Bioisosteric replacement strategy leads to novel DNA gyrase B inhibitors with improved potencies and properties.

The identification of novel 4-hydroxy-2-quinolone-3-carboxamide antibacterials with improved properties is of great value for the control of antibiotic resistance. In this study, a series of N-heteroaryl-substituted 4-hydroxy-2-quinolone-3-carboxamides were developed using the bioisosteric replacement strategy. As a result of our research, we discovered the two most potent GyrB inhibitors (WBX7 and WBX18), with IC50 values of 0.816 µM and 0.137 µM, respectively. Additional antibacterial activity screening indicated that WBX18 possesses the best antibacterial activity against MRSA, VISA, and VRE strains, with MIC values rangingbetween0.5and 2 µg/mL, which was 2 to over 32 times more potent than that of vancomycin. In vitro safety and metabolic stability, as well as in vivo pharmacokinetics assessments revealed that WBX18 is non-toxic to HUVEC and HepG2, metabolically stable in plasma and liver microsomes (mouse), and displays favorable in vivo pharmacokinetic properties. Finally, docking studies combined with molecular dynamic simulation showed that WBX18 could stably fit in the active site cavity of GyrB.

Bromine-Enhanced Generation and Epoxidation of Ethylene in Tandem CO2 Electrolysis Towards Ethylene Oxide.

The indirect electro-epoxidation of ethylene (C2 H4 ), produced from CO2 electroreduction (CO2 R), holds immense promise for CO2 upcycling to valuable ethylene oxide (EO). However, this process currently has a mediocre Faradaic efficiency (FE) due to sluggish formation and rapid dissociation of active species, as well as reductive deactivation of Cu-based electrocatalysts during the conversion of C2 H4 to EO and CO2 to C2 H4 , respectively. Herein, we report a bromine-induced dual-enhancement strategy designed to concurrently promote both C2 H4 -to-EO and CO2 -to-C2 H4 conversions, thereby improving EO generation, using single-atom Pt on N-doped CNTs (Pt1 /NCNT) and Br- -bearing porous Cu2 O as anode and cathode electrocatalysts, respectively. Physicochemical characterizations including synchrotron X-ray absorption, operando infrared spectroscopy, and quasi in situ Raman spectroscopy/electron paramagnetic resonance with theoretical calculations reveal that the favorable Br2 /HBrO generation over Pt1 /NCNT with optimal intermediate binding facilitates C2 H4 -to-EO conversion with a high FE of 92.2 %, and concomitantly, the Br- with strong nucleophilicity protects active Cu+ species in Cu2 O effectively for improved CO2 -to-C2 H4 conversion with a FE of 66.9 % at 800 mA cm-2 , superior to those in the traditional chloride-mediated case. Consequently, a single-pass FE as high as 41.1 % for CO2 -to-EO conversion can be achieved in a tandem system.

Iron accumulation and axonal damage of cerebellum in idiopathic cervical dystonia.

BACKGROUND AND PURPOSE: Postmortem brain study indicated that cerebellar Purkinje cell (PC) loss might be a pathological finding in patients with inherited and idiopathic cervical dystonia (ICD). The analysis of conventional magnetic resonance imaging brain scans failed to yield support for this finding. Previous studies have identified that iron overload can be the consequence of neuron death. The objectives of this study were to investigate iron distribution and demonstrate changes in axons in the cerebellum, providing evidence for PC loss in patients with ICD. METHODS: Twenty-eight patients with ICD (20 females) and 28 age- and sex-matched healthy controls were recruited. A spatially unbiased infratentorial template was applied to perform cerebellum optimized quantitative susceptibility mapping and diffusion tensor analysis based on magnetic resonance imaging. Voxel-wise analysis was performed to assess cerebellar tissue magnetic susceptibility and fractional anisotropy (FA) alterations, and the clinical relevance of these findings was investigated in the patients with ICD. RESULTS: Increased susceptibility values revealed by quantitative susceptibility mapping in the right lobule CrusI, CrusII, VIIb, VIIIa, VIIIb and IX were found in the patients with ICD. A reduced FA value was found across almost all the cerebellum; an FA value of the significant clusters within the right lobule VIIIa significantly correlated with the motor severity of patients with ICD (r = -0.575, p = 0.002). CONCLUSIONS: Our study provided evidence for cerebellar iron overload and axonal damage in patients with ICD, which may indicate PC loss and related axonal changes. These results provide evidence for the neuropathological findings in patients with ICD and further highlight the cerebellar involvement in the pathophysiology of dystonia.

