Acetylation of aldehyde dehydrogenase ALDH1L2 regulates cellular redox balance and the chemosensitivity of colorectal cancer to 5-fluorouracil.

Folate-mediated one-carbon metabolism (FOCM) is crucial in sustaining rapid proliferation and survival of cancer cells. The folate cycle depends on a series of key cellular enzymes, including aldehyde dehydrogenase 1 family member L2 (ALDH1L2) that is usually overexpressed in cancer cells, but the regulatory mechanism of ALDH1L2 remains undefined. In this study, we observed the significant overexpression of ALDH1L2 in colorectal cancer (CRC) tissues, which is associated with poor prognosis. Mechanistically, we identified that the acetylation of ALDH1L2 at the K70 site is an important regulatory mechanism inhibiting the enzymatic activity of ALDH1L2 and disturbing cellular redox balance. Moreover, we revealed that sirtuins 3 (SIRT3) directly binds and deacetylates ALDH1L2 to increase its activity. Interestingly, the chemotherapeutic agent 5-fluorouracil (5-Fu) inhibits the expression of SIRT3 and increases the acetylation levels of ALDH1L2 in colorectal cancer cells. 5-Fu-induced ALDH1L2 acetylation sufficiently inhibits its enzymatic activity and the production of NADPH and GSH, thereby leading to oxidative stress-induced apoptosis and suppressing tumor growth in mice. Furthermore, the K70Q mutant of ALDH1L2 sensitizes cancer cells to 5-Fu both in vitro and in vivo through perturbing cellular redox and serine metabolism. Our findings reveal an unknown 5-Fu-SIRT3-ALDH1L2 axis regulating redox homeostasis, and suggest that targeting ALDH1L2 is a promising therapeutic strategy to sensitize tumor cells to chemotherapeutic agents.

Association between modifiable lifestyle factors and telomere length: a univariable and multivariable Mendelian randomization study.

BACKGROUND: Telomere length has long been recognized as a valuable biomarker of aging and is inversely correlated with chronological age. Various lifestyle factors have been implicated in telomere shortening or preservation; however, the association between lifestyle factors and telomere length remains controversial. To address this issue, we conducted a Mendelian randomization (MR) analysis to investigate the potential causal associations between multiple lifestyle factors and telomere length. METHODS: Independent genetic variants strongly associated with lifestyle factors (tobacco smoking, sleep duration, insomnia, and physical activity) were selected as instrumental variables from corresponding genome-wide association studies (GWASs). Summary-level data for telomere length was obtained from a GWAS comprising 472,174 European ancestries. Univariable and multivariable MR analyses were performed to assess the relationships. RESULTS: The genetic liability to lifetime smoking was robustly associated with shorter telomere length (odd ratio [OR]: 0.882; 95% confidence interval [CI]: 0.847-0.918). Genetically predicted insomnia was also linked to shorter telomere length (OR: 0.972; 95% CI: 0.959-0.985), while no significant association was observed between sleep duration and telomere length. Furthermore, a suggestive association was found between moderate-to-vigorous physical activity and longer telomere length (OR: 1.680; 95% CI: 1.115-2.531). In multivariable MR analyses, adjusting for potential mediators such as body mass index, type 2 diabetes, alcohol consumption, and alcohol use disorder, the associations of lifetime smoking and insomnia with telomere length remained robust. CONCLUSION: Our findings suggest that smoking and insomnia may contribute to telomere shortening, while physical activity may play a role in telomere length maintenance. These findings underscore the importance of managing positive risk factors and adopting a healthy lifestyle to promote telomere health.

Stem cell antigen-1+cell-derived fibroblasts are crucial for cardiac fibrosis during heart failure.

