bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quinpirole ameliorates nigral dopaminergic neuron damage in Parkinson’s disease mouse model through activating GHS-R1a/D2R heterodimers
Authors: Tang Ting-ting , Bi Ming-xia , Diao Mei-ning , Zhang Xiao-yi , Chen Ling , Xiao Xue , Jiao Qian , Chen Xi , Yan Chun-ling , Du Xi-xun , Jiang Hong 
Published: March 2023

AbstractGrowth hormone secretagogue receptor 1a (GHS-R1a) is an important G protein-coupled receptor (GPCR) that regulates a variety of functions by binding to ghrelin. It has been shown that the dimerization of GHS-R1a with other receptors also affects ingestion, energy metabolism, learning and memory. Dopamine type 2 receptor (D2R) is a GPCR mainly distributed in the ventral tegmental area (VTA), substantia nigra (SN), striatum and other brain regions. In this study we investigated the existence and function of GHS-R1a/D2R heterodimers in nigral dopaminergic neurons in Parkinson’s disease (PD) models in vitro and in vivo. By conducting immunofluorescence staining, FRET and BRET analyses, we confirmed that GHS-R1a and D2R could form heterodimers in PC-12 cells and in the nigral dopaminergic neurons of wild-type mice. This process was inhibited by MPP+ or MPTP treatment. Application of QNP (10 μM) alone significantly increased the viability of MPP+-treated PC-12 cells, and administration of quinpirole (QNP, 1 mg/kg, i.p. once before and twice after MPTP injection) significantly alleviated motor deficits in MPTP-induced PD mice model; the beneficial effects of QNP were abolished by GHS-R1a knockdown. We revealed that the GHS-R1a/D2R heterodimers could increase the protein levels of tyrosine hydroxylase in the SN of MPTP-induced PD mice model through the cAMP response element binding protein (CREB) signaling pathway, ultimately promoting dopamine synthesis and release. These results demonstrate a protective role for GHS-R1a/D2R heterodimers in dopaminergic neurons, providing evidence for the involvement of GHS-R1a in PD pathogenesis independent of ghrelin.
Sequential targeting of PARP with carboplatin inhibits primary tumour growth and distant metastasis in triple-negative breast cancer
Authors: Beniey Michèle , Hubert Audrey , Haque Takrima , Cotte Alexia Karen , Béchir Nelly , Zhang Xiaomeng , Tran-Thanh Danh , Hassan Saima 
Published: March 2023

Abstract
Background
Patients with triple-negative breast cancer (TNBC) develop early recurrence. While PARP inhibitors (PARPi) have demonstrated potential in BRCA1/2-mutant (BRCAMUT) TNBC, durable responses will likely be achieved if PARPi are used in combination. It is plausible that sequential administration of a potent PARPi like talazoparib in combination with carboplatin can enhance primary tumour and metastasis inhibition in BRCAMUT and BRCA1/2 wild-type (BRCAWT) TNBCs, and decrease toxicity.

Methods
We evaluated the impact of the concurrent combination of talazoparib and carboplatin on cell survival in 13 TNBC cell lines. We compared the concurrent and sequential combination upon fork replication, migration and invasion. We also used three orthotopic xenograft models to evaluate primary tumour growth, distant metastasis, and toxicity.

Results
Concurrent talazoparib and carboplatin was synergistic in 92.3% of TNBC cell lines, independent of BRCA1/2-mutation status. The sequential combination decreased fork speed in normal cells, but not in TNBC cells. The talazoparib-first sequential combination resulted in a strong reduction in migration (70.4%, P < 0.0001), invasion (56.9%, P < 0.0001), lung micrometastasis (56.4%, P < 0.0001), and less toxicity in a BRCAWT model.

