocked the luteolin-induced neurotrophic activities and sensitized the cells to be less resistant to luteolin-mediated cytotoxicity.Other flavonoids also displayed similar properties in the cultures,indicating that these compounds act as hormetic pharmacological inducers that stimulate cells to become more resilient and adapt to threats.This study provides a unifying mechanistic explanation for the neuro-beneficial effects of luteolin and other flavonoids.
基金CAs Youth Interdisciplinary Team(JCTD-2022-06)the National Nature Science Foundation of China(31870209).
文摘Chromosomal rearrangements(CRs)often cause phenotypic variations.Although several major rearrangements have been identified in Triticeae,a comprehensive study of the order,timing,and breakpoints of CRs has not been conducted.Here,we reconstruct high-quality ancestral genomes for the most recent common ancestor(MRCA)of the Triticeae,and the MRCA of the wheat lineage(Triticum and Aegilops).The protogenes of MRCA of the Triticeae and the wheat lineage are 22,894 and 29,060,respectively,which were arranged in their ancestral order.By partitioning modern Triticeae chromosomes into sets of syntenic regions and linking each to the corresponding protochromosomes,we revisit the rye chromosome structural evolution and propose alternative evolutionary routes.The previously identified 4L/5L reciprocal translocation in rye and Triticum urartu is found to have occurred independently and is unlikely to be the result of chromosomal introgression following distant hybridization.We also clarify that the 4AL/7BS translocation in tetraploid wheat was a bidirectional rather than unidirectional translocation event.Lastly,we identify several breakpoints in protochromosomes that independently reoccur following Triticeae evolution,representing potential CR hotspots.This study demonstrates that these reconstructed ancestral genomes can serve as special comparative references and facilitate a better understanding of the evolution of structural rearrangements in Triticeae.
基金Supported by the Henan Province Science and Technology Development Plan,No.242102311124Key Medical Scientific and Technological Project of Henan Province,No.SBGJ202102188+1 种基金Henan Provincial Medical Science and Technology Project,No.LHGJ20221012Fundamental Research Funds for the Universities of Henan Province,No.NSFRF240308.
文摘BACKGROUND The causes of death in patients with advanced esophageal cancer are multi-factorial,with tumor metastasis being one of the important factors.Histone acetylation promotes the migration of esophageal squamous cell carcinoma(ESCC)cells,while the histone deacetylase inhibitor(HDACi)shows complex effects on tumor functions.AIM To comprehensively elucidate the impact and molecular mechanisms of trichostatin A(TSA),an HDACi,on cell migration in ESCC through bromodomain-containing protein(BRD4)/cellular myelocytomatosis oncogene(c-Myc)/endoplasmic reticulum(ER)-stress.METHODS The effects of TSA on ESCC cell lines Eca109 and EC9706 migration were evaluated using Transwell assays,with small interfering transfection and pathway-specific inhibitors to elucidate underlying mechanisms.The mRNA levels involved were examined by quantitative real-time polymerase chain reaction.Protein levels of acetylated histones H3(acH3)and acetylated histones H4,BRD4,c-Myc,as well as markers of ER stress and epithelial-mesenchymal transition(EMT),were analyzed using western blot.Additionally,this method was also used to examine acH3 levels in esophageal cancer tissues and adjacent tissues.Patient outcomes were subsequently tracked to identify prognostic indicators using Log-Rank tests and Cox multivariate analysis.RESULTS TSA promoted the migration of ESCC cells by stimulating the EMT process.TSA-mediated histone acetylation facilitated the recruitment of BRD4,a bromodomain-containing protein,triggering the expression of c-Myc.This cascade induced ER stress and enhanced EMT in ESCC cells.To further elucidate the underlying mechanism,we employed various interventions including the ER stress inhibitor 4-phenylbutyric acid,knockdown of c-Myc and BRD4 expression,and utilization of the BRD4 inhibitor carboxylic acid as well as the inhibitor of TSA 1.Mechanist-ically,these studies revealed that TSA-mediated histone acetylation facilitated the recruitment of BRD4,which in turn triggered the expression of c-Myc.This sequential activation induced ER stress and subsequently enhanced EMT,thereby promoting the migration of ESCC cells.Additionally,we examined histone acetylation levels in specimens from 43 patients with ESCC,including both tumor tissues and paired adjacent tissues.Statistical analysis unveiled a negative correlation between the level of histone acetylation and the long-term prognosis of patients with ESCC.CONCLUSION TSA promoted ESCC cell migration through the BRD4/c-Myc/ER stress pathway.Moreover,elevated histone acetylation in ESCC tissues correlated with poor ESCC prognosis.These findings enhance our understanding of ESCC migration and HDACi therapy.
基金Acknowledgments This work was supported by grants from the National Natural Science Foundation of China （No. 30873017） and the Key Program of the Natural Science Foundation of Tianjing （No. 08JCZDJC23300）. We thank Tianjin First Center Hospital for providing human laryngeal tissue samples. We also thank the College of Public Health of Tianjin Medical University for the technical assistance in fluorescent detection. The ArrayExpress accession numbers of miRNA microarray design and cDNA microarray design are A-MEXP-1506 and A-MEXP-1511. The ArrayExpress accession numbers of miRNA microarray experiment and eDNA microarray experiment are E-MEXP-2039 and E-MEXP-2056.