AIMS: Mesenchymal stem cells (MSCs) present in the heart cannot differentiate into cardiomyocytes, but may play a role in pathological conditions. Therefore, the aim of this study was to scrutinise the role and mechanism of MSC differentiation in vivo during heart failure. METHODS AND RESULTS: We performed single-cell RNA sequencing of total non-cardiomyocytes from murine and adult human hearts. By analysing the transcriptomes of single cells, we illustrated the dynamics of the cell landscape during the progression of heart hypertrophy, including those of stem cell antigen-1 (Sca1)+ stem/progenitor cells and fibroblasts. By combining genetic lineage tracing and bone marrow transplantation models, we demonstrated that non-bone marrow-derived Sca1+ cells give rise to fibroblasts. Interestingly, partial depletion of Sca1+ cells alleviated the severity of myocardial fibrosis and led to a significant improvement in cardiac function in Sca1-CreERT2;Rosa26-eGFP-DTA mice. Similar non-cardiomyocyte cell composition and heterogeneity were observed in human patients with heart failure. Mechanistically, our study revealed that Sca1+ cells can transform into fibroblasts and affect the severity of fibrosis through the Wnt4-Pdgfra pathway. CONCLUSIONS: Our study describes the cellular landscape of hypertrophic hearts and reveals that fibroblasts derived from Sca1+ cells with a non-bone marrow source largely account for cardiac fibrosis. These findings provide novel insights into the pathogenesis of cardiac fibrosis and have potential therapeutic implications for heart failure. Non-bone marrow-derived Sca1+ cells differentiate into fibroblasts involved in cardiac fibrosis via Wnt4-PDGFRα pathway.

Design, Synthesis, Antifungal Activity, and 3D-QSAR Study of Novel Quinoxaline-2-Oxyacetate Hydrazide.

Plant pathogenic fungi pose a major threat to global food security, ecosystem services, and human livelihoods. Effective and broad-spectrum fungicides are needed to combat these pathogens. In this study, a novel antifungal 2-oxyacetate hydrazide quinoxaline scaffold as a simple analogue was designed and synthesized. Their antifungal activities were evaluated against Botrytis cinerea (B. cinerea), Altemaria solani (A. solani), Gibberella zeae (G. zeae), Rhizoctonia solani (R. solani), Colletotrichum orbiculare (C. orbiculare), and Alternaria alternata (A. alternata). These results demonstrated that most compounds exhibited remarkable inhibitory activities and possessed better efficacy than ridylbacterin, such as compound 15 (EC50 = 0.87 µg/mL against G. zeae, EC50 = 1.01 µg/mL against C. orbiculare) and compound 1 (EC50 = 1.54 µg/mL against A. alternata, EC50 = 0.20 µg/mL against R. solani). The 3D-QSAR analysis of quinoxaline-2-oxyacetate hydrazide derivatives has provided new insights into the design and optimization of novel antifungal drug molecules based on quinoxaline.

Hydrogen attenuates postoperative pain through Trx1/ASK1/MMP9 signaling pathway.

BACKGROUND: Postoperative pain is a serious clinical problem with a poorly understood mechanism, and lacks effective treatment. Hydrogen (H2) can reduce neuroinflammation; therefore, we hypothesize that H2 may alleviate postoperative pain, and aimed to investigate the underlying mechanism. METHODS: Mice were used to establish a postoperative pain model using plantar incision surgery. Mechanical allodynia was measured using the von Frey test. Cell signaling was assayed using gelatin zymography, western blotting, immunohistochemistry, and immunofluorescence staining. Animals or BV-2 cells were received with/without ASK1 and Trx1 inhibitors to investigate the effects of H2 on microglia. RESULTS: Plantar incision surgery increased MMP-9 activity and ASK1 phosphorylation in the spinal cord of mice. MMP-9 knockout and the ASK1 inhibitor, NQDI-1, attenuated postoperative pain. H2 increased the expression of Trx1 in the spinal cord and in BV-2 cells. H2 treatment mimicked NQDI1 in decreasing the phosphorylation of ASK1, p38 and JNK. It also reduced MMP-9 activity, downregulated pro-IL-1ß maturation and IBA-1 expression in the spinal cord of mice, and ameliorated postoperative pain. The protective effects of H2 were abolished by the Trx1 inhibitor, PX12. In vitro, in BV-2 cells, H2 also mimicked NQDI1 in inhibiting the phosphorylation of ASK1, p38, and JNK, and also reduced MMP-9 activity and decreased IBA-1 expression induced by LPS. The Trx1 inhibitor, PX12, abolished the protective effects of H2 in BV-2 cells. CONCLUSIONS: For the first time, the results of our study confirm that H2 can be used as a therapeutic agent to alleviate postoperative pain through the Trx1/ASK1/MMP9 signaling pathway. MMP-9 and ASK1 may be the target molecules for relieving postoperative pain.

