Catalytic Asymmetric Addition and Telomerization of Butadiene with Enamine Intermediates

Herein,we report tunable asymmetric addition and telomerization of butadiene by synergistic chiral primary amine/achiral palladium catalysis.A selection of different achiral phosphine ligand in concert with the chiral primary amine-trifluoromethanesulfonic acid(TfOH)conjugates enables both chemo-and enantioselective control of the coupling with butadiene.Bidentate[(oxydi-2,1-phenylene)-bis-(diphenylphosphine)](DPEPhos)ligand led to 1,4-addition adduct whereas monodentate(p-Tol)3P ligand gave the telomerization product.A range ofα-branchedβ-ketoesters and aldehydes could be applied to afford allylation or telomerization products bearing allcarbon quaternary centers at high efficiency and good chemo-,regio-,and stereoselectivities.

A Study of Radiation-Induced Telomere Instability Using Multiplex Ligation-Dependent Probe Amplification (MLPA)

The integrity of the chromosomes for two WIL2-derived lymphoblastoid cell lines (TK6 and WTK1) in the presence and absence of ionizing radiation was analyzed by Multiplex Ligation-Dependent Probe Amplification (MLPA). The TK6 cell line has the native p53 tumor-suppressor gene, whereas WTK1 cells contain a p53 mutation. Each cell line was isolated pre- and post-irradiation (2 and 3 Gy) and analyzed by MLPA. The impact of irradiation on these two cell lines was investigated using probes that target specific regions on chromosomes associated with subtelomeric regions. Results indicate that WTK1 and TK6 are impacted differently after irradiation, and that each cell line presents its own unique MLPA profile. The most notable differences are the appearance of a number of probes in the post-irradiated MLPA profile that are not present in the controls, and two unique probe signals only seen in WTK1 cells. These results build on our previous studies that indicate how different human cell lines can be affected by radiation in significantly different ways depending on the presence or absence of wild type p53.

Hydroxyl Group-Enabled Highly Efficient Ligand for Pd-Catalyzed Telomerization of 1,3-Butadiene with CO_(2)

By introducing hydroxyl group into PPh3 ligand,a promoter-free palladium catalytic system based on(p-HOC6H4)PPh2 ligand was developed for the telomerization of 1,3-butadiene with CO_(2).High activity and selectivity towards CO_(2)-incorporated divinylδ-lactone monomer were achieved(TON/TOF:up to 4540/568 h–1;selectivity ofδ-lactone and its isomers:up to 97%).The key role of phenolic hydroxyl group of the ligand in attaining high activity was validated.The good performance of large-scale reaction in batch reactor demonstrated the potential utility of this simple catalytic system in valorizing CO_(2) with bulk chemical feedstock.

Role of mitophagy in the hallmarks of aging

Aging, subjected to scientific scrutiny, is extensively defined as a time-dependent decline in functions that involves the majority of organisms. The time-dependent accretion of cellular lesions is generally a universal trigger of aging, while mitochondrial dysfunction is a sign of aging. Dysfunctional mitochondria are identified and removed by mitophagy, a selective form of macroautophagy. Increased mitochondrial damage resulting from reduced biogenesis and clearance may promote the aging process. The primary purpose of this paper is to illustrate in detail the effects of mitophagy on aging and emphasize the associations between mitophagy and other signs of aging, including dietary restriction, telomere shortening, epigenetic alterations, and protein imbalance.The evidence regarding the effects of these elements on aging is still limited. And although the understanding of relationship between mitophagy and aging has been long-awaited, to analyze details of such a relationship remains the main challenge in aging studies.