文摘MicroRNAs are short regulatory RNAs that negatively modulate gene expression at the post-transcriptional level, and are deeply involved in the pathogenesis of several types of cancers. To investigate whether specific miRNAs and their target genes participate in the molecular pathogenesis of laryngeal carcinoma, oligonucleotide microarrays were used to assess the differential expression profiles of microRNAs and mRNAs in laryngeal carcinoma tissues compared with normal tissues. The oncogeuic miRNA, microRNA-21 （miR-21）, was found to he npregulated in laryngeal carcinoma tissues. Knockdown of miR-21 by specific antisense oligonucleotides inhibited the proliferation potential of HEp-2 cells, whereas overexpression of miR-21 elevated growth activity of the cells, as detected by the colony formation assay. The cell number reduction caused by miR-21 inhibition was due to the loss of control of the G1-S phase transition, instead of a noticeable increase in apoptosis. Subsequently, a new target gene of miR- 21, BTG2, was found to be downregulated in laryngeal carcinoma tissues. BTG2 is known to act as a pan-cell cycle regulator and tumor suppressor. These findings indicate that aberrant expression of miR-21 may contribute to the malignant phenotype of laryngeal carcinoma by maintaining a low level of BTG2. The identification of the oneogenic miR-21 and its target gene, BTG2, in laryngeal carcinoma is potentially valuable for cancer diagnosis and therapy.
基金supported by the National Natural Science Foundation of China,No.81274005Medical Science Research,Health Department of Hebei Province,No.20110173,20090588Hebei Education Department Science Foundation,No.2007302
文摘Oxidative stress and mitochondrial damage have been implicated in the pathogenesis of several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Oxidative stress is characterized by the overproduction of reactive oxygen species, which can induce mitochondrial DNA mutations, damage the mitochondrial respiratory chain, alter membrane permeability, and influence Ca2＋ homeostasis and mitochondrial defense systems. All these changes are implicated in the development of these neurodegenerative diseases, mediating or amplifying neuronal dysfunction and triggering neurodegeneration. This paper summarizes the contribution of oxidative stress and mitochondrial damage to the onset of neurodegenerative diseases and discusses strategies to modify mitochondrial dysfunction that may be attractive therapeutic interventions for the treatment of various neurodegenerative diseases.
基金This work was supported by the Major State Basic Research Development program of Chinathe National High Technology Research and Development Program of China.
文摘In multiloci-based genetic association studies of complex diseases, a powerful and high efficient tool for analyses oflinkage disequilibrium (LD) between markers, haplotype distributions and many chi-square/p values with a large numberof samples has been sought for long. In order to achieve the goal of obtaining meaningful results directly from raw data,we developed a robust and user-friendly software platform with a series of tools for analysis in association study withhigh efficiency. The platform has been well evaluated by several sets of real data.
基金Supported by National Natural Science Foundation of China,No.91029714,No.31071191,No.31270818 and No.31101000Natural Science Foundation of Tianjin,No.09JCZDJC17500 and No.12JCZDJC25100
文摘MicroRNAs(miRNAs) are a class of small noncoding RNAs that post-transcriptionally regulate the expression of many target genes via mRNA degradation or translation inhibition. Many studies have shown that miRNAs are involved in the modulation of gene expression and replication of hepatitis B virus(HBV) and hepatitis C virus(HCV) and play a pivotal role in host-virus interactions. Increasing evidence also demonstrates that viral infection leads to alteration of the miRNA expression profile in hepatic tissues or circulation. The deregulated miRNAs participate in hepatocellular carcinoma(HCC)initiation and progression by functioning as oncogenes or tumor suppressor genes by targeting various genes involved in cancer-related signaling pathways. The distinct expression pattern of miRNAs may be a useful marker for the diagnosis and prognosis of virus-related diseases considering the limitation of currently used biomarkers. Moreover, the role of deregulated miRNA in host-virus interactions and HCC development suggested that miRNAs may serve as therapeutic targets or astools. In this review, we summarize the recent findings about the deregulation and the role of miRNAs during HBV/HCV infection and HCC development, and we discuss the possible mechanism of action of miRNAs in the pathogenesis of virus-related diseases. Furthermore, we discuss the potential of using miRNAs as markers for diagnosis and prognosis as well as therapeutic targets and drugs.