The human lncRNA GOMAFU suppresses neuronal interferon response pathways affected in neuropsychiatric diseases.

Long noncoding RNAs (lncRNAs) play multifaceted roles in regulating brain gene networks. LncRNA abnormalities are thought to underlie the complex etiology of numerous neuropsychiatric disorders. One example is the human lncRNA gene GOMAFU, which is found dysregulated in schizophrenia (SCZ) postmortem brains and harbors genetic variants that contribute to the risk of SCZ. However, transcriptome-wide biological pathways regulated by GOMAFU have not been determined. How GOMAFU dysregulation contributes to SCZ pathogenesis remains elusive. Here we report that GOMAFU is a novel suppressor of human neuronal interferon (IFN) response pathways that are hyperactive in the postmortem SCZ brains. We analyzed recently released transcriptomic profiling datasets in clinically relevant brain areas derived from multiple SCZ cohorts and found brain region-specific dysregulation of GOMAFU. Using CRISPR-Cas9 to delete the GOMAFU promoter in a human neural progenitor cell model, we identified transcriptomic alterations caused by GOMAFU deficiency in pathways commonly affected in postmortem brains of SCZ and autism spectrum disorder (ASD), with the most striking effects on upregulation of numerous genes underlying IFN signaling. In addition, expression levels of GOMAFU target genes in the IFN pathway are differentially affected in SCZ brain regions and negatively associated with GOMAFU alterations. Furthermore, acute exposure to IFN-γ causes a rapid decline of GOMAFU and activation of a subclass of GOMAFU targets in stress and immune response pathways that are affected in SCZ brains, which form a highly interactive molecular network. Together, our studies unveiled the first evidence of lncRNA-governed neuronal response pathways to IFN challenge and suggest that GOMAFU dysregulation may mediate environmental risks and contribute to etiological neuroinflammatory responses by brain neurons of neuropsychiatric diseases.

ESE position statement on root resorption.

This Position Statement on root resorption represents the consensus of an expert committee convened by the European Society of Endodontology (ESE). The statement is based on current clinical and scientific evidence as well as the expertise of the committee. The aim is to provide clinicians with authoritative information on the aetiology, histopathology, clinical presentation and recommendations for the management of root resorption. It is the intention of the committee to update this position statement at appropriate intervals as further evidence emerges.

Present status and future directions: Root resorption.

Root resorption is the loss of dental hard tissue because of odontoclastic action. In permanent teeth, it is undesirable and pathological in nature. Root resorption may occur on the inner aspect of the root canal (internal root resorption) or on the outer aspect of the root (external root resorption). Regardless of its location, root resorption is irreversible, and may result in discomfort for the patient, requires management and/or, in some cases, results in the premature loss of the affected tooth. Root resorption is often challenging to accurately diagnose and manage. The aim of this narrative review is to present the relevant literature on the aetiology, pathogenesis, diagnosis and management, as well as discuss the future directions of diagnosis and management of root resorption.

Cardiac Metastasis of Cervical Cancer: A Case Report and Review of The Literature.