Interheteromolecular Hyperconjugation Boosts (De)hydrogenation for Reversible H2 Storage.

Interheteromolecular hyperconjugation is ubiquitous in organic systems, affecting bond length, dipole moments, conformations and so on, while its effect on (de)hydrogenation reactivity in a heterogeneous thermo-catalytic system has rarely been explored. Herein, the N-heterocycles containing a benzene ring and aliphatic chain [N-ethylcarbazole (NEC) and N-propylcarbazole (NPC)] were utilized to study the correlation between interheteromolecular hyperconjugation and catalytic (de)hydrogenation. Density functional theory calculations, variable-temperature 1 H nuclear magnetic resonance spectroscopy, and catalytic experiments showed that the presented hyperconjugation between NEC and NPC weakened the electron cloud density of aromatic rings and thus facilitated the reactivity with hydrogen featuring unpaired electrons. Therefore, an extremely low temperature of 80 °C was enough for the hydrogenation. Moreover, this interheteromolecular hyperconjugation was general in other N-heterocycles (e. g., N-methyindole and NPC) and was also effective to (de)deuterate as revealed by isotope experiments. This work expands the application of interheteromolecular hyperconjugation to heterogeneous thermocatalysis for reversible H2 storage.

Discovery of N-quinazolinone-4-hydroxy-2-quinolone-3-carboxamides as DNA gyrase B-targeted antibacterial agents.

Emerging drug resistance is generating an urgent need for novel and effective antibiotics. A promising target that has not yet been addressed by approved antibiotics is the bacterial DNA gyrase subunit B (GyrB), and GyrB inhibitors could be effective against drug-resistant bacteria, such as methicillin-resistant S. aureus (MRSA). Here, we used the 4-hydroxy-2-quinolone fragment to search the Specs database of purchasable compounds for potential inhibitors of GyrB and identified AG-690/11765367, or f1, as a novel and potent inhibitor of the target protein (IC50: 1.21 µM). Structural modification was used to further identify two more potent GyrB inhibitors: f4 (IC50: 0.31 µM) and f14 (IC50: 0.28 µM). Additional experiments indicated that compound f1 is more potent than the others in terms of antibacterial activity against MRSA (MICs: 4-8 µg/mL), non-toxic to HUVEC and HepG2 (CC50: approximately 50 µM), and metabolically stable (t1/2: > 372.8 min for plasma; 24.5 min for liver microsomes). In summary, this study showed that the discovered N-quinazolinone-4-hydroxy-2-quinolone-3-carboxamides are novel GyrB-targeted antibacterial agents; compound f1 is promising for further development.

Characterization and Antioxidant Activity of Mannans from Saccharomyces cerevisiae with Different Molecular Weight.

Polysaccharides were extracted from natural sources with various biological activities, which are strongly influenced by their chemical structure and molecular weight. In this research, mannans polysaccharides were obtained from Saccharomyces cerevisiae by ethanol precipitation. The molecular weight of YM50, YM70, and YM90 mannans was 172.90 kDa, 87.09 kDa, and 54.05 kDa, respectively. Scanning electron microscopy of YM 90 mannans showed a rough surface with numerous cavities, while the surfaces of YM50 and YM70 were relatively smooth. Sepharose CL-6B and FTIR indicated that mannans had the characteristic bands of polysaccharides. The antioxidant activities of polysaccharides were evaluated in vitro using various assays. Mannans showed a good scavenging activity of DPPH radicals which depend on the molecular weight and concentration, and a higher scavenging activity of hydroxyl radical than ferric-reducing power activities. For the three types of mannans, cytotoxicity and hemolytic activity were rarely detected in mice erythrocytes and Caco-2 cells. Those results could contribute to the further application of mannans from Saccharomyces cerevisiae in the food and medicine industry.