EPAS1 prevents telomeric damage-induced senescence by enhancing transcription of TRF1,TRF2,and RAD50

Telomeres are nucleoprotein structures located at the end of each chromosome,which function in terminal protection and genomic stability.Telomeric damage is closely related to replicative senescence in vitro and physical aging in vivo.As relatively long-lived mammals based on body size,bats display unique telomeric patterns,including the upregulation of genes involved in alternative lengthening of telomeres(ALT),DNA repair,and DNA replication.At present,however,the relevant molecular mechanisms remain unclear.In this study,we performed cross-species comparison and identified EPAS1,a well-defined oxygen response gene,as a key telomeric protector in bat fibroblasts.Bat fibroblasts showed high expression of EPAS1,which enhanced the transcription of shelterin components TRF1 and TRF2,as well as DNA repair factor RAD50,conferring bat fibroblasts with resistance to senescence during long-term consecutive expansion.Based on a human single-cell transcriptome atlas,we found that EPAS1 was predominantly expressed in the human pulmonary endothelial cell subpopulation.Using in vitro-cultured human pulmonary endothelial cells,we confirmed the functional and mechanistic conservation of EPAS1 in telomeric protection between bats and humans.In addition,the EPAS1 agonist M1001 was shown to be a protective compound against bleomycin-induced pulmonary telomeric damage and senescence.In conclusion,we identified a potential mechanism for regulating telomere stability in human pulmonary diseases associated with aging,drawing insights from the longevity of bats.

Association between Dietary Collagen Consumption and Telomere Length: National Health and Nutrition Examination Survey

Background: Bioactive peptides derived from hydrolyzed collagen have broad physiological functions and beneficial effects on human health, ranging from reducing skin aging to modifying lipid metabolism. Telomere length shortening is an established biomarker of cellular aging. It is not known if collagen consumption is associated with telomere length protection. Our purpose was to investigate the relationship between dietary collagen consumption and telomere length in a nationally representative US adult population. Methods: We analyzed the data of 6173 adults aged 20 - 84 from the National Health and Nutrition Examination Survey (NHANES) 1999-2002. Multivariable linear regression and a generalized additive model with smoothing plot were used to assess the association between the total collagen consumption and log-transformed leukocyte telomere length (LTL). Results: Compared with the lowest quartile of total collagen (Q1), we found that the second quartile of collagen (Q2) consumption (1.36 - 3.40 g/1000kcal) was positively associated with telomere length (β: 0.017;95% CI: 0.006, 0.028;P = 0.022) in the females while no association in the males (β: −0.003;95% CI: −0.019, 0.012;P = 0.678) and overall population (β: 0.008;95% CI: −0.002, 0.018;P = 0.141). The association in the females is nonlinear with an inflection point of 2.5 g/1000kcal (P for non-linearity: Conclusion: In conclusion, moderate dietary collagen has a positive and nonlinear association with telomere length in US females, while no significant associations were found in the males and the overall population.

Hematopoietic stem cell transplantation of aplastic anemia by relative with mutations and normal telomere length: A case report

BACKGROUND Immunosuppressive therapy and matched sibling donor hematopoietic stem cell transplantation(MSD-HSCT)are the preferred treatments for aplastic anemia(AA).CASE SUMMARY In this report,we describe a 43-year-old male patient with severe AA who carried BRIP1(also known as FANCJ),TINF2,and TCIRG1 mutations.Screening of the family pedigree revealed the same TINF2 mutation in his mother and older brother,with his older brother also carrying the BRIP1 variant and demonstrating normal telomere length and hematopoietic function.The patient was successfully treated with oral cyclosporine A,eltrombopag,and acetylcysteine,achieving remission 4 years after receiving MSD-HSCT from his older brother.CONCLUSION This case provides a valuable clinical reference for individuals with suspected pathogenic gene mutations,normal telomere length,and hematopoietic function,highlighting them as potential donors for patients with AA.

SYNTHESIS AND CHARACTERIZATION OF POLYROTAXANES MADE FROM α-CDs THREADED ONTO TRIBLOCK COPOLYMERS WITH PEG AS A CENTRAL AXLE AND FLANKED BY TWO LOW MOLECULAR WEIGHT POLYSTYRENES AS OUTER STOPPERS

A study has been conducted on the synthesis and characterization of a kind of novel polyrotaxanes comprisingα- cyclodextrins (α-CDs) threaded on triblock eopolymers with poly(ethylene glycol) (PEG) as a central axle and flanked by two low molecular weight polystyrenes as outer stoppers.Styrene was allowed to telomerize with polypseudorotaxanes as chain transfer agents made from the self-assembly of a distal thiol-capped PEG with a varying amount ofα-CDs in the presence of a redox initiation system at 40~C i...