BACKGROUND: Cervical cancer cardiac metastasis is a rare disease with a poor prognosis. It has been reported that the disease often is more detected at autopsy and has no standardized treatment options. CASE PRESENTATION: Here, we report a patient with cardiac metastasis from cervical cancer who initially suffered nonspecific symptoms, such as chest tightness. CONCLUSION: A review of cases of cardiac metastasis from cervical cancer in over a decade was performed. Pretreatment data were provided for such matters, which may be helpful for diagnosis and treatment in the future.

Nicotine Attenuates Osteoarthritis Pain and Matrix Metalloproteinase-9 Expression via the α7 Nicotinic Acetylcholine Receptor.

Osteoarthritis (OA) is a degenerative joint disease that causes chronic disability among the elderly. Despite recent advances in symptomatic management of OA by pharmacological and surgical approaches, there remains a lack of optimal approaches to manage inflammation in the joints, which causes cartilage degradation and pain. In this study, we investigated the efficacy and underlying mechanisms of nicotine exposure in attenuating joint inflammation, cartilage degradation, and pain in a mouse model of OA. A mouse model of OA was induced by injection of monosodium iodoacetate into the knee joint. Cell culture models were also used to study the efficacy and underlying mechanisms of nicotine treatment in attenuating symptoms of OA. Nicotine treatment reduced mechanical allodynia, cartilage degradation, and the upregulation of matrix metalloproteinase-9 (MMP-9), a hallmark of joint inflammation in OA, in mice treated with monosodium iodoacetate. The effects of nicotine were abolished by the selective α7 nicotinic acetylcholine receptor (nAChR) blocker, methyllycaconitine . In RAW264.7 cells and murine primary bone marrow-derived macrophages, nicotine significantly inhibited MMP-9 production induced by LPS. In addition, nicotine significantly enhanced PI3K/Akt and inhibited NF-κB translocation from the cytosol to the nucleus in an α7-nAChR-dependent manner, suggesting that nicotine acts on α7-nAChRs to inhibit MMP-9 production by macrophages through modulation of the PI3K/Akt-NF-κB pathway. Our results provide novel evidence that nicotine can attenuate joint inflammation and pain in experimental OA via α7-nAChRs. α7-nAChR could thus serve as a highly promising target to manage joint inflammation and pain in OA.

Long Noncoding RNA LIPE-AS1 Drives Prostate Cancer Progression by Functioning as a Competing Endogenous RNA for microRNA-654-3p and Thereby Upregulating Hepatoma-Derived Growth Factor.

INTRODUCTION: Information regarding the expression and roles of LIPE antisense RNA 1 (LIPE-AS1) in prostate cancer (PCa) progression is currently limited. We experimentally determined LIPE-AS1 expression in PCa tissues and cell lines. The specific functions of LIPE-AS1 in the oncogenicity of PCa were explored by evaluating a series of cellular functions. Moreover, the molecular mechanisms underlying the oncogenic roles of LIPE-AS1 in PCa were investigated. METHODS: The expression level of LIPE-AS1 was determined via quantitative reverse transcription polymerase chain reaction. Functional experiments, including the Cell Counting Kit-8 assay, Transwell migration and invasion assays, and tumor xenograft experiments, were used to determine the effects of LIPE-AS1 on PCa cells. The putative miRNA-binding LIPE-AS1 was predicted via bioinformatics analysis and further verified using the luciferase reporter and RNA immunoprecipitation assays. RESULTS: LIPE-AS1 was expressed at high levels in PCa cells; this result is consistent with that of The Cancer Genome Atlas database. Patients with PCa manifesting high LIPE-AS1 expression had shorter overall survival than those manifesting low LIPE-AS1 expression. Downregulated LIPE-AS1 inhibited PCa cell proliferation, migration, and invasion in vitro and impaired tumor growth in vivo. With respect to its mechanism, LIPE-AS1 functioned as a competing endogenous RNA for microRNA-654-3p (miR-654-3p) in PCa cells, and hepatoma-derived growth factor (HDGF) was the direct target of miR-654-3p. HDGF was positively regulated by LIPE-AS1 in PCa cells via the absorption of miR-654-3p. Rescue experiments confirmed that miR-654-3p downregulation or HDGF overexpression counteracts the inhibitory effects of LIPE-AS1 depletion on PCa cell proliferation, migration, and invasion. CONCLUSION: LIPE-AS1 promotes PCa malignancy by targeting the miR-654-3p/HDGF axis. Determining the LIPE-AS1/miR-654-3p/HDGF pathway may increase our understanding of PCa pathogenesis and contribute toward a wider applied scope.

