Publications by authors named "Yin Yuan"

279 Publications

The synergy of dietary supplements LI01 and TC01 in alleviating liver failure in rats treated with D-galactosamine.

Food Funct 2021 Sep 21. Epub 2021 Sep 21.

State Key Laboratory for Diagnosis, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

() has been widely used in dietary supplements and clinical treatments. Previous studies demonstrated the protective effect of LI01 on liver injury induced by D-galactosamine (D-GaIN) in rats. Accumulating evidence indicates that and are highly coordinated; so in this study, we focus on the synergistic effect of LI01 and TC01 on the alleviation of liver injury caused by D-GaIN in rats and aim to find out the underlying interaction between the two strains. We observed reduced hepatic damage in the D-GaIN-treated rats with probiotic pre-administration, characterized by lower levels of AST and ALT ( < 0.05) and decreased HAI (Histological Activity Index) scores. Moreover, cotreatment with LI01 and TC01 more effectively decreases proinflammatory cytokines TNF-α, MCP-1 and M-CSF ( < 0.05) so as to inhibit systemic inflammation. Gut barrier dysfunction was ameliorated with compound probiotic pretreatment, as evidenced by the ultrastructure integrity, decreased histological score and elevated TJP-1 expression. What's more, supplementation with LI01 and TC01 markedly alleviates gut dysbiosis in the G-DaIN-treated rats, with enrichment of short chain fatty acid (SCFA) producers and group, a decreased / (F/B) ratio and depletion of proinflammatory microbes, such as and . This study highlights the synergistic effect of dietary supplements LI01 and TC01 on the protection against liver failure, which is probably altering gut microbiota.
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http://dx.doi.org/10.1039/d1fo01807hDOI Listing
September 2021

Efficacy and safety of acupuncture in the treatment of postherpetic neuralgia: A protocol for systematic review and network meta-analysis.

Medicine (Baltimore) 2021 Sep;100(36):e27088

Second Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang Province, China.

Background: It is simple, convenient, inexpensive, proven, extensive, and safe for acupuncture in the treatment of postherpetic neuralgia (PHN). However, there are no comparisons between various acupuncture therapies that can directly and effectively provide specific guidance to clinicians. The development of a guideline for the optimization of acupuncture for PHN is of great importance for the development of clinical acupuncture. Therefore, we attempted to design a study protocol for a network meta-analysis of randomized controlled trials of acupuncture for PHN to provide evidence to support the treatment of acupuncture for PHN.

Methods: A search of 8 databases, Chinese Scientific Journal Database, China National Knowledge Infrastructure Database, Wanfang, China Biomedical Literature Database, PubMed, Cochrane Library, Embase, and Web of Science, was conducted to collect randomized controlled trials about acupuncture for PHN. RevMan 5.3 and Stata 14.0 software were used for data analysis.

Results: This meta-analysis will provide additional and more robust evidence for acupuncture treatment of PHN. Our findings will assist clinicians in making treatment decisions.

Conclusion: This study will provide comprehensive and reliable evidence-based evidence for the treatment of PHN with acupuncture.
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http://dx.doi.org/10.1097/MD.0000000000027088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428706PMC
September 2021

Clinical, surgical characteristics and long-term outcomes of lumbar hernia.

BMC Surg 2021 Aug 26;21(1):332. Epub 2021 Aug 26.

Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.

Background/aim: Lumbar hernia is caused by a defect in the abdominal wall. Due to its rarity, there is no established consensus on optimal treatment for lumbar hernia yet. Thus, we here investigated the clinical, surgical characteristics and outcomes of lumbar hernia by collecting 28 such patients from our hospital.

Methods: Patients diagnosed with lumbar hernia from our institution between April 2011 and August 2020 were retrospectively collected in this study. Demographics, clinical characteristics and surgical information were recorded.

Results: A consecutive series of 28 patients with lumbar hernia were retrospectively collected, including 13 males (46%) and 15 females (54%). The ages of the patients ranged from 5 to 79 years (median: 55 years), with a mean age of 55.6 ± 14.9 years. A total of 7 cases had a history of previous lumbar trauma or surgery. There were 11 (39%), 15 (54%) and 2 (7.1%) cases had right, left and bilateral lumbar hernia, respectively. Superior and inferior lumbar hernia were found in 25 (89%) and 3 (11%) patients. General anesthesia was adopted in 16 cases (group A), whereas 12 patients received local anesthesia (group B). Patients in the group B had a shorter hospital stay than that of the group A (3.5 ± 1.3 days vs. 7.1 ± 3.2 days, p = 0.001), as well as total hospitalization expenses between the two groups (2989 ± 1269 dollars vs. 1299 ± 229 dollars, p < 0.001). With a median follow-up duration of 45.9 months (range: 1-113 months), only 1 (3%) lumbar hernias recurred for the entire cohort.

Conclusions: Lumbar hernia is a relatively rare entity, and inferior lumbar hernia is rarer. It is feasible to repair lumbar hernia under local anesthesia.
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http://dx.doi.org/10.1186/s12893-021-01328-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394050PMC
August 2021

HOTAIR promotes gefitinib resistance through modification of EZH2 and silencing p16 and p21 in non-small cell lung cancer.

J Cancer 2021 25;12(18):5562-5572. Epub 2021 Jul 25.

Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China.

