tbuckley/cabot-search huggingface dataset:
Can exercise benefits be harnessed with drugs? A new way to combat neurodegenerative diseases by boosting neurogenesis
Authors: Renqing Zhao
Journal: Translational Neurodegeneration (2024)

Adult hippocampal neurogenesis (AHN) is affected by multiple factors, such as enriched environment, exercise, ageing, and neurodegenerative disorders. Neurodegenerative disorders can impair AHN, leading to progressive neuronal loss and cognitive decline. Compelling evidence suggests that individuals engaged in regular exercise exhibit higher production of proteins that are essential for AHN and memory. Interestingly, specific molecules that mediate the effects of exercise have shown effectiveness in promoting AHN and cognition in different transgenic animal models. Despite these advancements, the precise mechanisms by which exercise mimetics induce AHN remain partially understood. Recently, some novel exercise molecules have been tested and the underlying mechanisms have been proposed, involving intercommunications between multiple organs such as muscle-brain crosstalk, liver-brain crosstalk, and gut-brain crosstalk. In this review, we will discuss the current evidence regarding the effects and potential mechanisms of exercise mimetics on AHN and cognition in various neurological disorders. Opportunities, challenges, and future directions in this research field are also discussed.
Avenanthramide A potentiates Bim-mediated antineoplastic properties of 5-fluorouracil via targeting KDM4C/MIR17HG/GSK-3β negative feedback loop in colorectal cancer
Authors: Rong Fu, Zhangfeng Dou, Ning Li, Xueyuan Fan, Sajid Amin, Jinqi Zhang, Yuqing Wang, Zongwei Li, Zhuoyu Li, Peng Yang
Journal: Acta Pharmaceutica Sinica B (2024)

Chemoresistance to 5-fluorouracil (5-FU) is a significant challenge in treating colorectal cancer (CRC). Novel combined regimens to thwart chemoresistance are therefore urgently needed. Herein, we demonstrated that the combination of Avenanthramide A (AVN A) and 5-FU has significant therapeutic advantages against CRC. Mechanistically, AVN A directly binds to the S198 site of the histone lysine demethylase KDM4C to promote its degradation, which subsequently fosters H3K9me3 occupancy on the MIR17HG promoter to block its transcription and derepress Bim expression. AVN A enhanced the therapeutic efficacy of 5-FU via impairing the KDM4C/MIR17HG/GSK-3β negative feedback loop. Importantly, the clinical correlation of the KDM4C/MIR17HG/Bim signaling axis with 5-FU response was validated in the refractory CRC patients. We provide evidence for the enhanced effectiveness of 5-FU when combined with AVN A in chemoresistant xenografts, CRC organoids, and Apc Min/+ mouse model. Additionally, AVN A mitigated the systemic adverse effects of 5-FU. Overall, our findings demonstrate that combinatorial therapy with AVN A and 5-FU represents an appealing opportunity and highlights KDM4C/MIR17HG/GSK-3β negative feedback loop which confers therapeutically exploitable vulnerability to chemo-refractory CRC patients.
Risk of De Novo Barrett’s Esophagus Post Sleeve Gastrectomy: A Systematic Review and Meta-Analysis of Studies with Long-Term Follow-Up
Authors: Saurabh Chandan, Shahab R. Khan, Smit S. Deliwala, Dushyant S. Dahiya, Babu P. Mohan, Daryl Ramai, Syed M. Saghir, Banreet S. Dhindsa, Lena L. Kassab, Antonio Facciorusso, Kalyana Nandipati, Dennis Yang, Douglas G. Adler
Journal: Clinical Gastroenterology and Hepatology (2024)
Automated Neutrophil Quantification and Histological Score Estimation in Ulcerative Colitis
Authors: Jun Ohara, Yasuharu Maeda, Noriyuki Ogata, Takanori Kuroki, Masashi Misawa, Shin-Ei Kudo, Tetsuo Nemoto, Toshiko Yamochi, Marietta Iacucci
Journal: Clinical Gastroenterology and Hepatology (2024)
Estimating the economic effect of harm associated with high risk prescribing of oral non-steroidal anti-inflammatory drugs in England: population based cohort and economic modelling study
Authors: Elizabeth M Camacho, Leonie S Penner, Amy Taylor, Bruce Guthrie, Anthony J Avery, Darren M Ashcroft, Daniel R Morales, Gabriel Rogers, Antony Chuter, Rachel A Elliott
Journal: BMJ (2024)

To quantify prevalence, harms, and NHS costs in England of problematic oral non-steroidal anti-inflammatory drug (NSAID) prescribing in high risk groups.
Cord blood banking: Experts raise concern over claims made for stem cell applications: Video 1
Authors: Jacklin Kwan
Journal: BMJ (2024)