Conclusion
The sequential combination of talazoparib and carboplatin is an effective approach to inhibit micrometastatic disease, providing rationale for the use of this combination in early TNBC patients.
STOML2 restricts mitophagy and increases chemosensitivity in pancreatic cancer through stabilizing PARL-induced PINK1 degradation
Authors: Qin Cheng , Wang Yuanyang , Zhao Bangbo , Li Zeru , Li Tianyu , Yang Xiaoying , Zhao Yutong , Wang Weibin 
Published: March 2023

AbstractPancreatic cancer remains one of the most lethal diseases with a relatively low 5-year survival rate, and gemcitabine-based chemoresistance occurs constantly. Mitochondria, as the power factory in cancer cells, are involved in the process of chemoresistance. The dynamic balance of mitochondria is under the control of mitophagy. Stomatin-like protein 2 (STOML2) is located in the mitochondrial inner membrane and is highly expressed in cancer cells. In this study, using a tissue microarray (TMA), we found that high STOML2 expression was correlated with higher survival of patients with pancreatic cancer. Meanwhile, the proliferation and chemoresistance of pancreatic cancer cells could be retarded by STOML2. In addition, we found that STOML2 was positively related to mitochondrial mass and negatively related to mitophagy in pancreatic cancer cells. STOML2 stabilized PARL and further prevented gemcitabine-induced PINK1-dependent mitophagy. We also generated subcutaneous xenografts to verify the enhancement of gemcitabine therapy induced by STOML2. These findings suggested that STOML2 regulated the mitophagy process through the PARL/PINK1 pathway, thereby reducing the chemoresistance of pancreatic cancer. STOML2-overexpression targeted therapy might be helpful for gemcitabine sensitization in the future.
Targeting oxeiptosis-mediated tumor suppression: a novel approach to treat colorectal cancers by sanguinarine
Authors: Pallichankandy Siraj , Thayyullathil Faisal , Cheratta Anees Rahman , Subburayan Karthikeyan , Alakkal Ameer , Sultana Mehar , Drou Nizar , Arshad Muhammad , Tariq Saeed , Galadari Sehamuddin 
Published: March 2023

AbstractOxeiptosis is a recently identified reactive oxygen species (ROS)-sensitive, caspase independent, non-inflammatory regulated cell death pathway. The activation of Kelch-like ECH-associated protein 1-Phosphoglycerate mutase 5-Apoptosis inducing factor mitochondria associated 1 (KEAP1-PGAM5-AIFM1) pathway is the key signaling event in the execution of oxeiptosis. In the present study, we demonstrate that sanguinarine (SNG), a quaternary benzophenanthridine alkaloid, induces oxeiptosis in human colorectal cancer (CRC) cells via ROS, specifically hydrogen peroxide (H2O2)-dependent activation of KEAP1-PGAM5-AIFM1 signaling axis. Whilst, knockdown of KEAP1, PGAM5, and AIFM1 largely abolishes SNG-induced oxeiptosis, hence reinforcing the importance of the role of this pathway in the SNG-mediated cytotoxicity. Moreover, extracellular addition of H2O2 sensitizes SNG-induced oxeiptosis in CRC cells, while removal of intracellular ROS by ROS scavengers, not only alleviated the overproduction of ROS caused by SNG, but also reversed the biochemical events associated with oxeiptosis. Finally, in vivo study demonstrates that SNG effectively reduces the tumor growth in HT-29 xenograft mouse model through features associated with oxeiptosis. This study highlights oxeiptosis as a novel tumor suppressive mechanism and further investigation of the role of oxeiptosis in cancer treatment is warranted.
Dual roles of TRIM3 in colorectal cancer by retaining p53 in the cytoplasm to decrease its nuclear expression
Authors: Han Yang , Lu Su , Song Chenlong , Xuan Yi , Zhang Meng , Cai Hong 
Published: March 2023