The long non-coding RNA Hox transcript antisense intergenic RNA (HOTAIR) plays a critical role in tumorigenesis as well as drug resistance in various cancers. However, the molecular mechanism by which HOTAIR induces gefitinib resistance in non-small cell lung cancer is to date unclear. In the present study, we revealed that HOTAIR is upregulated in gefitinib-resistant lung cancer cells and over-expression of HOTAIR enhances gefitinib resistance in lung cancer cells. In addition, the overexpression of HOTAIR promotes cell cycle progression through epigenetic regulation of EZH2/H3K27. Silencing of EZH2 by either siRNA or inhibitors sensitized the lung cancer cells to gefitinib. Inhibition of EZH2 induces expression of p16 and p21, whereas levels of CDK4, cyclinD1, E2F1, and LSD1 are significantly decreased in PC-9 cells overexpressing HOTAIR. ChIP-PCR experiments indicate that HOTAIR increases H3K27me3 recruitment to the promoter of p16 and p21 in PC-9 lung cancer cells overexpressing HOTAIR. In xenograft mouse models, overexpressing HOTAIR in lung cancer tissues decreased p16 and p21 proteins. Taken together, these data suggest that HOTAIR contributes to gefitinib resistance by regulating EZH2 and p16 and p21. Targeting HOTAIR may be a novel therapeutic strategy for treating gefitinib-resistance in non-small cell lung cancer.
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http://dx.doi.org/10.7150/jca.56093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364642PMC
July 2021

Comparative safety and tolerability of approved PARP inhibitors in cancer: A systematic review and network meta-analysis.

Pharmacol Res 2021 Oct 11;172:105808. Epub 2021 Aug 11.

Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; Research Laboratory of Tumor Epigenetics and Genomics for General Surgery, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address:

Background: We aimed to evaluate comparative safety and tolerability of the approved PARP inhibitors in people with cancer.

Methods: Eligible studies included randomized controlled trials comparing an approved PARP inhibitor (fluzoparib, olaparib, rucaparib, niraparib, or talazoparib) with placebo or chemotherapy in cancer patients. Outcomes of interest included: serious adverse event (SAE), discontinuation due to adverse event (AE), interruption of treatment due to AE, dose reduction due to AE, and specific grade 1-5 AEs.

Results: Ten trials including 3763 participants and six treatments (olaparib, rucaparib, niraparib, talazoparib, placebo, and protocol-specified single agent chemotherapy) were identified. SAE and discontinuation of treatment did not differ significantly among the four approved PARP inhibitors. Regarding interruption of treatment and dose reduction due to AE, statistically significant differences and statistically non-significant trend were observed. Talazoparib is associated with a higher risk of interruption of treatment and dose reduction (excluding rucaparib) due to AE as compared with the other drugs. Niraparib showed a trend of lower risk of AE related dose reduction as compared with the other drugs. Furthermore, there were significant differences in specific grade 1-5 AE among the four drugs.

Conclusion: The safety profile of the four approved PARP inhibitors is comparable in terms of SAE and AE-related discontinuation of treatment. Statistically significant differences in the AEs spectrum and AEs related dose interruption and dose reduction demonstrated the prompt identification of AE and dose personalization seem mandatory to obtain maximal benefit from PARP inhibitors.
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http://dx.doi.org/10.1016/j.phrs.2021.105808DOI Listing
October 2021

Comprehensive Characterization of Integrin Subunit Genes in Human Cancers.

Front Oncol 2021 16;11:704067. Epub 2021 Jun 16.

Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, China.

Although integrin subunit genes (ITGs) have been reported to be associated with some human cancer types, a systematic assessment of ITGs across human cancers is lacking. Hence, we performed comprehensive analyses to investigate mRNA expression, copy number variation (CNV), DNA methylation, mutation, and clinical landscapes of ITGs in more than 8000 cancer patients from The Cancer Genome Atlas (TCGA) dataset. Landscapes of ITGs were established across 20 human cancer types. We observed that ITGs are extensively dysregulated with heterogeneity in different system cancer types, part of which are driven by CNV, DNA hypomethylation or mutation. Furthermore, dysregulated prognosis-related ITGs were systematically identified in each cancer type, including ITGA11 in stomach adenocarcinoma (STAD). The models based on dysregulated ITGs with clinical relevance and TNM staging indexes are good indicators in STAD and head and neck squamous cell carcinoma. Finally, ITGA11 is overexpressed and associated with poor survival in STAD cases from the TCGA and additionally Gene Expression Omnibus cohorts. Functionally, ITGA11 knockdown inhibits malignant phenotypes in STAD cell lines AGS and MKN45, demonstrating the oncogenic role of ITGA11 in STAD. Together, this study highlights the important roles of ITGs in tumorigenesis as potential prognostic biomarkers, and provide an effective resource that identifies cancer-related genes of ITGs in human cancers.
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http://dx.doi.org/10.3389/fonc.2021.704067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242346PMC
June 2021

Integrated analysis of long non-coding RNAs and mRNAs associated with malignant transformation of gastrointestinal stromal tumors.

Cell Death Dis 2021 07 3;12(7):669. Epub 2021 Jul 3.

Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.

Malignant transformation of gastrointestinal stromal tumors (GISTs) is correlated with poor prognosis; however, the underlying biological mechanism is not well understood. In the present study, low-risk (LR) GISTs, GISTs categorized as high-risk based on tumor size (HBS), and on mitotic rate (HBM) were collected for RNA sequencing. Candidate hub lncRNAs were selected by Oncomine analysis. Expression of a selected hub lncRNA, DNM3OS, and its correlation with patients' prognosis were analyzed using FISH staining, followed with the determination of function and underlying mechanism. Our results revealed a series of key pathways and hub lncRNAs involved in the malignant transformation of GISTs. Oncomine analysis revealed a tight association between clinical signatures and DNM3OS and suggested that DNM3OS is a hub lncRNA that is involved in the Hippo signaling pathway. In addition, DNM3OS was upregulated in HBS, HBM, and HBS/M GIST and correlated with worse prognosis in patients with GISTs. In addition, DNM3OS promoted GIST cell proliferation and mitosis by regulating the expression of GLUT4 and CD36. Collectively, these results improve our understanding of the malignant transformation of GISTs and unveil a series of hub lncRNAs in GISTs.
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http://dx.doi.org/10.1038/s41419-021-03942-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254811PMC
July 2021

The Relationship Between the Gut Microbiome and Neurodegenerative Diseases.

Neurosci Bull 2021 Jul 3. Epub 2021 Jul 3.

State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.