Structural basis of resistance of mutant RET protein-tyrosine kinase to its inhibitors nintedanib and vandetanib.

RET is a transmembrane growth factor receptor. Aberrantly activated RET is found in several types of human cancer and is a target for treating RET aberration-associated cancer. Multiple clinically relevant RET protein-tyrosine kinase inhibitors (TKIs) have been identified, but how TKIs bind to RET is unknown except for vandetanib. Nintedanib is a RET TKI that inhibits the vandetanib-resistant RET(G810A) mutant. Here, we determined the X-ray co-crystal structure of RET kinase domain-nintedanib complex to 1.87 Å resolution and a RET(G810A) kinase domain crystal structure to 1.99 Å resolution. We also identified a vandetanib-resistant RET(L881V) mutation previously found in familial medullary thyroid carcinoma. Drug-sensitivity profiling of RET(L881V) revealed that it remains sensitive to nintedanib. The RET-nintedanib co-crystal structure disclosed that Leu-730 in RET engages in hydrophobic interactions with the piperazine, anilino, and phenyl groups of nintedanib, providing a structural basis for explaining that the p.L730V mutation identified in nine independently isolated cell lines resistant to nintedanib. Comparisons of RET-nintedanib, RET(G810A), and RET-vandetanib crystal structures suggested that the solvent-front Ala-810 makes hydrophobic contacts with a methyl group and aniline in nintedanib and blocks water access to two oxygen atoms of vandetanib, resulting in an energetic penalty for burying polar groups. Of note, even though the p.L881V mutation did not affect sensitivity to nintedanib, RET(L881V) was resistant to nintedanib analogs lacking a phenyl group. These results provide structural insights into resistance of RET mutants against the TKIs nintedanib and vandetanib.

Lipidated α/Sulfono-α-AA heterogeneous peptides as antimicrobial agents for MRSA.

Though antibiotics have been used for decades to treat bacterial infections, there is a great need for new treatment methods. Bacteria are becoming resistant to conventional antibiotics, as is the case with Methicillin resistant Staphylococcus aureus (MRSA). Herein we report the design of a series of lipidated α/Sulfono-α-AA heterogeneous peptides as mimics for Host Defense Peptides (HDPs). Utilizing fluorescence microscopy and depolarization techniques, our compounds demonstrate the ability to kill Gram-positive bacteria through cell membrane disruption. This mechanism of action makes it difficult for bacteria to develop resistance. Further time kill studies and hemolytic assays have also proven these compounds to be efficient in their ability to eradicate bacteria cells while remaining non-toxic to human red blood cells. This new class of peptidomimetics shows promise for the future antibiotic treatment of MRSA.

A multicenter randomized controlled trial of a modified Valsalva maneuver for cardioversion of supraventricular tachycardias.

CLINICAL QUESTION: Valsalva maneuver is a recognized treatment for supraventricular tachycardia, but in clinical setting it has a low chance to achieve successful cardioversion. Studies suggested that the postural modification of valsalva maneuver may improve the rate of cardioversion. We further modified the maneuver and conduct a multicenter randomized controlled trial to test its efficacy. RESEARCH IN CONTEXT: Appelboam A, Reuben A, Mann C, et al. Postural modification of the standard Valsalva maneuver for emergency treatment for supraventricular tachycardias (REVERT): a randomized controlled trial. Lancet 2015; 386 (10005):1747-53 [1]. Allison Michaud, PhD, Eddy Lang. Leg lift Valsalva maneuver for treatment of supraventricular tachycardias. CJEM 2017; 19(3):235-237 [2]. OBJECTIVE: To verify the efficacy of the modified Valsalva maneuver in SVT in Chinese population and simplify the operation process further.