AbstractColorectal cancer is a very heterogeneous disease caused by the interaction of genetic and environmental factors. P53, as a frequent mutation gene, plays a critical role in the adenoma-carcinoma transition during the tumorous pathological process. Our team discovered TRIM3 as a tumor-associated gene in CRC by high-content screening techniques. TRIM3 demonstrated both tumor-suppressive and tumorigenic features in cell experiments dependent on the cell status of wild or mutant p53. TRIM3 could directly interact with the C terminus of p53 (residues 320 to 393), a common segment of wtp53 and mutp53. Moreover, TRIM3 could exert different neoplastic features by retaining p53 in the cytoplasm to decrease its nuclear expression in a wtp53 or mutp53-dependent pathway. Chemotherapy resistance develops in nearly all patients with advanced CRC and seriously limits the therapeutic efficacies of anticancer drugs. TRIM3 could reverse the chemotherapy resistance of oxaliplatin in mutp53 CRC cells by degradation of mutp53 in the nuclei to downregulate the multidrug resistance gene. Therefore, TRIM3 could be a potential therapeutic strategy to improve the survival of CRC patients with mutp53.
Downregulation of Sox8 mediates monosodium urate crystal-induced autophagic impairment of cartilage in gout arthritis
Authors: Xiao Lu , Lin Shudian , Xu WenChao , Sun Erwei 
Published: March 2023

AbstractThe deposition of monosodium urate (MSU) crystals in arthritic joints of gout seriously damages cartilage. This study aimed to investigate whether MSU crystal-induced cartilage impairment was related to autophagic signaling. mRNAs of cartilage from MSU-induced gouty arthritis rat model were sequenced. MSU crystal-treated human chondrocytes were used to evaluate the function of Sox8. The recombinant Sox8 lentiviral vector (lenti-Sox8) was applied to upregulate the expression of Sox8. Transfection of the mRFP-GFP-LC3 plasmid was evaluated by confocal microscopy. The autophagic vacuoles were stained with monodansylcadaverine and examined by flow cytometry. The morphology of autophagosomes was observed by transmission electron microscopy. The ratio of LC3-II/I in the presence or absence of bafilomycin A1 and the expression levels of Beclin1, Sox8, p-PI3K, PI3K, p-AKT, AKT, p-mTOR, and mTOR were detected by Western blot. In vivo, the effect of Sox8 on cartilage of acute gouty model rats was evaluated by safranin-O/fast green staining and Western blot. The expression of Sox8 was significantly downregulated both in vivo and in vitro. In chondrocytes, MSU crystals reduced the expression of Sox8, inhibited the PI3K/AKT/mTOR signaling pathway, and increased the level of autophagy. Overexpression of Sox8 notably inhibited MSU crystal-induced autophagy by rescuing the phosphorylation levels in the PI3K/AKT/mTOR signaling pathway. In vivo, overexpression of Sox8 remarkably alleviated cartilage damage in acute gouty model rats. These results indicate that downregulation of Sox8 plays an important role in MSU-induced chondrocyte autophagy by modulating PI3K/AKT/mTOR signaling, and overexpression of Sox8 may serve as a novel therapy to prevent the impairment of cartilage in gout arthritis.
JMJD1C promotes smooth muscle cell proliferation by activating glycolysis in pulmonary arterial hypertension
Authors: Zhang Chen , Sun Yue , Guo Yingying , Xu Jingjing , Zhao Haiyan 
Published: March 2023