Many recent studies have shown that the gut microbiome plays important roles in human physiology and pathology. Also, microbiome-based therapies have been used to improve health status and treat diseases. In addition, aging and neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, have become topics of intense interest in biomedical research. Several researchers have explored the links between these topics to study the potential pathogenic or therapeutic effects of intestinal microbiota in disease. But the exact relationship between neurodegenerative diseases and gut microbiota remains unclear. As technology advances, new techniques for studying the microbiome will be developed and refined, and the relationship between diseases and gut microbiota will be revealed. This article summarizes the known interactions between the gut microbiome and neurodegenerative diseases, highlighting assay techniques for the gut microbiome, and we also discuss the potential therapeutic role of microbiome-based therapies in diseases.
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http://dx.doi.org/10.1007/s12264-021-00730-8DOI Listing
July 2021

MiR-296-5p ameliorates deep venous thrombosis by inactivating S100A4.

Exp Biol Med (Maywood) 2021 Jun 30:15353702211023034. Epub 2021 Jun 30.

Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou 215006, China.

Deep venous thrombosis is one of the most common venous thromboembolic diseases and has a low cure rate and a high postoperative recurrence rate. Furthermore, emerging evidence indicates that microRNAs are involved in deep venous thrombosis. miR-296-5p is an important microRNA that plays a critical role in various cellular functions, and S100A4 is closely related to vascular function. miR-296-5p is downregulated in deep venous thrombosis patients, and its predicted target S100A4 is upregulated in deep venous thrombosis patients. Therefore, it was hypothesized that miR-296-5p may play a vital role in the development of deep venous thrombosis by targeting S100A4. An Ox-LDL-stimulated HUVEC and deep venous thrombosis mouse model was employed to detect the biological functions of miR-296-5p and S100A4. Dual luciferase reporter assays and pull-down assays were used to authenticate the interaction between miR-296-5p and S100A4. ELISA and Western blotting were employed to detect the protein levels of thrombosis-related factors and the endothelial-to-mesenchymal transition (EndMT)-related factors. The miR-296-5p levels were reduced, while the S100A4 levels were enhanced in deep venous thrombosis patients, and the miR-296-5p levels were negatively correlated with the S100A4 levels in deep venous thrombosis patients. miR-296-5p suppressed S100A4 expression by targeting the 3' UTR of S100A4. MiR-296-5p knockdown accelerated ox-LDL-induced HUVEC apoptosis, oxidative stress, thrombosis-related factor expression, and EndMT, while S100A4 knockdown antagonized these effects in ox-LDL-induced HUVECs. S100A4 knockdown reversed the effect induced by miR-296-5p knockdown. Moreover, the studies revealed that miR-296-5p knockdown in deep venous thrombosis mice exacerbated deep venous thrombosis formation, whereas S100A4 knockdown had the opposite effect. These results indicate that elevated miR-296-5p inhibits deep venous thrombosis formation by inhibiting S100A4 expression. Both miR-296-5p and S100A4 may be potential diagnostic markers and therapeutic targets for deep venous thrombosis.
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http://dx.doi.org/10.1177/15353702211023034DOI Listing
June 2021

Comprehensive molecular and clinical characterization of SLC1A5 in human cancers.

Pathol Res Pract 2021 Aug 12;224:153525. Epub 2021 Jun 12.

Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi 214062, Jiangsu, China; Laboratory of Cancer Epigenetics, Wuxi School of Medicine, Jiangnan University, Wuxi 214122, Jiangsu, China. Electronic address:

Although SLC1A5 has been reported to be closely associated with some cancer types, a comprehensive and systematic assessment of SLC1A5 across human cancers is lacking. Thus, Pan-cancer analysis of SLC1A5 was performed across 30 types of human cancers in this study. We examined mRNA expression, protein expression, copy number variation (CNV), DNA methylation, clinical relevance, cell functions, drug response and total immune infiltrates of SLC1A5 in more than 9000 patients across 30 human cancer types from The Cancer Genome Atlas (TCGA) dataset. Additionally, nine independent Gene Expression Omnibus datasets, more than 800 cancer cell lines from the Cancer Cell Line Encyclopedia dataset and the Project Achilles dataset were used to validate our findings in the TCGA dataset. Landscapes of SLC1A5 were established across multiple cancers. We showed that SLC1A5 is upregulated in multiple cancers, particularly in digestive and respiratory system cancers. SLC1A5 upregulation may be driven by CNV gain and DNA hypomethylation in human cancers. Furthermore, SLC1A5 overexpression is associated with tumor progression and poor survival in multiple cancers. Moreover, we systematically explored the potential effects of SLC1A5 expression on cell functions and drug response in human cancers. SLC1A5 knockdown showed significant proliferation-inhibiting effects in most human cancer types, especially in the digestive system and KRAS-mutant cancers. SLC1A5 expression is associated with proliferation activities of KRAS-mutant cancer cell lines and drug response of many anti-cancer drugs. Finally, we demonstrated that SLC1A5-realted tumor immune microenvironment characteristics showed strong heterogeneity in human cancers. Taken together, our findings highlight the important roles of SLC1A5 in tumorigenesis, progression, prognosis and therapy.
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http://dx.doi.org/10.1016/j.prp.2021.153525DOI Listing
August 2021

PPARγ Mediates the Anti-Epithelial-Mesenchymal Transition Effects of FGF1 in Chronic Kidney Diseases via Inhibition of TGF-β1/SMAD3 Signaling.

Front Pharmacol 2021 3;12:690535. Epub 2021 Jun 3.

The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

Podocytes are essential components of the glomerular basement membrane. Epithelial-mesenchymal-transition (EMT) in podocytes results in proteinuria. Fibroblast growth factor 1 (FGF1) protects renal function against diabetic nephropathy (DN). In the present study, we showed that treatment with an FGF1 variant with decreased mitogenic potency (FGF1) inhibited podocyte EMT, depletion, renal fibrosis, and preserved renal function in two nephropathy models. Mechanistic studies revealed that the inhibitory effects of FGF1 podocyte EMT were mediated by decreased expression of transforming growth factor β1 via upregulation of PPARγ. FGF1 enhanced the interaction between PPARγ and SMAD3 and suppressed SMAD3 nuclei translocation. We found that the anti-EMT activities of FGF1 were independent of glucose-lowering effects. These findings expand the potential uses of FGF1 in the treatment of diseases associated with EMT.
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http://dx.doi.org/10.3389/fphar.2021.690535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209477PMC
June 2021

H2A.Z acetylation by lincZNF337-AS1 via KAT5 implicated in the transcriptional misregulation in cancer signaling pathway in hepatocellular carcinoma.