The association between entrapment and depression among migrant workers in China: a social rank theory based study.

BACKGROUND: Migrant workers are a group susceptible for depression evolution due to occupational maladaptive triggers. The social rank theory illustrates the pathology process from defensive adaptation to depression, pointing out the early prevention of depression by discovering entrapment. This study aims to reveal the relationship between migrant workers' entrapment and depressive symptoms. METHODS: A total of 1805 migrant workers in Shenzhen were recruited by stratified multi-stage sampling. Sample's demographic, behavioral and psychosocial characteristics were described and analyzed to reveal the relationship between entrapment and depressive symptoms. The Receiver Operator Characteristic was performed to find the optimal cut-off point of Entrapment Scale for predicting depressive symptoms. RESULTS: In the binary logistic regression of sociodemographic variables, migrant workers who were married (univariate odds ratio (ORu) = 0.69, 95% Confidence Interval (CI) = 0.56-0.84), owned 1 or 2 children (ORu = 0.71, 95% CI = 0.58-0.86), had been working over 10 years (ORu = 0.71, 95% CI = 0.54-0.95), earned > 4999 yuan per month (ORu = 0.68, 95% CI = 0.47-0.99; multivariate odds ratio (ORm) = 0.57, 95% CI = 0.38-0.87) or with low risks of alcohol use disorders (ORu = 0.51, 95% CI = 0.34-0.75) had lower risks of depressive symptoms. After adjusted the aforementioned significant sociodemographic variables, migrant workers with severer entrapment were more likely to have depressive symptoms (adjusted odds ratio (ORa) = 1.13, 95% CI = 1.12-1.15). Besides, the study proved the reliability and validity of the Chinese version Entrapment Scale, preferring a two-dimensional structure, and 11 was the optimal cut-off value of this scale for predicting depressive symptoms among migrant workers. CONCLUSIONS: This result indicates the potential value of entrapment according to the social rank theory on facilitating early prevention of migrant works' depression and the application value of Entrapment Scale for effectively measuring mental status among migrant workers.

Emerging Electrocatalysts for Water Oxidation under Near-Neutral CO2 Reduction Conditions.

Electrocatalytic CO2 reduction reaction (CO2 RR), which produces valuable fuels and chemicals under near-neutral conditions, offers a renewable approach to alleviate the global energy crisis as well as the increasing concerns on climate change. However, to implement this strategy, one of the major challenges, the sluggish kinetics of the paired oxygen evolution reaction (OER) at anode, needs to be surmounted. It is therefore highly desirable to explore high-performance and cost-effective OER electrocatalysts suitable for CO2 RR conditions, which is very different from those widely investigated under acidic or alkaline conditions. In this review, the ongoing development of OER electrocatalysts under near pH-neutral CO2 -saturated (bi)carbonate solutions are highlighted and the future opportunities are discussed. It is started with a brief introduction on OER paired with CO2 RR, the relevant theoretical tools such as density functional theory (DFT) and particularly machine learning (ML), and the operando characterization techniques. Then, there are some detailed discussions of recent progress on the rational design of OER electrocatalysts under CO2 RR conditions ranging from noble-metal oxides to nonprecious metal phosphides, carbonates, (hydro)oxides, and so on. Finally, a perspective for developing OER electrocatalysts integrated with CO2 electroreduction is proposed.

AdipoRon Attenuates Hypertension-Induced Epithelial-Mesenchymal Transition and Renal Fibrosis via Promoting Epithelial Autophagy.