AbstractPulmonary arterial hypertension (PAH) is a chronic disorder characterized by hyperproliferation of pulmonary arterial smooth muscle cells (PASMCs). JMJD1C, a member of the Jumonji domain containing C (JMJC) histone demethylase family, contributes to cardiovascular dysfunction. However, the role of JMJD1C in PAH remains unknown. Mice were exposed to hypoxia to mimic several features associated with PAH clinically. We found that JMJD1C was highly expressed in the lungs of mice after hypoxia exposure. JMJD1C knockdown ameliorated hypoxia-induced right ventricular remodeling and thickening of the pulmonary arterial wall. PASMC hyperproliferation and resistance to apoptosis in mice exposed to hypoxia were suppressed by JMJD1C inhibition. We demonstrated that JMJD1C silencing reduced glycolytic enzymes (HK2, PGK1 and LDHA) and lactate overaccumulation in the lungs of mice exposed to hypoxia. In vitro, hypoxia-induced hyperproliferation and activated glycolytic processes in mouse PASMCs were impaired by JMJD1C knockdown. In addition, the activation of STAT3 signaling by hypoxia was suppressed by JMJD1C silencing both in vivo and in vitro. The overexpression of STAT3 reversed the inhibitory effect of JMJD1C depletion on proliferation and glycolysis in PASMCs under hypoxia. Thus, JMJD1C induces glycolytic processes by activating STAT3 signaling to promote PASMC proliferation and pulmonary vascular remodeling, suggesting the potential role of JMJD1C in regulating the metabolic program and vascular remodeling in PAH.
Two sporadic cases of childhood-onset Hailey-Hailey disease with superimposed mosaicism
Authors: Asahina Yasuhiko , Tahara Umi , Aoki Satomi , Nakabayashi Kazuhiko , Tateishi Chiharu , Hayashi Daisuke , Amagai Masayuki , Tsuruta Daisuke , Kubo Akiharu 
Published: March 2023

AbstractA prenatal second-hit genetic change that occurs on the wild-type allele in an embryo with a congenital pathogenic variant allele results in mosaicism of monoallelic and biallelic defect of the gene, which is called superimposed mosaicism. Superimposed mosaicism of Hailey-Hailey disease (HHD) has been demonstrated in one familial case. Here, we report two unrelated HHD cases with superimposed mosaicism: a congenital monoallelic pathogenic variant of ATP2C1, followed by a postzygotic copy-neutral loss of heterozygosity. Uniquely, neither patient had a family history of HHD at the time of presentation. In the first case, the congenital pathogenic variant had occurred de novo. In the second case, the father had the pathogenic variant but had not yet developed skin symptoms. Our cases showed that superimposed mosaicism in HHD can lack a family history and that genetic analysis is crucial to classify the type of mosaicism and evaluate the risk of familial occurrence.
Exome sequencing in individuals with congenital anomalies of the kidney and urinary tract (CAKUT): a single-center experience
Authors: Riedhammer Korbinian M. , Ćomić Jasmina , Tasic Velibor , Putnik Jovana , Abazi-Emini Nora , Paripovic Aleksandra , Stajic Natasa , Meitinger Thomas , Nushi-Stavileci Valbona , Berutti Riccardo , Braunisch Matthias C. , Hoefele Julia 
Published: March 2023

AbstractIndividuals with congenital anomalies of the kidney and urinary tract (CAKUT) show a broad spectrum of malformations. CAKUT can occur in an isolated fashion or as part of a syndromic disorder and can lead to end-stage kidney failure. A monogenic cause can be identified in ~12% of affected individuals. This study investigated a single-center CAKUT cohort analyzed by exome sequencing (ES). Emphasis was placed on the question whether diagnostic yield differs between certain CAKUT phenotypes (e.g., bilateral kidney affection, unilateral kidney affection or only urinary tract affection). 86 unrelated individuals with CAKUT were categorized according to their phenotype and analyzed by ES to identify a monogenic cause. Prioritized variants were rated according to the recommendations of the American College of Medical Genetics and Genomics and the Association for Clinical Genomic Science. Diagnostic yields of different phenotypic categories were compared. Clinical data were collected using a standardized questionnaire. In the study cohort, 7/86 individuals had a (likely) pathogenic variant in the genes PAX2, PBX1, EYA1, or SALL1. Additionally, in one individual, a 17q12 deletion syndrome (including HNF1B) was detected. 64 individuals had a kidney affection, which was bilateral in 36. All solved cases (8/86, 9%) had bilateral kidney affection (diagnostic yield in subcohort: 8/36, 22%). Although the diagnostic yield in CAKUT cohorts is low, our single-center experience argues, that, in individuals with bilateral kidney affection, monogenic burden is higher than in those with unilateral kidney or only urinary tract affection.
Evaluation of care with intravitreal aflibercept treatment for UK patients with diabetic macular oedema: DRAKO study 24-month real-world outcomes
Authors: Sivaprasad Sobha , Ghanchi Faruque , Kelly Simon P. , Kotagiri Ajay , Talks James , Scanlon Peter , McGoey Hellen , Nolan Andrew , Saddiq Moneeb , Napier Jackie 
Published: March 2023