Cell Death Dis 2021 06 12;12(6):609. Epub 2021 Jun 12.

The Department of General Surgery of Hospital Affiliated 5 to Nantong University(Taizhou People's Hospital), Taizhou, Jiangsu Province, China.

In eukaryotes, histones and their variants are essential for chromatin structure and function; both play important roles in the regulation of gene transcription, as well as the development of tumors. We aimed to explore the genomics data of hepatocellular carcinoma (HCC), combined with literature analysis, in terms of the histone variant H2A.Z. Cell phenotype assay confirmed the effect of H2A.Z on the proliferation, metastasis, apoptosis, and cell cycle of HCC cells. H2A.Z was shown to function via the tumor dysregulation signaling pathway, with BCL6 as its interacting protein. In addition, the acetylation level of H2A.Z was higher in HCC and was related to tumor formation. We found the acetylation of H2A.Z to be related to and regulated by lincZNF337-AS1. LincZNF337-AS1 was found to bind to H2A.Z and KAT5 at different sites, promoting the acetylation of H2A.Z through KAT5. We concluded that, in HCC, H2A.Z is an oncogene, whose acetylation promotes the transcription of downstream genes, and is regulated by lincZNF331-AS1.
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http://dx.doi.org/10.1038/s41419-021-03895-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197763PMC
June 2021

Iron Regulates the Warburg Effect and Ferroptosis in Colorectal Cancer.

Front Oncol 2021 18;11:614778. Epub 2021 May 18.

State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

Iron promotes the proliferation of cancer cells, but it also contributes to cell death. Here we explored whether iron could promote the Warburg effect of colorectal cancer (CRC) cells and suppress sensitivity to ferroptosis by inducing reactive oxygen species (ROS) and regulating nuclear factor erythroid 2-related factor 2 (NRF2). In this study, cell proliferation abilities were measured by CCK-8, EdU incorporation, and colony formation assays. Seahorse XF96 respirometry assays were used to detect the Warburg effect and the level of ROS was assess by DCFH-DA fluorescent probes. Results showed that iron exposure promoted the Warburg effect of CRC cells by inducing ROS and activating NRF2 both and . In addition, iron exposure also induced ferroptosis in CRC cells, but at the same time its inhibitory proteins SLC7A11 and GPX4 were also upregulated, indicating an enhanced resistance to ferroptosis. Our results revealed that iron can effectively promote tumorigenesis. Meanwhile, iron elimination or a low-iron diet might be valid therapeutic approaches for CRC.
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http://dx.doi.org/10.3389/fonc.2021.614778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169994PMC
May 2021

Expression of STAT3 and vasculogenic mimicry in gallbladder carcinoma promotes invasion and metastasis.

Exp Ther Med 2021 Jul 9;22(1):738. Epub 2021 May 9.

Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China.

Surgical treatment of gallbladder carcinoma remains challenging, while targeted therapy has been demonstrated to have potential. In the present study, the effect of signal transducer and activator of transcription 3 (STAT3) expression and vasculogenic mimicry (VM) on the occurrence and development of gallbladder carcinoma was evaluated. A total of 72 patients with gallbladder carcinoma and 10 patients with chronic cholecystitis were examined. Immunohistochemical staining was performed to determine the positive expression rates of STAT3. Periodic acid Schiff CD34 double staining was performed to detect VM in the gallbladder carcinoma group. STAT3 expression and VM in gallbladder carcinoma tissues was compared among patients with different clinical characteristics. In postoperative patients with gallbladder cancer, the relationship of the postoperative recurrence time with STAT3 expression and VM was assessed. STAT3 expression in gallbladder carcinoma tissue was significantly higher than that in cholecystitis tissue (P<0.05). STAT3 expression levels and VM were positively correlated in gallbladder carcinoma tissue. STAT3 protein expression in gallbladder carcinoma tissues differed significantly among patients with different degrees of differentiation and clinical stages (P<0.05). Among the 51 patients who completed the 3-year follow-up, the mean time to relapse was 17.353 and 35.647 months in those with high and low STAT3 expression, respectively, with significant differences (P<0.05). The VM structure was detected in 47 cases (92.15%) and not detected in four cases (7.84%), which exhibited no immediate recurrence after surgery, and the difference in the mean postoperative recurrence time was significant (22.38 vs. 36.00 months, respectively; P<0.05). In gallbladder carcinoma tissues, a lower degree of differentiation, higher malignancy degree and higher clinical stage were associated with higher expression of STAT3 and VM. Thus, STAT3 may promote VM formation in the process of tumor occurrence, development and metastasis. Therefore, STAT3 as a regulatory target, may inhibit the proliferation and invasion of tumor cells and block the development of VM, thereby representing a suitable target for antitumor angiogenesis therapy.
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http://dx.doi.org/10.3892/etm.2021.10170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138270PMC
July 2021

Melatonin induces the rejuvenation of long-term ex vivo expanded periodontal ligament stem cells by modulating the autophagic process.

Stem Cell Res Ther 2021 04 29;12(1):254. Epub 2021 Apr 29.

Department of Periodontology, School of Stomatology, State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Fourth Military Medical University, 145th West Changle Road, Xi'an, 710032, Shaanxi, People's Republic of China.

Background: Stem cells that have undergone long-term ex vivo expansion are most likely functionally compromised (namely cellular senescence) in terms of their stem cell properties and therapeutic potential. Due to its ability to attenuate cellular senescence, melatonin (MLT) has been proposed as an adjuvant in long-term cell expansion protocols, but the mechanism underlying MLT-induced cell rejuvenation remains largely unknown.