Marketing by some private biobanks may be misleading expectant parents about the procedure's value, writes Jacklin Kwan Umbilical cord blood banking has gained prominence in the past decade as an option for expectant parents worried about their child's future health.1 Parents pay private biobank companies up to £3000 (excluding annual storage fees) to freeze their baby's cord blood, which contains stem cells, in case the infant develops a condition that could be treated with stem cell therapy. Video 1 Umbilical cord blood banking: overinflated claims of stem cells' application? Cells4Life, which claims to be the UK's largest private biobank for cord blood banking, says that its particular method delivers more stem cells from umbilical cord blood than its competitors' processes. For this marketing message it relies on research published in the Journal of Stem Cells Research, Development & Therapy . Publication of this research took place just 17 days after receipt of the manuscript, a timescale far shorter than is typical for peer reviewed journals. Two editors listed on the journal's editorial board say they did not in fact hold these roles, The BMJ discovered (box 1). Box 1 ### Claim of superior technology by UK's largest private biobank raises questions Cells4Life says it is the UK's largest provider of cord blood banking services. The firm markets its proprietary technology TotiCyte—a "precise, low concentration mixture of two solutions," the cryoprotectants dimethyl sulfoxide (DMSO) and dextran—as the reason why, after collection, processing, and freezing, its samples have three times as many stem cells as competitors that use other processing methods (assuming that freezing and collection are kept the same across all methods). Patricia Murray, professor of stem cells and regenerative medicine at the University of Liverpool, says that there is no clear scientific reason why TotiCyte should outperform market alternatives. "All they've got in TotiCyte is DMSO and dextran, which are well established cryoprotectants," she … RETURN TO TEXT
Personal protective effect of wearing surgical face masks in public spaces on self-reported respiratory symptoms in adults: pragmatic randomised superiority trial
Authors: Runar Barstad Solberg, Atle Fretheim, Ingeborg Hess Elgersma, Mette Fagernes, Bjørn Gunnar Iversen, Lars G Hemkens, Christopher James Rose, Petter Elstrøm
Journal: BMJ (2024)

Abstract Objective To evaluate the personal protective effects of wearing versus not wearing surgical face masks in public spaces on self-reported respiratory symptoms over a 14 day period. Design Pragmatic randomised superiority trial. Setting Norway. Participants 4647 adults aged ≥18 years: 2371 were assigned to the intervention arm and 2276 to the control arm. Interventions Participants in the intervention arm were assigned to wear a surgical face mask in public spaces (eg, shopping centres, streets, public transport) over a 14 day period (mask wearing at home or work was not mentioned). Participants in the control arm were assigned to not wear a surgical face mask in public places. Main outcome measures The primary outcome was self-reported respiratory symptoms consistent with a respiratory infection. Secondary outcomes included self-reported and registered covid-19 infection and self-reported sick leave. Results Between 10 February 2023 and 27 April 2023, 4647 participants were randomised of whom 4575 (2788 women (60.9%); mean age 51.0 (standard deviation 15.0) years) were included in the intention-to-treat analysis: 2313 (50.6%) in the intervention arm and 2262 (49.4%) in the control arm. 163 events (8.9%) of self-reported symptoms consistent with respiratory infection were reported in the intervention arm and 239 (12.2%) in the control arm. The marginal odds ratio was 0.71 (95% confidence interval (CI) 0.58 to 0.87; P=0.001) favouring the face mask intervention. The absolute risk difference was −3.2% (95% CI −5.2% to −1.3%; P&lt;0.001). No statistically significant effect was found on self- reported (marginal odds ratio 1.07, 95% CI 0.58 to 1.98; P=0.82) or registered covid-19 infection (effect estimate and 95% CI not estimable owing to lack of events in the intervention arm). Self-reported sick leave was equally distributed between the intervention and control groups (marginal odds ratio 1.00, 0.81 to 1.22; P=0.97). Conclusion Wearing a surgical face mask in public spaces over 14 days reduces the risk of self-reported symptoms consistent with a respiratory infection, compared with not wearing a surgical face mask. Trial registration ClinicalTrials.gov NCT05690516 .
Long-term durability between parent and child patient-reported outcomes in eosinophilic esophagitis
Authors: Lisa J. Martin, Xue Zhang, Mirna Chehade, Carla M. Davis, Evan S. Dellon, Gary W. Falk, Sandeep K. Gupta, Ikuo Hirano, Girish S. Hiremath, David A. Katzka, Paneez Khoury, John Leung, Paul Menard-Katcher, Nirmala Gonsalves, Robert D. Pesek, Jonathan M. Spergel, Joshua B. Wechsler, Kara Kliewer, Nicoleta C. Arva, Margaret H. Collins, Maria Pletneva, Guang-Yu Yang, Glenn T. Furuta, Marc E. Rothenberg, Seema S. Aceves
Journal: Journal of Allergy and Clinical Immunology (2024)
Diagnostic accuracy of the Fibrosis-4 index for advanced liver fibrosis in nonalcoholic fatty liver disease with type 2 diabetes: A systematic review and meta-analysis
Authors: Ji Won Han, Hee Yeon Kim, Jung Hwan Yu, Mi Na Kim, Young Eun Chon, Ji Hyun An, Young-Joo Jin, Miyoung Choi, Seung Up Kim, Han Ah Lee, Dae Won Jun
Journal: Clinical and Molecular Hepatology (2024)