Abstract
Background/ Objectives
DRAKO (NCT02850263) was a 24-month, prospective, observational, multi-centre cohort study that enrolled patients diagnosed with diabetic macular oedema (DMO) including central involvement. The study aimed to evaluate standard of care intravitreal aflibercept (IVT-AFL) treatment in the UK. This analysis describes the 12-month outcomes for patients with prior anti–vascular endothelial growth factor (VEGF) treatment for DMO other than IVT-AFL (C2), and 2-year outcomes for both anti-VEGF treatment–naïve patients (C1) and C2 patients.

Methods
Study eyes were treated with IVT-AFL as per local standard of care. Mean changes in best-corrected visual acuity (BCVA) in ETDRS letters and central subfield thickness (CST) were stratified by baseline factors. Changes in diabetic retinopathy assessments, glycated haemoglobin A1c levels and vision-related quality of life (QoL) were evaluated alongside numbers of injections administered and safety outcomes.

Results
For C1, mean (SD) changes from baseline in BCVA of +0.7 (12.7) letters and CST of –123.3 (104.3) µm were observed at Month 24. For C2, mean (SD) changes from baseline for BCVA of + 0.2 (10.2) letters and –0.3 (13.0) letters, and CST of –79.1 (137.6) µm and −91.6 (132.9) µm, were observed at 12 and 24 months, respectively. In Year 2, C1 and C2 patients received a mean of 3.7 and 4.3 injections, respectively.

Conclusions
Year 2 results indicate that IVT-AFL is an effective treatment for DMO in real-world UK clinical practice, despite relatively low injection numbers. The high baseline visual acuity and QoL scores were maintained and there was further improvement in anatomical outcomes.
Ultrathin Descemet Stripping Automated Endothelial Keratoplasty (UT-DSAEK) versus Descemet Membrane Endothelial Keratoplasty (DMEK)—a systematic review and meta-analysis
Authors: Hurley Daire J. , Murtagh Patrick , Guerin Marc 
Published: March 2023

AbstractBackground/ObjectivesEndothelial keratoplasty (EK) is a commonly performed transplant procedure used in the treatment of corneal endothelial dysfunction. The aim of this systematic review and meta-analysis is to evaluate the differences in visual acuity outcomes, endothelial cell density (ECD) and complications between two forms of EK, ultrathin Descemet stripping automated endothelial keratoplasty (UT-DSAEK) and Descemet membrane endothelial keratoplasty (DMEK).MethodsA literature search of MEDLINE, Embase and Cochrane Library was conducted to identify studies reporting comparative results of UT-DSAEK versus DMEK. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was used for search strategy. Of 141 titles, 7 studies met the inclusion criteria; best corrected visual acuity (BCVA) (LogMAR), ECD (cells/mm2), and complications were compared, with all statistical analysis performed using Review Manager.ResultsA total of 362 eyes were included for analysis. DMEK resulted in significantly better BCVA at 3 months (0.14 vs 0.22,p = 0.003), 6 months (0.08 vs 0.18,p = 0.005) and 1 year post-op (0.07 vs 0.14,p = 0.0005). UT-DSAEK resulted in significantly lower total complications (25.2% vs 57.3%,p = 0.0001) and rates of re-bubbling (11.0% vs 33.7%,p = 0.004). No differences were found in ECD between the two procedures (1541 vs 1605,p = 0.77).ConclusionsDMEK results in superior visual acuity rates with quicker recovery. However, UT-DSAEK has a more favourable complication profile, particularly regarding lower rates of re-bubbling. Both are valuable options in the treatment of corneal endothelial disease and choice of procedure may depend on surgical expertise.
Frequency of coexistent eye diseases and cognitive impairment or dementia: a systematic review and meta-analysis
Authors: Xu Ying , Phu Jack , Aung Htein Linn , Hesam-Shariati Negin , Keay Lisa , Tully Phillip J. , Booth Andrew , Anderson Craig S. , Anstey Kaarin J. , Peters Ruth 
Published: March 2023