Methods: Human periodontal ligament stem cells (PDLSCs) were isolated and cultured ex vivo for up to 15 passages, and cells from passages 2, 7, and 15 (P2, P7, and P15) were used to investigate cellular senescence and autophagy change in response to long-term expansion and indeed the following MLT treatment. Next, we examined whether MLT could induce cell rejuvenation by restoring the autophagic processes of damaged cells and explored the underlying signaling pathways. In this context, cellular senescence was indicated by senescence-associated β-galactosidase (SA-β-gal) activity and by the expression of senescence-related proteins, including p53, p21, p16, and γ-H2AX. In parallel, cell autophagic processes were evaluated by examining autophagic vesicles (by transmission electronic microscopy), autophagic flux (by assessing mRFP-GFP-LC3-transfected cells), and autophagy-associated proteins (by Western blot assay of Atg7, Beclin-1, LC3-II, and p62).

Results: We found that long-term in vitro passaging led to cell senescence along with impaired autophagy. As expected, MLT supplementation not only restored cells to a younger state but also restored autophagy in senescent cells. Additionally, we demonstrated that autophagy inhibitors could block MLT-induced cell rejuvenation. When the underlying signaling pathways involved were investigated, we found that the MLT receptor (MT) mediated MLT-related autophagy restoration by regulating the PI3K/AKT/mTOR signaling pathway.

Conclusions: The present study suggests that MLT may attenuate long-term expansion-caused cellular senescence by restoring autophagy, most likely via the PI3K/AKT/mTOR signaling pathway in an MT-dependent manner. This is the first report identifying the involvement of MT-dependent PI3K/AKT/mTOR signaling in MLT-induced autophagy alteration, indicating a potential of autophagy-restoring agents such as MLT to be used in the development of optimized clinical-scale cell production protocols.
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http://dx.doi.org/10.1186/s13287-021-02322-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082824PMC
April 2021

The qualitative analysis of characteristic of callers to a psychological hotline at the early stage of COVID-19 in China.

BMC Public Health 2021 04 28;21(1):809. Epub 2021 Apr 28.

Department of medical, The Fourth People's Hospital of Chengdu, Sichuan province, 610039, Chengdu city, China.

Background: As the outbreak of COVID-19, traditional face-to-face psychological intervention are difficult to achieve, so hotline becomes available and recommended strategies. The callers' characteristic could help us to study their experiences of emotional distress, as well as the reasons for calling during the pandemic, which can be used to inform future service design and delivery.

Methods: The information of 1558 callers called our hospital' s hotline for help from February 3, 2020, to March 16, 2020 were collected in the form of Tick-box and Free text, and the inductive content analysis was undertaken focusing on the reasons for caller engagement.

Results: It was indicated that more than half of the callers are female (59.7%), mostly between the age of 18-59 (76.5%). The average age was 37.13 ± 13.76 years old. The average duration of a call to the hotline was 10.03 ± 9.84 min. The most frequent description emotional state were anxious (45.1%) and calm (30.3%), with the sub-sequence of scared (18.2%), sad (11.9%), and angry (6.9%). All callers displayed a wide range of reasons for calling, with needing support around their emotion (64.6%), seeking practical help (44.0%), and sleep problems (20.3%) constituting the majority of calls. Among the subthemes, 314 callers thought the epidemic has made them upset, 198 asked questions about the epidemic, and 119 reported their life routines were disrupted. The prevalence of key reasons does not appear to differ over time. Through their feedback, 79.1% agreed that they felt emotionally better after calling, and 95.0% agreed that hotline had helped them.

Conclusions: During the epidemic, the most concern of the public is still related to epidemics and its adverse effects. Fortunately, the hotline can be an active and effective rescue measure after an emergency happened.
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http://dx.doi.org/10.1186/s12889-021-10883-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079161PMC
April 2021

Hypoxia inhibits RANKL-induced ferritinophagy and protects osteoclasts from ferroptosis.

Free Radic Biol Med 2021 06 22;169:271-282. Epub 2021 Apr 22.

Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, 201301, China. Electronic address:

Ferroptosis is a new form of regulated cell death. Several studies have demonstrated that ferroptosis was involved in multiple diseases. However, the precise role of ferroptosis in osteoporosis remains unclear. Here, we demonstrated that ferroptosis was involved in osteoclasts over the course of RANKL-induced differentiation, and it was induced by iron-starvation response and ferrintinophagy. Mechanistically, under normoxia but not hypoxia, ferroptosis could be induced due to iron-starvation response (increased transferrin receptor 1, decreased ferritin) followed by RANKL stimulation, and this was attributed to the down-regulation of aconitase activity. We further investigated intracellular iron homeostasis and found that ferritinophagy, a process initiated by FTH-NCOA4 complex autophagosome degradation, was activated followed by RANKL stimulation under normoxia. Interestingly, these processes could not be observed under hypoxia. Moreover, we demonstrated that HIF-1α contributed to the decrease of ferritinophagy and autophagy flux under hypoxia. Additionally, HIF-1α impair autophagy flux via inhibition of autophagosome formation under hypoxia in BMDMs. In vivo study, we indicated that HIF-1α specific inhibitor 2ME2 prevent OVX bone loss. In conclusion, our study comprehensively investigated the role of ferroptosis in osteoclasts in vitro and in vivo, and innovatively suggested that targeting HIF-1α and ferritin thus inducing ferroptosis in osteoclasts could be an alternative in treatment of osteoporosis.
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http://dx.doi.org/10.1016/j.freeradbiomed.2021.04.027DOI Listing
June 2021

HET0016 attenuates the stemness of breast cancer cells through targeting CYP4Z1.

Mol Carcinog 2021 06 18;60(6):413-426. Epub 2021 Apr 18.

Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China.