Telomere erosion is independent of microsatellite instability but related to loss of heterozygosity in gastric cancer

AIM To correlate the length of the telomere to microsatellite instability (MSI) and loss of heterozygosity (LOH) of APC, MCC and DCC genes in gastric carcinomas.METHODS Telomeric restriction fragment (TRF) length of gastric cancer was measured with Southern blot. LOH of APC, MCC and DCC genes, microsatellite instability (MSI) and frameshift mutation of hMSH6, TGF-βR Ⅱ and BAX genes were analyzed by PCR-based methods.RESULTS Sixty-eight cases of sporadic gastric carcinoma were studied for MSI using five microsatellite markers. MSI in at least one locus was detected in 17 (25%) of 68 tumors analyzed. Frameshift mutations of hMSH6, TGF-βR Ⅱ and BAX were detected in 2,6 and 3 of gastric carcinomas respectively showing high MSI (≥ 2 loci, n = 8), but none was found in those showing Iow MSI (only one locus, n = 9) or MSS (tumor lacking MSI or stable, n = 51). Thirty-five cases, including all high MSI and Iow MSl, were studied for TRF. The mean TRF length was not correlated with clinicopathological parameters.No association was observed between TRF length and MSI or frameshift mutation. On the contrary, LOH at the DCC locus was related to telomere shortening (P＜ 0.01). This tendency was also observed in APC and MCC genes,although there was no statistical significance.CONCLUSION The development of gastric cancer can arise through two different genetic pathways. In high MSI gastric cancers, defective mismatch repair allows mutations to accumulate and generate the high MSI phenotype. In gastric cancers showing either Iow MSI or MSS, multiple deletions may represent the LOH pathway.Telomere erosion is independent of high MSI phenotype but related to the LOH pathway in gastric cancer.

Antisense telomerase RNA induced human gastric cancer cell apoptosis

INTRODUCTION Human tissue homeostasis is precisely regulated bycellular division,differentiation and death.Normalhuman somatic cells progressively lose telomererestriction fragment(TRF)length with eachsuccessive cell division,eventually leading tocellular quiescence,chromosomal end-degradationand apoptosis.On the contrary,stabilization oftelomere lengths by expressing telomerase,an RNA-dependent DNA polymerase,may be involved incellular immortality and carcinogenesis.

Telomere and telomerase in chronic liver disease and hepatocarcinoma

The pathogenesis of liver cirrhosis is not completely elucidated.Although in the majority of patients,the risk factors may be identified in B and C viral hepatitis,alcohol intake,drugs or fatty liver disease,there is a small percentage of patients with no apparent risk factors.In addition,the evolution of chronic liver disease is highly heterogeneous from one patient to another.Among patient with identical risk factors,some rapidly progress to cirrhosis and hepatocellular carcinoma(HCC)whereas others have a benign course.Therefore,a genetic predisposition may contribute to the development of cirrhosis and HCC.Evidence supporting the role of genetic factors as a risk for cirrhosis has been accumulating during the past years.In addition to the results from epidemiological studies,polymorphisms studies and data on twins,the concept of telomere shortening as a genetic risk factor for chronic liver disease and HCC has been proposed.Here we review the literature on telomerase mutations,telomere shortening and liver disease including hepatocellular carcinoma.

Mesenchymal stem cells-based therapy as a potential treatment in neurodegenerative disorders: is the escape from senescence an answer?

Aging is the most prominent risk factor contributing to the development of neurodegenerative disorders. In the United States, over 35 million of elderly people suffer from age-related diseases. Aging impairs the self-repair ability of neuronal cells, which undergo progressive deterioration. Once initiated, this process hampers the already limited regenerative power of the central nervous system, making the search for new therapeutic strategies particularly difficult in elderly affected patients. So far, mesenchymal stem cells have proven to be a viable option to ameliorate certain aspects of neurodegeneration, as they possess high proliferative rate and differentiate in vitro into multiple lineages. However, accumulating data have demonstrated that during longterm culture, mesenchymal stem cells undergo spontaneous transformation. Transformed mesenchymal stem cells show typical features of senescence, including the progressive shortening of telomers, which results in cell loss and, as a consequence, hampered regenerative potential. These evidences, in line with those observed in mesenchymal stem cells isolated from old donors, suggest that senescence may represent a limit to mesenchymal stem cells exploitation in therapy, prompting scholars to either find alternative sources of pluripotent cells or to arrest the age-re- lated transformation. In the present review, we summarize findings from recent literature, and critically discuss some of the major hurdles encountered in the search of appropriate sources of mesenchymal stem cells, as well as benefits arising from their use in neurodegenerative diseases. Finally, we provide some insights that may aid in the development of strategies to arrest or, at least, delay the aging of mesenchymal stem cells to improve their therapeutic potential.