Background/Aims: The Fibrosis-4 index (FIB-4) is a noninvasive test widely used to rule out advanced liver fibrosis (AF) in patients with nonalcoholic fatty liver disease (NAFLD). However, its diagnostic accuracy in NAFLD patients with type 2 diabetes mellitus (T2DM) is controversial due to the high prevalence of AF in this population.Methods: Research focusing on the diagnostic accuracy of FIB-4 for liver fibrosis as validated by liver histology in NAFLD patients with T2DM was included, and 12 studies (n=5,624) were finally included in the meta-analysis. Sensitivity, specificity, hierarchical summary receiver operating characteristic (HSROC), positive predictive values (PPVs), and negative predictive values (NPVs) at low cutoffs (1.3–1.67) and high cutoffs (2.67–3.25) for ruling in and out AF were calculated.Results: At low cutoffs, the meta-analysis revealed a sensitivity of 0.74, specificity of 0.62, and HSROC of 0.75. At high cutoffs, the analysis showed a sensitivity of 0.33, specificity of 0.92, and HSROC of 0.85, suggesting FIB-4 as useful for identifying or excluding AF. In subgroup analyses, high mean age and F3 prevalence were associated with lower sensitivity. The calculated NPV and PPV were 0.82 and 0.49 at low cutoffs, whereas the NPV was 0.28 and the PPV was 0.70 at high cutoffs. There were insufficient estimated NPVs &lt;0.90 at a hypothesized prevalence of AF &gt;30% at an FIB-4 cutoff range of 1.3–1.67.Conclusions: Collectively, FIB-4 has moderate diagnostic accuracy for identifying or excluding AF in NAFLD patients with T2DM, but more evidence must be accumulated due to the limited number of currently reported studies and their heterogeneity.
DNA methylome analysis reveals epigenetic alteration of complement genes in advanced metabolic dysfunction-associated steatotic liver disease
Authors: Amal Magdy, Hee-Jin Kim, Hanyong Go, Jun Min Lee, Hyun Ahm Sohn, Keeok Haam, Hyo-Jung Jung, Jong-Lyul Park, Taekyeong Yoo, Eun-Soo Kwon, Dong Hyeon Lee, Murim Choi, Keon Wook Kang, Won Kim, Mirang Kim
Journal: Clinical and Molecular Hepatology (2024)

Background/Aims: Blocking the complement system is a promising strategy to impede the progression of metabolic dysfunction–associated steatotic liver disease (MASLD). However, the interplay between complement and MASLD remains to be elucidated. This comprehensive approach aimed to investigate the potential association between complement dysregulation and the histological severity of MASLD.Methods: Liver biopsy specimens were procured from a cohort comprising 106 Korean individuals, which included 31 controls, 17 with isolated steatosis, and 58 with metabolic dysfunction–associated steatohepatitis (MASH). Utilizing the Infinium Methylation EPIC array, thorough analysis of methylation alterations in 61 complement genes was conducted. The expression and methylation of nine complement genes in a murine MASH model were examined using quantitative RT-PCR and pyrosequencing.Results: Methylome and transcriptome analyses of liver biopsies revealed significant (&lt;i&gt;P&lt;/i&gt;&lt;0.05) hypermethylation and downregulation of &lt;i&gt;C1R, C1S, C3, C6, C4BPA&lt;/i&gt;, and &lt;i&gt;SERPING1&lt;/i&gt;, as well as hypomethylation (&lt;i&gt;P&lt;/i&gt;&lt;0.0005) and upregulation (&lt;i&gt;P&lt;/i&gt;&lt;0.05) of &lt;i&gt;C5AR1, C7&lt;/i&gt;, and &lt;i&gt;CD59&lt;/i&gt;, in association with the histological severity of MASLD. Furthermore, DNA methylation and the relative expression of nine complement genes in a MASH diet mouse model aligned with human data.Conclusions: Our research provides compelling evidence that epigenetic alterations in complement genes correlate with MASLD severity, offering valuable insights into the mechanisms driving MASLD progression, and suggests that inhibiting the function of certain complement proteins may be a promising strategy for managing MASLD.
Loss of the tumour suppressor LKB1/STK11 uncovers a leptin-mediated sensitivity mechanism to mitochondrial uncouplers for targeted cancer therapy
Authors: Andriani Angelopoulou, Giorgos Theocharous, Dimitrios Valakos, Aikaterini Polyzou, Sophia Magkouta, Vassilios Myrianthopoulos, Sophia Havaki, Marco Fiorillo, Ioanna Tremi, Konstantinos Vachlas, Theodoros Nisotakis, Dimitris-Foivos Thanos, Anastasia Pantazaki, Dimitris Kletsas, Jiri Bartek, Russell Petty, Dimitris Thanos, Rory J McCrimmon, Angelos Papaspyropoulos, Vassilis G Gorgoulis
Journal: Molecular Cancer (2024)