Abstract
Objective
We aim to quantify the co-existence of age-related macular degeneration (AMD), glaucoma, or diabetic retinopathy (DR) and cognitive impairment or dementia.

Method
MEDLINE, EMBASE, PsycINFO and CINAHL were searched (to June 2020). Observational studies reporting incidence or prevalence of AMD, glaucoma, or DR in people with cognitive impairment or dementia, and of cognitive impairment or dementia among people with AMD, glaucoma, or DR were included.

Results
Fifty-six studies (57 reports) were included but marked by heterogeneities in the diagnostic criteria or definitions of the diseases, study design, and case mix. Few studies reported on the incidence. Evidence was sparse but consistent in individuals with mild cognitive impairment where 7.7% glaucoma prevalence was observed. Prevalence of AMD and DR among people with cognitive impairment ranged from 3.9% to 9.4% and from 11.4% to 70.1%, respectively. Prevalence of AMD and glaucoma among people with dementia ranged from 1.4 to 53% and from 0.2% to 25.9%, respectively. Prevalence of DR among people with dementia was 11%. Prevalence of cognitive impairment in people with AMD, glaucoma, and DR ranged from 8.4% to 52.4%, 12.3% to 90.2%, and 3.9% to 77.8%, respectively, and prevalence of dementia in people with AMD, glaucoma and DR ranged from 9.9% to 62.6%, 2.5% to 3.3% and was 12.5%, respectively.

Conclusions
Frequency of comorbid eye disease and cognitive impairment or dementia varied considerably. While more population-based estimations of the co-existence are needed, interdisciplinary collaboration might be helpful in the management of these conditions to meet healthcare needs of an ageing population.

Trial registration
PROSPERO registration: CRD42020189484.
Y chromosome-linked variation affects locomotor activity in male Drosophila melanogaster and is robust to differences in thermal environment
Authors: Layh Sean , Nagarajan-Radha Venkatesh , Lemos Bernardo , Dowling Damian K. 
Published: March 2023

AbstractAlthough containing genes important for sex determination, genetic variation within the Y chromosome was traditionally predicted to contribute little to the expression of sexually dimorphic traits. This prediction was shaped by the assumption that the chromosome harbours few protein-coding genes, and that capacity for Y-linked variation to shape adaptation would be hindered by the chromosome’s lack of recombination and holandric inheritance. Consequently, most studies exploring the genotypic contributions to sexually dimorphic traits have focused on the autosomes and X chromosome. Yet, several studies have now demonstrated that the Y chromosome harbours variation affecting male fitness, moderating the expression of hundreds of genes across the nuclear genome. Furthermore, emerging results have shown that expression of this Y-linked variation may be sensitive to environmental heterogeneity, leading to the prediction that Y-mediated gene-by-environment interactions will shape the expression of sexually dimorphic phenotypes. We tested this prediction, investigating whether genetic variation across six distinct Y chromosome haplotypes affects the expression of locomotor activity, at each of two temperatures (20 and 28 °C) in male fruit flies (Drosophila melanogaster). Locomotor activity is a sexually dimorphic trait in this species, previously demonstrated to be under intralocus sexual conflict. We demonstrate Y haplotype effects on male locomotor activity, but the rank order and magnitude of these effects were unaltered by differences in temperature. Our study contributes to a growing number of studies demonstrating Y-linked effects moderating expression of traits evolving under sexually antagonistic selection, suggesting a role for the Y chromosome in shaping outcomes of sexual conflict.