基金National Medicinal Plants Board. Govt,of India,New Delhi,India for providing financial assistance in the form of Senior Research Fellowship to cam' out the present study
文摘Objective:To evaluate the antioxidant activity of aqueous extract of Atoringa oleifeta M.oleifera) young leaves by in vivo as well as in vitro assays.Methods:In vitro study included estimation of total phenolic,total ilavonol,total flavonoid and total antioxidant power(FRAP assay).Tn addition, in vivo study was done with the identified most effective dose of 200 nig/kg of its lyophilized powder on normal and diabetic rats.Its effect on different oxidative free radical scavenging enzymes,viz,superoxide dismutase(SOD),catalase(CAT),glutathione-S-transferase(GST),lipid peroxide(LPO) contents were measured.Results:Significant increase in activities of SOD.CAT, GST while,a decrease in LPO content was observed.Whereas,total phenolic,flavonoid and ilavonol contents in the extract were found to be 120 mg/g of CAK,40.5 mg/g of QEK and 12.12 mg/g of QE,respectively.On the other hand.FRAP assay results of M.oleifera leaves was(85.00±5.00)μM of Fe^+/g of extract powder.Conclusions:The significant antioxidant activities of M.oleifera leaves from both in vivo as well as in vitro studies suggests that the regular intake of its leaves through diet can protect normal as well as diabetic patients against oxidative damage.
文摘Liver fibrosis accompanies the progression of chronic liver diseases independent of etiologies,such as hepatitis viral infection,alcohol consumption,and metabolicassociated fatty liver disease.It is commonly associated with liver injury,inflammation,and cell death.Liver fibrosis is characterized by abnormal accumulation of extracellular matrix components that are expressed by liver myofibroblasts such as collagens and alpha-smooth actin proteins.Activated hepatic stellate cells contribute to the major population of myofibroblasts.Many treatments for liver fibrosis have been investigated in clinical trials,including dietary supplementation(e.g.,vitamin C),biological treatment(e.g.,simtuzumab),drug(e.g.,pegbelfermin and natural herbs),genetic regulation(e.g.,non-coding RNAs),and transplantation of stem cells(e.g.,hematopoietic stem cells).However,none of these treatments has been approved by Food and Drug Administration.The treatment efficacy can be evaluated by histological staining methods,imaging methods,and serum biomarkers,as well as fibrosis scoring systems,such as fibrosis-4 index,aspartate aminotransferase to platelet ratio,and non-alcoholic fatty liver disease fibrosis score.Furthermore,the reverse of liver fibrosis is slowly and frequently impossible for advanced fibrosis or cirrhosis.To avoid the lifethreatening stage of liver fibrosis,anti-fibrotic treatments,especially for combined behavior prevention,biological treatment,drugs or herb medicines,and dietary regulation are needed.This review summarizes the past studies and current and future treatments for liver fibrosis.
基金supported in part by the National Natural Science Foundation of China(No.8157279091629302+1 种基金 31270818)the Natural Science Foundation of Tianjin (No.12JCZDJC25100,14JCYBJC26400,16JCYBJC42400)
文摘Objective：Previous studies have identified that kazrin is a constituent of desmosome and influences intercellular adhesion,growing development and morphology.We previously cloned another new isoform,kazrin F and found that it has anti-apoptotic effects on human glioma cell line.To further explore whether kazrin F is involved in tumorigenesis,we investigated its expression and role in cervical cancer（CC） cells.Methods：The role of kazrin F and miR-186 in CC was determined by 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide（MTT） assay,colony formation,transwell,and apoptosis assays.Using enhanced green fluorescent protein（EGFP） reporter assays,reverse transcription-quantitative polymerase chain reaction（RT-qPCR） and western blot analysis,we identified kazrin F post-transcriptional regulation by miR-186.Results：We demonstrate that kazrin F is highly expressed in CC tissues compared with the adjacent noncancerous tissues and promotes cell proliferation,colony formation,migration and invasion in HeLa and C33 A cells by suppressing apoptosis and facilitating epithelial-to-mesenchymal transition（EMT）.Furthermore,miR-186 was confirmed as a regulator of kazrin F dysregulation.An EGFP reporter assay proved that miR-186 directly targets the 3＇-untranslated region（3＇UTR） of kazrin F and downregulates its expression,and miR-186 expression showed an inverse correlation with kazrin F levels in CC tissues.In addition,overexpression of miR-186 suppressed the malignant behaviors of CC cells.The ectopic expression of kazrin F rescued the inhibitory effects of miR-186.Conclusions：Our findings indicate that the upregulation of kazrin F due to downregulated miR-186 levels contributes to malignancy,and highlight the significance of kazrin F in CC tumorigenesis.
文摘Hepatocellular carcinoma(HCC) is the leading cause of cancer-related death worldwide. Diabetes mellitus, a risk factor for cancer, is also globally endemic. The clinical link between these two diseases has been the subject of investigation for a century, and diabetes mellitus has been established as a risk factor for HCC. Accordingly, metformin, a first-line oral anti-diabetic, was first proposed as a candidate anti-cancer agent in 2005 in a cohort study in Scotland. Several subsequent large cohort studies and randomized controlled trials have not demonstrated significant efficacy for metformin in suppressing HCC incidence and mortality in diabetic patients; however, two recent randomized controlled trials have reported positive data for the tumor-preventive potential of metformin in non-diabetic subjects. The search for biological links between cancer and diabetes has revealed intracellular pathways that are shared by cancer and diabetes. The signal transduction mechanisms by which metformin suppresses carcinogenesis in cell lines or xenograft tissues and improves chemoresistance in cancer stem cells have also been elucidated. This review addresses the clinical and biological links between HCC and diabetes mellitus and the anti-cancer activity of metformin in clinical studies and basic experiments.