Characterization of nucleohistone and nucleoprotamine components in the mature human sperm nucleus

Aim： To simultaneously determine the localization of histones and protamines within human sperm nuclei. Methods： Immunofluorescence of the core histones and protamines and fluorescence in situ hybridization of the telomere region of chromosome 16 was assessed in decondensed human sperm nuclei. Results： Immunofluorescent localization of histones, protamine 1 （PRM1） and protamine 2 （PRM2） along with fluorescence in situ hybridization localization of chromosome 16 telomeric sequences revealed a discrete distribution in sperm nuclei. Histones localized to the posterior ring region （i.e. the sperm nuclear annulus）, whereas PRM1 and PRM2 appeared to be dispersed throughout the entire nucleus. Conclusion： The co-localization of the human core sperm histones with the telomeric regions of chromosome 16 is consistent with the reorganization of specific non-protamine regions into a less compacted state.

Influence of the h TERT rs2736100 polymorphism on telomere length in gastric cancer

AIM: To investigate the functional consequences of rs2736100 polymorphism in telomere length and examine its link to gastric cancer risk.METHODS: Telomere length and human telomerase reverse transcriptase(h TERT) m RNA expression were measured in 35 gastric cancer tissues and 5 cell lines and correlated to rs2736100 polymorphism. The relationship between rs2736100 polymorphism and the risk of gastric cancer were examined in 243 gastric cancer patients and 246 healthy individuals.RESULTS: The rs2736100 A allele carrier is closely associated with reduced h TERT m RNA expression and shortened telomere length in gastric cancer tissue and cell lines. When gastric cancers were stratified by histological subtype,telomere length and h TERT m RNA levels were significantly increased in those with the C/C genotype in intestinal-type gastric cancer,but not in diffuse-type gastric cancer. Interestingly,there was no significant difference in the genotype and allele frequencies of the rs2736100 polymorphism between the patients with gastric cancer and healthy controls.CONCLUSION: The rs2736100 polymorphism of the h TERT gene is involved in the regulation of h TERT expression and telomere length,but not in the risk of gastric cancer.

Telomere,telomerase and digestive cancer

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Cytogenetic characterization and description of an X_1X_1X_2X_2/X_1X_2Y sex chromosome system in Collichthys lucidus(Richardson,1844)

The chromosomes of spinyhead croaker Collichthys lucidus（Richardson,1844） were characterized for the first time by fluorescence staining,self genomic in situ hybridization（self-GISH）,and multicolor fluorescence in situ hybridization（FISH） with 18 SrDNA,5 SrDNA and telomeric sequence probes.The female karyotype has exclusively 24 pairs of acrocentric chromosomes（2 n=48 a,NF=48）,while the male one consists of 22 pairs of acrocentric chromosomes,2 monosomic acrocentric chromosomes and a metacentric chromosome（2 n=1 m＋46 a,NF=48）.The difference between female and male karyotypes indicates the presence of a sex chromosome of X1 X1 X2 X2/X1 X2 Y type,where Y is the unique metacentric chromosome in the male karyotype.As revealed by FISH,5 S r DNA and 18 S r DNA sites were mapped at syntenic position of the largest acrocentric chromosome（X_1）,and the short arms of the Y chromosome as well.An X_1-chromosome specific interstitial telomeric signal（ITS） was detected overlapping the 5 S r DNA sites.In addition,self-GISH revealed that the repetitive DNAs accumulated on all the putative sex chromosome.Chromosome fusion accompanied by a partial deletion in the ancestral karyotype（2 n=48 a） is hypothesized for the origin of such multiple sex chromosome system.The present study,as the first description of differentiated sex chromosome in family Sciaenidae,will give clues to the studies on the sex chromosome of other Sciaenids.