Ours and other previous studies have shown that CYP4Z1 is specifically and highly expressed in breast cancer, and acts as a promoter for the stemness of breast cancer cells. Here, we explored whether targeting CYP4Z1 could attenuate the stemness of breast cancer cells using HET0016, which has been confirmed to be an inhibitor of CYP4Z1 by us and others. Using the transcriptome-sequencing analysis, we found that HET0016 suppressed the expression of cancer stem cell (CSC) markers and stem cell functions. Additionally, HET0016 indeed reduced the stemness of breast cancer cells, as evident by the decrease of stemness marker expression, CD44 /CD24 subpopulation with stemness, mammary-spheroid formation, and tumor-initiating ability. Moreover, HET0016 suppressed the metastatic capability through in vitro and in vivo experiments. Furthermore, we confirmed that HET0016 suppressed CYP4Z1 activity, and HET0016-induced inhibition on the stemness and metastasis of breast cancer cells was rescued by CYP4Z1 overexpression. Thus, our results demonstrate that HET0016 can attenuate the stemness of breast cancer cells through targeting CYP4Z1.
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http://dx.doi.org/10.1002/mc.23302DOI Listing
June 2021

Cancer-associated fibroblasts in gastric cancer affect malignant progression via the CXCL12-CXCR4 axis.

J Cancer 2021 19;12(10):3011-3023. Epub 2021 Mar 19.

Department of Pathology, Medical College of Soochow University, Soochow University, Suzhou, China.

Cancer-associated fibroblasts (CAFs) are principal constituents of the tumor microenvironment (TME) and play a critical role in tumor progression. The CXCL12/CXCR4 axis regulates multiple facets of the TME. The aim of this study was to determine the relationship between CXCL12 expression in CAFs and the malignant progression of gastric cancer (GC). In the GEO (Gene Expression Omnibus) database, we performed transcriptome analysis on paired gastric cancer RNA sequencing samples, and scRNA analysis was performed on advanced malignant GC samples from the scRNA sequencing data set. Fibroblast cells were co-cultured with GC cells, and invasion, migration, epithelial-mesenchymal transformation (EMT) were determined. After blocking the expression of fibroblast CXCL12, cells were co-cultured with a GC cell line. Detection of GC cell line invasion, migration, EMT and CXCR4, Wnt5a and β-Catenin expression levels was performed. Primary CAFs and gastric normal fibroblasts were isolated and CXCL12 mRNA and protein expression were determined. In addition, a cohort of 285 GC cases was established, protein expression was evaluated immunohistochemically, and prognostic results were analyzed. GC transcriptome analysis suggested that cytokine-cytokine receptor interaction and the Wnt signaling pathway in GC tissues were significantly up-regulated. scRNA analysis of advanced malignant GC samples showed that severe intestinal metaplasia (SIM) in GC specimens of different malignant grades had obvious fibroblast clusters compared to non-atrophic gastritis (NAG) and early gastric cancer (EGC). In the SIM group, fibroblast cluster, CXCL12, CXCR4, and Wnt5a were overexpressed. Co-culturing with fibroblast cells significantly increased the invasion, migration, and EMT of GC cells, and blocking CXCL12 in CAFs disturbed the expression of Wnt5a and β-catenin. In our cohort of GC patients, high CXCL12 expression in CAFs significantly correlated with histological grade (P = 0.012) and TNM stage (P = 0.014), as well as with poor overall survival (p = 0.0107). High expression of CXCL12 in CAFs in a GC microenvironment can affect the migration, invasion, and EMT of GC cells. Furthermore, it can cause poor prognosis in patients with GC.
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http://dx.doi.org/10.7150/jca.49707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040897PMC
March 2021

FGF1 prevents diabetic cardiomyopathy by maintaining mitochondrial homeostasis and reducing oxidative stress via AMPK/Nur77 suppression.

Signal Transduct Target Ther 2021 Mar 24;6(1):133. Epub 2021 Mar 24.

School of Pharmaceutical Sciences and Center for Structural Biology, Wenzhou Medical University, Wenzhou, Zhejiang, China.

As a classically known mitogen, fibroblast growth factor 1 (FGF1) has been found to exert other pleiotropic functions such as metabolic regulation and myocardial protection. Here, we show that serum levels of FGF1 were decreased and positively correlated with fraction shortening in diabetic cardiomyopathy (DCM) patients, indicating that FGF1 is a potential therapeutic target for DCM. We found that treatment with a FGF1 variant (FGF1) with reduced proliferative potency prevented diabetes-induced cardiac injury and remodeling and restored cardiac function. RNA-Seq results obtained from the cardiac tissues of db/db mice showed significant increase in the expression levels of anti-oxidative genes and decrease of Nur77 by FGF1 treatment. Both in vivo and in vitro studies indicate that FGF1 exerted these beneficial effects by markedly reducing mitochondrial fragmentation, reactive oxygen species (ROS) generation and cytochrome c leakage and enhancing mitochondrial respiration rate and β-oxidation in a 5' AMP-activated protein kinase (AMPK)/Nur77-dependent manner, all of which were not observed in the AMPK null mice. The favorable metabolic activity and reduced proliferative properties of FGF1 testify to its promising potential for use in the treatment of DCM and other metabolic disorders.
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http://dx.doi.org/10.1038/s41392-021-00542-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991671PMC
March 2021

A towering genome: Experimentally validated adaptations to high blood pressure and extreme stature in the giraffe.

Sci Adv 2021 Mar 17;7(12). Epub 2021 Mar 17.

School of Ecology and Environment, Northwestern Polytechnical University, Xi'an 710072, China.

The suite of adaptations associated with the extreme stature of the giraffe has long interested biologists and physiologists. By generating a high-quality chromosome-level giraffe genome and a comprehensive comparison with other ruminant genomes, we identified a robust catalog of giraffe-specific mutations. These are primarily related to cardiovascular, bone growth, vision, hearing, and circadian functions. Among them, the giraffe gene is an outlier with seven unique amino acid substitutions not found in any other ruminant. Gene-edited mice with the giraffe-type show exceptional hypertension resistance and higher bone mineral density, both of which are tightly connected with giraffe adaptations to high stature. Our results facilitate a deeper understanding of the molecular mechanism underpinning distinct giraffe traits, and may provide insights into the study of hypertension in humans.
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http://dx.doi.org/10.1126/sciadv.abe9459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968835PMC
March 2021

Long noncoding RNA MCM3AP-AS1 enhances cell proliferation and metastasis in colorectal cancer by regulating miR-193a-5p/SENP1.