A Rare Constrictive Pericarditis with Complete Separation between the Visceral and Parietal Pericardium: A Case Report.

BACKGROUND: Pericarditis is the most common form of pericardial disease, while constrictive pericarditis is challenging in diagnosis and is easily overlooked. CASE REPORT: A 30-year-old female presented with abdominal distension and mild lower extremity edema for 3 months. The patient was initially suspected of having cirrhosis caused by Wilson Disease. Following liver biopsy and multiple investigation, thickened, calcified pericardium was detected by echocardiography and chest computed tomography. The patient was finally diagnosed with chronic constrictive pericarditis and received pericardiectomy. Intraoperatively, we found that the heart was entirely constricted by the thickened and calcified visceral pericardium, which was completely separated from the parietal pericardium. The patient received successful pericardiectomy and had relief of symptoms after surgery. CONCLUSION: Patients with constrictive pericarditis may present with symptoms similar to that of chronic liver diseases, which makes it difficult and complicated for diagnosis. This case highlights the importance of comprehensive preoperative evaluation and maintaining clinical suspicion of pericarditis in patients with features of elevated systemic venous pressure. In addition, constrictive pericarditis with complete separation between visceral and parietal pericardium has seldom been reported.

Interactive Repression of MYRF Self-Cleavage and Activity in Oligodendrocyte Differentiation by TMEM98 Protein.

Myelin sheath formed by oligodendrocytes (OLs) is essential for the rapid propagation of action potentials in the vertebrate CNS. Myelin regulatory factor (MYRF) is one of the critical factors that control OL differentiation and myelin maintenance. Previous studies showed that MYRF is a membrane-bound transcription factor associated with the endoplasmic reticulum (ER). After self-cleavage, the N-fragment of MYRF is released from the ER and translocated into the nucleus where it functions as a transcription factor to activate myelin gene expression. At present, it remains unknown whether MYRF self-cleavage and functional activation can be regulated during OL differentiation. Here, we report that TMEM98, an ER-associated transmembrane protein, is capable of binding to the C-terminal of MYRF and inhibiting its self-cleavage and N-fragment nuclear translocation. In the developing CNS, TMEM98 is selectively expressed in early maturing OLs in mouse pups of either sex. Forced expression of TMEM98 in embryonic chicken spinal cord of either sex suppresses endogenous OL differentiation and MYRF-induced ectopic expression of myelin genes. These results suggest that TMEM98, through inhibiting the self-cleavage of MYRF, functions as a negative feedback regulator of MYRF in oligodendrocyte differentiation and myelination.SIGNIFICANCE STATEMENT MYRF protein is initially synthesized as an ER-associated membrane protein that undergoes autoproteolytic cleavage to release the N-fragment, which is then transported into the nucleus and activates the transcription of myelin genes. To date, the molecular mechanisms that regulate the self-cleavage and function of MYRF in regulating oligodendrocyte differentiation have remained unknown. In this study, we present the molecular and functional evidence that TMEM98 membrane protein physically interacts with MYRF in the ER and subsequently blocks its self-cleavage, N-terminal nuclear translocation, and functional activation of myelin gene expression. To our knowledge, this is the first report on the regulation of MYRF self-proteolytic activity and function by an interacting protein, providing new insights into the molecular regulation of OL differentiation and myelinogenesis.

Design, synthesis and antifungal activities of novel pyrrole- and pyrazole-substituted coumarin derivatives.