Hypertension-induced epithelial-mesenchymal transition (EMT) is a major mechanism of renal fibrosis. Adiponectin protects against hypertension-induced target organ damage. AdipoRon is an orally active synthetic adiponectin receptor agonist. However, it is unclear whether AdipoRon could attenuate EMT and renal fibrosis in hypertensive mice. C57BJ/6J mice were utilized to induce DOCA-salt-sensitive hypertensive model. Hypertension results in an altered adiponectin expression and promotes EMT in the kidney. In vitro, AdipoRon inhibits aldosterone (Aldo)-induced EMT and promotes autophagic flux in HK-2 epithelial cells. Mechanically, AdipoRon activates AMPK/ULK1 pathway in epithelial cells. Blockade of AMPK activation, as well as inhibition of autophagy, blocks the effects of AdipoRon on Aldo-induced EMT. Moreover, AdipoRon treatment promotes autophagy and improves renal fibrosis in DOCA-salt-hypertensive mice. Our data suggest that AdipoRon could be a potential therapeutic option to prevent renal fibrosis in hypertensive patients. Graphical abstract.

Pose Filter-Based Ensemble Learning Enables Discovery of Orally Active, Nonsteroidal Farnesoid X Receptor Agonists.

Farnesoid X receptor (FXR) agonists can reverse dysregulated bile acid metabolism, and thus, they are potential therapeutics to prevent and treat nonalcoholic fatty liver disease. The low success rate of FXR agonists' R&D and the side effects of clinical candidates such as obeticholic acid make it urgent to discover new chemotypes. Unfortunately, structure-based virtual screening (SBVS) that can speed up drug discovery has rarely been reported with success for FXR, which was likely hindered by the failure in addressing protein flexibility. To address this issue, we devised human FXR (hFXR)-specific ensemble learning models based on pose filters from 24 agonist-bound hFXR crystal structures and coupled them to traditional SBVS approaches of the FRED docking plus Chemgauss4 scoring function. It turned out that the hFXR-specific pose filter ensemble (PFE) was able to improve ligand enrichment significantly, which rendered 3RUT-based SBVS with its PFE the ideal approach for FXR agonist discovery. By screening of the Specs chemical library and in vitro FXR transactivation bioassay, we identified a new class of FXR agonists with compound XJ034 as the representative, which would have been missed if the PFE was not coupled. Following that, we performed in-depth biological studies which demonstrated that XJ034 resulted in a downtrend of intracellular triglyceride in vitro, significantly decreased the serum/liver TG in high fat diet-induced C57BL/6J obese mice, and more importantly, showed metabolic stabilities in both plasma and liver microsomes. To provide insight into further structure-based lead optimization, we solved the crystal structure of hFXR complexed with compound XJ034, uncovering a unique hydrogen bond between compound XJ034 and residue Y375. The current work highlights the power of our pose filter-based ensemble learning approach in terms of scaffold hopping and provides a promising lead compound for further development.

N-thiadiazole-4-hydroxy-2-quinolone-3-carboxamides bearing heteroaromatic rings as novel antibacterial agents: Design, synthesis, biological evaluation and target identification.