Cancer Med 2021 04 8;10(7):2470-2481. Epub 2021 Mar 8.

Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China.

Background: Accumulating evidences have shown that long noncoding RNAs (lncRNAs) play key roles in many diseases, including cancer. Several studies reported that MCM3AP antisense RNA 1 (MCM3AP-AS1) was associated with the tumorigenesis and progression. However, the specific function and mechanism of MCM3AP-AS1 in colorectal cancer (CRC) have not been fully understood.

Methods: The expression of MCM3AP-AS1 was detected by quantitative reverse transcription PCR (RT-qPCR) in CRC tissues and matched noncancerous tissues (NCTs). CCK-8 assay, colony formation assay, transwell assay, xenograft and lung metastasis mouse models were used to examine the tumor-promoting function of MCM3AP-AS1 in vitro and in vivo. The binding relationship between MCM3AP-AS1, miR-193a-5p and sentrin-specific peptidase 1 (SENP1) were screened and identified by databases, RT-qPCR, dual luciferase reporter assay and western blot.

Results: In the present study, we got that the expression of MCM3AP-AS1 was higher in CRC tissues than in paired NCTs, and increased MCM3AP-AS1 expression was associated with adverse outcomes in CRC patients. Functional experiments in vitro revealed that silencing of MCM3AP-AS1 could inhibit the proliferation, colony formation, migratory, and invasive abilities of CRC cells. The mouse models of xenograft and lung metastasis further confirmed that in vivo silencing MCM3AP-AS1 could significantly inhibit the growth and metastasis of CRC. Further mechanism studies indicated that MCM3AP-AS1 could sponge miR-193a-5p and inhibit the activity of it. What is more, SENP1 was proved to be a novel target of miR-193a-5p and could be upregulated by MCM3AP-AS1. At last, we observed that SENP1 overexpression in CRC tissues was closely related to unfavorable prognosis.

Conclusion: Taken together, we identified in CRC the MCM3AP-AS1/miR-193a-5p/SENP1 regulatory axis, which affords a therapeutic possibility for CRC.
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http://dx.doi.org/10.1002/cam4.3830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982620PMC
April 2021

Ultra-bright green-emitting phosphors with an internal quantum efficiency of over 90% for high-quality WLEDs.

Dalton Trans 2021 Mar 5;50(12):4159-4166. Epub 2021 Mar 5.

Collaborative Innovation Center of Rare-Earth Optical Functional Materials and Devices Development, School of Physics and Opto-Electronic Technology, Baoji University of Arts and Sciences, Baoji, Shaanxi 721016, P. R. China.

There is an urgent need to develop phosphors with high quantum efficiencies (QEs) since white light-emitting diodes (WLEDs) have emerged as a new generation of illumination materials. Utilizing energy transfer to improve the absorption of activators and adjust the emission colors of samples is one effective strategy. Here, color-tunable phosphors of the form CaAlO:Ce,Tb were synthesized aiming at efficient energy transfer from Ce to Tb. Since Tb can be suitably sensitized by Ce, the co-doped phosphors can be effectively excited by near-ultraviolet (NUV) light. The internal QE of CaAlO:0.04Ce,0.04Tb under 350 nm excitation is as high as 92.55%, and the external QE is 71.02%. A WLED fabricated from BAM:Eu, CaAlO:0.04Ce,0.04Tb, and CaAlSiN:Eu with a 365 nm LED chip exhibited a correlated color temperature (CCT) of 4706 K and a color rendering index (CRI, R) of 81.44. The energy transfer mechanism and thermal stability of the phosphor were also investigated. The results provide an effective approach for developing highly efficient green-emitting phosphors for NUV WLEDs.
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http://dx.doi.org/10.1039/d1dt00345cDOI Listing
March 2021

The peak levels of highly sensitive troponin I predicts in-hospital mortality in COVID-19 patients with cardiac injury: a retrospective study.

Eur Heart J Acute Cardiovasc Care 2021 Mar;10(1):6-15

Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Ave, Wuhan, 430022 Hubei, China.

Aims: To investigate the association between levels of highly sensitive troponin I (hs-troponin I) and mortality in novel coronavirus disease 2019 (COVID-19) patients with cardiac injury.

Methods And Results: We retrospectively reviewed the medical records of all COVID-19 patients with increased levels of hs-troponin I from two hospitals in Wuhan, China. Demographic information, laboratory test results, cardiac ultrasonographic findings, and electrocardiograms were collected, and their predictive value on in-hospital mortality was explored using multivariable logistic regression. Of 1500 patients screened, 242 COVID-19 patients were enrolled in our study. Their median age was 68 years, and (48.8%) had underlying cardiovascular diseases. One hundred and seventy-six (72.7%) patients died during hospitalization. Multivariable logistic regression showed that C-reactive protein (>75.5 mg/L), D-dimer (>1.5 μg/mL), and acute respiratory distress syndrome were risk factors of mortality, and the peak hs-troponin I levels (>259.4 pg/mL) instead of the hs-troponin I levels at admission was predictor of death. The area under the receiver operating characteristic curve of the peak levels of hs-troponin I for predicting in-hospital mortality was 0.79 (95% confidence interval, 0.73-0.86; sensitivity, 0.80; specificity, 0.72; P < 0.0001).

Conclusion: Our results demonstrated that the risk of in-hospital death among COVID-19 patients with cardiac injury can be predicted by the peak levels of hs-troponin I during hospitalization and was significantly associated with oxygen supply-demand mismatch, inflammation, and coagulation.
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http://dx.doi.org/10.1093/ehjacc/zuaa019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665398PMC
March 2021

Differences in Immune Responses between Children and Adults with COVID-19.