We synthesized a series of novel pyrrole- and pyrazole-substituted coumarin derivatives and evaluated their antifungal activity against six phytopathogenic fungi in vitro. The primary assay results demonstrated that some designed compounds displayed potent activities. Among them, compounds 5g, 6a, 6b, 6c, 6d and 6h exhibited more effective control than Osthole against Cucumber anthrax and Alternaria leaf spot. Furthermore, compound 5g displayed stronger antifungal activity against Rhizoctorzia solani (EC50 = 15.4 µg/mL) than positive control Osthole (EC50 = 67.2 µg/mL).

Orthogonal Halogen-Bonding-Driven 3D Supramolecular Assembly of Right-Handed Synthetic Helical Peptides.

Peptide-mediated self-assembly is a prevalent method for creating highly ordered supramolecular architectures. Herein, we report the first example of orthogonal C-X⋅⋅⋅X-C/C-X⋅⋅⋅π halogen bonding and hydrogen bonding driven crystalline architectures based on synthetic helical peptides bearing hybrids of l-sulfono-γ-AApeptides and natural amino acids. The combination of halogen bonding, intra-/intermolecular hydrogen bonding, and intermolecular hydrophobic interactions enabled novel 3D supramolecular assembly. The orthogonal halogen bonding in the supramolecular architecture exerts a novel mechanism for the self-assembly of synthetic peptide foldamers and gives new insights into molecular recognition, supramolecular design, and rational design of biomimetic structures.

microRNA-383 suppresses the PI3K-AKT-MTOR signaling pathway to inhibit development of cervical cancer via down-regulating PARP2.

This study aims to evaluate the effect of the regulatory relationship between microRNA-383 (miR-383) and PARP2 in the cell migration and invasion in human with cervical cancer (CC) via the PI3K-AKT-MTOR signaling pathway. Cancerous tissues and corresponding paracancerous tissues were collected from 115 patients with CC. The positive expression rate of PARP2 was detected by immunohistochemistry. HeLa cells with highest miR-383 expression were selected and assigned into the blank, negative control (NC), miR-383 mimic, miR-383 inhibitor, si-PARP2, and miR-383 inhibitor + si-PARP2 groups. qRT-PCR and Western blot were performed to evaluate the expression of miR-383, PI3K, AKT, mTOR, PARP2, and p70S6K. MTT assay were utilized to measure cell viability. Transwell assay were applied to evaluate cell invasion and metastasis. Dual luciferase reporter assay identified that PARP2 is a target gene of miR-383. Cancerous tissues manifested higher expression of PI3K, AKT, mTOR, PARP2, and p70S6K but lower miR-383 expression than paracancerous tissues. Compared with the blank and NC groups, the miR-383 mimic and si-PARP2 groups had decreased expression of PI3K, AKT, mTOR, PARP2, and p70S6K mRNA and protein. In the miR-383 mimic and si-PARP2 groups, the cell viability, migration, and invasion were descended, in comparison to the blank and NC groups. All above parameters showed an opposite trend in the miR-383 inhibitor group when compared with the blank and NC groups. This study demonstrates that miR-383 could down-regulate PARP2 to protect against CC by inhibiting PI3K-AKT-MTOR signaling pathway.

Hydrogen-Bonding-Driven 3D Supramolecular Assembly of Peptidomimetic Zipper.

Hydrogen-bonding-driven three-dimensional (3D) assembly of a peptidomimetic zipper has been established for the first time by using an α/AApeptide zipper that assembles into a de novo lattice arrangement through two layers of hydrogen-bonded linker-directed interactions. Via a covalently bridged 1D 413-helix, drastic enhancement in stability has been achieved in the formed 3D crystalline supramolecular architecture as evidenced by gas-sorption studies. As the first example of an unnatural peptidic zipper, the dimensional augmentation of the zipper differs from metal-coordinated strategies, and may have general implications for the preparation of peptidic functional materials for a variety of future applications.