Due to the occurrence of antibiotic resistance, bacterial infectious diseases have become a serious threat to public health. To overcome antibiotic resistance, novel antibiotics are urgently needed. N-thiadiazole-4-hydroxy-2-quinolone-3-carboxamides are a potential new class of antibacterial agents, as one of its derivatives was identified as an antibacterial agent against S. aureus. However, no potency-directed structural optimization has been performed. In this study, we designed and synthesized 37 derivatives, and evaluated their antibacterial activity against S. aureus ATCC29213, which led to the identification of ten potent antibacterial agents with minimum inhibitory concentration (MIC) values below 1 µg/mL. Next, we performed bacterial growth inhibition assays against a panel of drug-resistant clinical isolates, including methicillin-resistant S. aureus, and cytotoxicity assays with HepG2 and HUVEC cells. One of the tested compounds named 1-ethyl-4-hydroxy-2-oxo-N-(5-(thiazol-2-yl)-1,3,4-thiadiazol-2-yl)-1,2-dihydroquinoline-3-carboxamide (g37) showed 2 to 128-times improvement compared with vancomycin in term of antibacterial potency against the tested strains (MICs: 0.25-1 µg/mL vs. 1-64 µg/mL) and an optimal selective toxicity (HepG2/MRSA, 110.6 to 221.2; HUVEC/MRSA, 77.6-155.2). Further, comprehensive evaluation indicated that g37 did not induce resistance development of MRSA over 20 passages, and it has been confirmed as a bactericidal, metabolically stable, orally active antibacterial agent. More importantly, we have identified the S. aureus DNA gyrase B as its potential target and proposed a potential binding mode by molecular docking. Taken together, the present work reports the most potent derivative of this chemical series (g37) and uncovers its potential target, which lays a solid foundation for further lead optimization facilitated by the structure-based drug design technique.

Bacterial Lipoprotein Biosynthetic Pathway as a Potential Target for Structure-based Design of Antibacterial Agents.

BACKGROUND: Antibiotic resistance is currently a serious problem for global public health. To this end, discovery of new antibacterial drugs that interact with novel targets is important. The biosynthesis of lipoproteins is vital to bacterial survival and its inhibitors have shown efficacy against a range of bacteria, thus bacterial lipoprotein biosynthetic pathway is a potential target. METHODS: At first, the literature that covered the basic concept of bacterial lipoprotein biosynthetic pathway as well as biochemical characterization of three key enzymes was reviewed. Then, the recently resolved crystal structures of the three enzymes were retrieved from Protein Data Bank (PDB) and the essential residues in the active sites were analyzed. Lastly, all the available specific inhibitors targeting this pathway and their Structure-activity Relationship (SAR) were discussed. RESULTS: We briefly introduce the bacterial lipoprotein biosynthetic pathway and describe the structures and functions of three key enzymes in detail. In addition, we present much knowledge on ligand recognition that may facilitate structure-based drug design. Moreover, we focus on the SAR of LspA inhibitors and discuss their potency and drug-likeness. CONCLUSION: This review presents a clear background of lipoprotein biosynthetic pathway and provides practical clues for structure-based drug design. In particular, the most up-to-date knowledge on the SAR of lead compounds targeting this pathway would be a good reference for discovery of a novel class of antibacterial agents.

Morphology-Controlled Synthesis of H-type MFI Zeolites with Unique Stacked Structures through a One-Pot Solvent-Free Strategy.

H-type aluminosilicate zeolites are extensively used as solid-acid catalysts and support materials in industrial catalysis. However, the conventional synthesis methods involving hydrothermal syntheses and ion-exchange processes suffer from severe water pollution and toxic gas emissions. Herein, H-type MFI zeolite catalysts with a unique stacked structure were directly synthesized in the presence of NH4 F and with the help of zeolite confinement through a solvent-free route without further ion-exchange procedures. A range of ex situ and in situ characterization procedures were used to provide evidence of the simultaneous use of pre-made ZSM-5 and NH4 F as a confined Al source and mineralizer, respectively. The confined zeolite framework of ZSM-5 prevented the formation of AlFx species between NH4 F and Al atoms, ensuring that the prepared samples had desirable acidic properties. Moreover, the resulting morphology could be controlled by using different silica substrates. The obtained H-type MFI zeolites showed excellent catalytic performance in methanol-to-gasoline reactions owing to their unique structure and directly exposed acidic sites. The developed one-pot strategy provides an alternative method for the facile synthesis of H-type zeolites with defined morphology.

Discovery of potent PTP1B inhibitors via structure-based drug design, synthesis and in vitro bioassay of Norathyriol derivatives.