Curr Med Sci 2021 Feb 13;41(1):58-61. Epub 2021 Feb 13.

Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.

Over 85 590 000 individuals have been infected with severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2). Although there have been an increasing number of reports on coronavirus disease 2019 (COVID-19), it is unclear why infected children show milder symptoms than adults. A retrospective case study was performed at two designated hospitals for COVID-19. Patients (56 children and 63 adults) with confirmed SARS-CoV-2 infection and mild pneumonia were randomly enrolled in this study. The median age of the children was 7.0 years, and 51.79% of them were boys. The median age of the adults was 57 years, and 47.62% were men. The most common symptoms were fever, cough, sputum and diarrhoea. There were no significant differences in symptoms between children and adult patients. In terms of immunological indices on admission, adult patients displayed typical leukopenia and markedly higher levels of IL-2, IL-4, and IL-6 than child patients. The elevation of IL-2, IL-4 and IL-6 in adults induced more extensive lung injury. The effective and non-aggressive immune response successfully resisted SARS-CoV-2 invasion and maintained mild symptoms in child patients. The correlation of higher IL-2, IL-4, and IL-6 with the lung injury might be evidence that preventing excessive cytokine production can avoid further lung damage in these patients.
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http://dx.doi.org/10.1007/s11596-021-2318-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881906PMC
February 2021

A systematic review of body contouring surgery in post-bariatric patients to determine its prevalence, effects on quality of life, desire, and barriers.

Obes Rev 2021 05 9;22(5):e13201. Epub 2021 Feb 9.

Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China.

Many post-bariatric patients have impaired health-related quality of life (HRQoL) due to excess skin following weight loss; however, it is inconclusive whether body contouring surgery (BCS) improves this impairment. We aimed to comprehensively summarize existing evidence of the effect of BCS on the HRQoL (primary outcome) and determine the prevalence of, the desire for, and barriers to BCS (secondary outcomes). Randomized controlled trials, cohort, cross-sectional, case-control, and longitudinal studies were systematically searched in PubMed, Embase, the Cochrane Central, and Web of Science. After screening 1923 potential records, 24 studies (representing 6867 participants) were deemed eligible. Only 18.5% of respondents from cross-sectional studies underwent BCS, with abdominal BCS as the most common procedure. Most participants desired BCS but listed "cost" and "lacking reimbursement" as the main barriers. Results suggest that most post-bariatric patients who underwent BCS experienced improvements in their HRQoL, which could be seen in almost every dimension evaluated, including body image and physical and psychosocial functions. Therefore, both bariatric and plastic surgeons should regard BCS not only as an aesthetic supplement but also as a vital part of functional recovery in the surgery-mediated weight loss journey and, thus, provide it to more post-bariatric patients.
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http://dx.doi.org/10.1111/obr.13201DOI Listing
May 2021

Variant-selective stereopure oligonucleotides protect against pathologies associated with C9orf72-repeat expansion in preclinical models.

Nat Commun 2021 02 8;12(1):847. Epub 2021 Feb 8.

Department of Neurology, University of Massachusetts, Worcester, MA, USA.

A large GC-repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Neuronal degeneration associated with this expansion arises from a loss of C9orf72 protein, the accumulation of RNA foci, the expression of dipeptide repeat (DPR) proteins, or all these factors. We report the discovery of a new targeting sequence that is common to all C9orf72 transcripts but enables preferential knockdown of repeat-containing transcripts in multiple cellular models and C9BAC transgenic mice. We optimize stereopure oligonucleotides that act through this site, and we demonstrate that their preferential activity depends on both backbone stereochemistry and asymmetric wing design. In mice, stereopure oligonucleotides produce durable depletion of pathogenic signatures without disrupting protein expression. These oligonucleotides selectively protect motor neurons harboring C9orf72-expansion mutation from glutamate-induced toxicity. We hypothesize that targeting C9orf72 with stereopure oligonucleotides may be a viable therapeutic approach for the treatment of C9orf72-associated neurodegenerative disorders.
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http://dx.doi.org/10.1038/s41467-021-21112-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870851PMC
February 2021

Stereochemistry Enhances Potency, Efficacy, and Durability of Antisense Oligonucleotides In Vitro and In Vivo in Multiple Species.

Transl Vis Sci Technol 2021 01 12;10(1):23. Epub 2021 Jan 12.

Wave Life Sciences, Cambridge, MA, USA.

Purpose: Antisense oligonucleotides have been under investigation as potential therapeutics for many diseases, including inherited retinal diseases. Chemical modifications, such as chiral phosphorothioate (PS) backbone modification, are often used to improve stability and pharmacokinetic properties of these molecules. We aimed to generate a stereopure (metastasis-associated lung adenocarcinoma transcript 1) antisense oligonucleotide as a tool to assess the impact stereochemistry has on potency, efficacy, and durability of oligonucleotide activity when delivered by intravitreal injection to eye.

Methods: We generated a stereopure oligonucleotide (MALAT1-200) and assessed the potency, efficacy, and durability of its RNA-depleting activity compared with a stereorandom mixture, MALAT1-181, and other controls in in vitro assays, in vivo mouse and nonhuman primate (NHP) eyes, and ex vivo human retina cultures.

Results: The activity of the stereopure oligonucleotide is superior to its stereorandom mixture counterpart with the same sequence and chemical modification pattern in in vitro assays, in vivo mouse and NHP eyes, and ex vivo human retina cultures. Findings in NHPs showed durable activity of the stereopure oligonucleotide in the retina, with nearly 95% reduction of RNA maintained for 4 months postinjection.

Conclusions: An optimized, stereopure antisense oligonucleotide shows enhanced potency, efficacy, and durability of RNA depletion in the eye compared with its stereorandom counterpart in multiple preclinical models.

Translational Relevance: As novel therapeutics, stereopure oligonucleotides have the potential to enable infrequent administration and low-dose regimens for patients with genetic diseases of the eye.
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http://dx.doi.org/10.1167/tvst.10.1.23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804567PMC
January 2021
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