Telomeric associations of chromosomes in patients with esophageal squamous cell carcinomas

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Telomeres,telomerase and colorectal cancer

Colorectal cancer(CRC)is the third most common cancer worldwide and,despite improved treatments,is still an important cause of cancer-related deaths.CRC encompasses a complex of diseases arising from a multistep process of genetic and epigenetic events.Besides heterogeneity in the molecular and biological features of CRC,chromosomal instability is a hallmark of cancer and cancer cells may also circumvent replicative senescence and acquire the ability to sustain unlimited proliferation.Telomere/telomerase interplay is an important mechanism involved in both genomic stability and cellular replicative potential,and its dysfunction plays a key role in the oncogenetic process.The erosion of telomeres,mainly because of cell proliferation,may be accelerated by specific alterations in the genes involved in CRC,such as APC and MSH2.Although there is general agreement that the shortening of telomeres plays a role in the early steps of CRC carcinogenesis by promoting chromosomal instability,the prognostic role of telomere length in CRC is still under debate.The activation of telomerase reverse transcriptase(TERT),the catalytic component of the telomerase complex,allows cancer cells to grow indefinitely by maintaining the length of the telomeres,thus favouring tumour formation/progression.Several studies indicate that TERT increases with disease progression,and most studies suggest that telomerase is a useful prognostic factor.Plasma TERT mRNA may also be a promising marker for the minimally invasive monitoring of disease progression and response to therapy.

Expression of hTERT, p53 and PCNA in Cystitis Glandularis

To examine the expression of human telomere reverse transcriptase （hTERT）, p53 and proliferating cell nuclear antigen （PCNA） in cystitis glandulafis, 38 patients were divided into two grouips： group A （including 18 cases of papillary cystitis glandularis） and group B （including 20 subjects with normal bladder mucosa）. All the cases were immunohistochemically examined by using antibodies specifically against p53 and PCNA, and hTERT was determined by in situ hybridization. hTERT was found in 6 cases （33.3%） and p53 was detected in 4 cases （22.2%） in group A, while they were not detected in group B. There were significant differences in hTERT and p53 expression between groups A and B （P〈0.05 for both）. PCNA was detected in 7 cases （38.9%） in group A and 1 case （5.0%） in group B, and significant difference in PCNA expression was found between the two groups （P〈0.05）. The expressions of hTERT, p53 and PCNA were significantly higher in group A than in group B, suggesting that papillary cystitis glandularis is predisposed to cancerous change, and p53, PCNA, hTERT may be related to the malignant alteration.

RELATIONSHIP BETWEEN TELOMERE LENGTH AND RADIOSENSITIVITY IN VARIOUS HUMAN CANCER CELL LINES

Objective： To investigate the relationship between telomere length and radiosensitivity in various human cancer cell lines with the expectation to find a valid and common predictor of radiosensitivity for different cancers. Methods： Eight human cancer cell lines were used, including five human breast cancer cell lines （ZR-75-30, MCF-7, MDA-MB-435S, T-47-D, F539-1590）, two human larynx squamous carcinoma cell lines （Hep-2 and Hep-2R） and a human malignant glioma cell line （U251）. Among them, the radioresistant cell line Hep-2R was isolated and established from a radiosensitive human larynx squamous carcinoma cell line Hep-2 by our center. The radiobiological characteristics of the eight lines were analyzed by the method of colony-forming assay and the radiosensitivity parameters were calculated. Telomere length was analyzed by TRF （mean Telomere Restriction Fragments） length assay. Results： The radioresistance of Hep-2R cell line proved to be stable in long-term passaged cultures as well as in frozen samples. Radiosensitivity parameters are different among those lines. The SF2 values of Hep-2 and U251 are 0.4148 and 0.7520, respectively; The SF2 values of breast cancer cell lines are between those of Hep-2 and U251. The TRF of Hep-2R is 11.12Kb, longer than three times that of its parental counterpart. There is a positive correlation both between SF2 and TRF （r=-0.786, P〈0.05）, and between Do and TRF （r=0.905, P〈0.01）. Conclusion： It is concluded that radiosensitivity and telomere length （TRF） are negatively correlated, TRF could be a valid predictor for radiosensitivity.