Protein tyrosine phosphatase 1B (PTP1B) has recently been identified as a potential target of Norathyriol. Unfortunately, Norathyriol is not a potent PTP1B inhibitor, which somewhat hinders its further application. Based on the fact that no study on the relationship of chemical structure and PTP1B inhibitory activity of Norathyriol has been reported so far, we attempted to perform structural optimization so as to improve the potency for PTP1B. Via structure-based drug design (SBDD), a rational strategy based on the binding mode of Norathyriol to PTP1B, we designed 26 derivatives with substitutions at the four phenolic hydroxyl groups of Norathyriol. By chemical synthesis and in vitro bioassay, we identified seven PTP1B inhibitors that were more potent than Norathyriol, of which XWJ24 showed the highest potency (IC50: 0.6 µM). We also found out that XWJ24 was a competitive inhibitor and showed the 4.5-fold selectivity over its close homolog, TC-PTP. Through molecular docking of XWJ24 against PTP1B, we highlighted the essential role of its hydrogen bond with Asp181 for PTP1B inhibition and identified a potential halogen bond with Asp48 that was not observed for Norathyriol. The current data indicate that our SBDD strategy is effective to discover potent PTP1B-targeted Norathyriol derivatives, and XWJ24 is a promising lead compound for further development.

The discovery of novel HDAC3 inhibitors via virtual screening and in vitro bioassay.

Histone deacetylase 3 (HDAC3) is a potential target for the treatment of human diseases such as cancers, diabetes, chronic inflammation and neurodegenerative diseases. Previously, we proposed a virtual screening (VS) pipeline named "Hypo1_FRED_SAHA-3" for the discovery of HDAC3 inhibitors (HDAC3Is) and had thoroughly validated it by theoretical calculations. In this study, we attempted to explore its practical utility in a large-scale VS campaign. To this end, we used the VS pipeline to hierarchically screen the Specs chemical library. In order to facilitate compound cherry-picking, we then developed a knowledge-based pose filter (PF) by using our in-house quantitative structure activity relationship- (QSAR-) modelling approach and coupled it with FRED and Autodock Vina. Afterward, we purchased and tested 11 diverse compounds for their HDAC3 inhibitory activity in vitro. The bioassay has identified compound 2 (Specs ID: AN-979/41971160) as a HDAC3I (IC50 = 6.1 µM), which proved the efficacy of our workflow. As a medicinal chemistry study, we performed a follow-up substructure search and identified two more hit compounds of the same chemical type, i.e. 2-1 (AQ-390/42122119, IC50 = 1.3 µM) and 2-2 (AN-329/43450111, IC50 = 12.5 µM). Based on the chemical structures and activities, we have demonstrated the essential role of the capping group in maintaining the activity for this class of HDAC3Is. In addition, we tested the hit compounds for their in vitro activities on other HDACs, including HDAC1, HDAC2, HDAC8, HDAC4 and HDAC6. We have identified these compounds are HDAC1/2/3 selective inhibitors, of which compound 2 show the best selectivity profile. Taken together, the present study is an experimental validation and an update to our earlier VS strategy. The identified hits could be used as starting structures for the development of highly potent and selective HDAC3Is.

A concise synthesis of (±)-7-O-galloyltricetiflavan.

(±)-7-O-galloyltricetiflavan (1a) was synthesized successfully in five steps from the commercially available trihydroxyacetophenone (2) and trimethoxybenzoyl chloride (3). The flavone 4a was prepared in a one-pot reaction and it gave hex-O-methylflavan 6 followed by acylation and reduction. However, the demethylation of flavan 6, 5-O-acetylflavan 10 and 5-O-phenylacetylflavan 11 by BBr3 gave all the hydrolyzed fragments 7 and 8 as the major products. By contrast, in the same condition, hept-O-methylflavan 9 could provide the desired product (±)-7-O-galloyltricetiflavan (1a) in 91% yield. The additional 5-O-B-Br2 complex may stabilize the ester bond during the demethylation process.

The association between telomere length and cancer risk in population studies.

Telomeres are crucial in the maintenance of chromosome integrity and genomic stability. A series of epidemiological studies have examined the association between telomere length and the risk of cancers, but the findings remain conflicting. We performed literature review and meta-analysis to demonstrate the relationship between telomere length and cancer risk. A total of 23,379 cases and 68,792 controls from 51 publications with 62 population studies were included in this meta-analysis to assess the association between overall cancer or cancer-specific risk and telomere length. General association and dose-response relationship were evaluated based on two and three groups, respectively. The estimates of association were evaluated with odds ratios and 95% confidence intervals by the random-effects or fixed-effects model based on heterogeneity test. We observed a non-significant association between short telomeres and overall risk of cancer. Convincing evidence was observed for the association of short telomeres with an increased risk of gastrointestinal tumor and head and neck cancer. Significant dose-response associations were also observed for gastrointestinal tumor and head and neck cancer. Our findings indicate that telomeres may play diverse roles in different cancers, and short telomeres may be risk factors for the tumors of digestive system.

Telomere length, genetic variants and risk of squamous cell carcinoma of the head and neck in Southeast Chinese.

Telomere dysfunction participates in malignant transformation and tumorigenesis. Previous studies have explored the associations between telomere length (TL) and cancer susceptibility; however, the findings are inconclusive. The associations between genetic variants and TL have been verified by quite a few genome-wide association studies (GWAS). Yet, to date, there was no published study on the relationship between TL, related genetic variants and susceptibility to squamous cell carcinoma of the head and neck (SCCHN) in Chinese. Hence, we detected relative telomere length (RTL) by using quantitative PCR and genotyped seven selected single nucleotide polymorphisms by TaqMan allelic discrimination assay in 510 SCCHN cases and 913 controls in southeast Chinese. The results showed that RTL was significantly associated with SCCHN risk [(adjusted odds ratio (OR) = 1.19, 95% confidence interval (CI) = 1.08-1.32, P = 0.001]. Furthermore, among seven selected SNPs, only G allele of rs2736100 related to RTL in Caucasians was significantly associated with both the decreased RTL (P = 0.002) and the increased susceptibility to SCCHN in Chinese (additive model: adjusted OR = 1.17, 95%CI = 1.00-1.38, P = 0.049). These findings provide evidence that shortened TL is a risk factor for SCCHN, and genetic variants can contribute to both TL and the susceptibility to SCCHN in southeast Chinese population.

U-shaped association between telomere length and esophageal squamous cell carcinoma risk: a case-control study in Chinese population.

Telomeres play a critical role in biological ageing by maintaining chromosomal integrity and preventing chromosome ends fusion. Epidemiological studies have suggested that inter-individual differences of telomere length could affect predisposition to multiple cancers, but evidence regarding esophageal squamous cell carcinoma (ESCC) was still uncertain. Several telomere length-related single nucleotide polymorphisms (TLSNPs) in Caucasians have been reported in genome-wide association studies. However, the effects of telomere length and TL-SNPs on ESCC development are unclear. Therefore, we conducted a case-control study (1045 ESCC cases and 1433 controls) to evaluate the associations between telomere length, TL-SNPs, and ESCC risk in Chinese population. As a result, ESCC cases showed overall shorter relative telomere length (RTL) (median: 1.34) than controls (median: 1.50, P < 0.001). More interestingly, an evident nonlinear U-shaped association was observed between RTL and ESCC risk (P < 0.001), with odds ratios (95% confidence interval) equal to 2.40 (1.84-3.14), 1.36 (1.03-1.79), 1.01 (0.76-1.35), and 1.37 (1.03-1.82) for individuals in the 1st (the shortest), 2nd, 3rd, and 5th (the longest) quintile, respectively, compared with those in the 4th quintile as reference group. No significant associations were observed between the eight reported TL-SNPs and ESCC susceptibility. These findings suggest that either short or extremely long telomeres may be risk factors for ESCC in the Chinese population.