Abstract Non-small cell lung cancer (NSCLC) constitutes one of the deadliest and most common malignancies. The LKB1/STK11 tumour suppressor is mutated in ∼ 30% of NSCLCs, typically lung adenocarcinomas (LUAD). We implemented zebrafish and human lung organoids as synergistic platforms to pre-clinically screen for metabolic compounds selectively targeting LKB1-deficient tumours. Interestingly, two kinase inhibitors, Piceatannol and Tyrphostin 23, appeared to exert synthetic lethality with LKB1 mutations. Although LKB1 loss alone accelerates energy expenditure, unexpectedly we find that it additionally alters regulation of the key energy homeostasis maintenance player leptin (LEP), further increasing the energetic burden and exposing a vulnerable point; acquired sensitivity to the identified compounds. We show that compound treatment stabilises Hypoxia-inducible factor 1-alpha (HIF1A) by antagonising Von Hippel-Lindau (VHL)-mediated HIF1A ubiquitination, driving LEP hyperactivation. Importantly, we demonstrate that sensitivity to piceatannol/tyrphostin 23 epistatically relies on a HIF1A-LEP-Uncoupling Protein 2 (UCP2) signaling axis lowering cellular energy beyond survival, in already challenged LKB1-deficient cells. Thus, we uncover a pivotal metabolic vulnerability of LKB1-deficient tumours, which may be therapeutically exploited using our identified compounds as mitochondrial uncouplers.
Gut microbiome and metabolome signatures in liver cirrhosis-related complications
Authors: Satya Priya Sharma, Haripriya Gupta, Goo-Hyun Kwon, Sang Yoon Lee, Seol Hee Song, Jeoung Su Kim, Jeong Ha Park, Min Ju Kim, Dong-Hoon Yang, Hyunjoon Park, Sung-Min Won, Jin-Ju Jeong, Ki-Kwang Oh, Jung A Eom, Kyeong Jin Lee, Sang Jun Yoon, Young Lim Ham, Gwang Ho Baik, Dong Joon Kim, Ki Tae Suk
Journal: Clinical and Molecular Hepatology (2024)

Background/Aims: Shifts in the gut microbiota and metabolites are interrelated with liver cirrhosis progression and complications. However, causal relationships have not been evaluated comprehensively. Here, we identified complication-dependent gut microbiota and metabolic signatures in patients with liver cirrhosis.Methods: Microbiome taxonomic profiling was performed on 194 stool samples (52 controls and 142 cirrhosis patients) via V3-V4 16S rRNA sequencing. Next, 51 samples (17 controls and 34 cirrhosis patients) were selected for fecal metabolite profiling via gas chromatography mass spectrometry and liquid chromatography coupled to time-of-flight mass spectrometry. Correlation analyses were performed targeting the gut-microbiota, metabolites, clinical parameters, and presence of complications (varices, ascites, peritonitis, encephalopathy, hepatorenal syndrome, hepatocellular carcinoma, and deceased).Results: &lt;i&gt;Veillonella&lt;/i&gt; bacteria, &lt;i&gt;Ruminococcus gnavus&lt;/i&gt;, and &lt;i&gt;Streptococcus pneumoniae&lt;/i&gt; are cirrhosis-related microbiotas compared with control group. &lt;i&gt;Bacteroides ovatus, Clostridium symbiosum, Emergencia timonensis, Fusobacterium varium&lt;/i&gt;, and &lt;i&gt;Hungatella&lt;/i&gt;_uc were associated with complications in the cirrhosis group. The areas under the receiver operating characteristic curve (AUROCs) for the diagnosis of cirrhosis, encephalopathy, hepatorenal syndrome, and deceased were 0.863, 0.733, 0.71, and 0.69, respectively. The AUROCs of mixed microbial species for the diagnosis of cirrhosis and complication were 0.808 and 0.847, respectively. According to the metabolic profile, 5 increased fecal metabolites in patients with cirrhosis were biomarkers (AUROC &gt;0.880) for the diagnosis of cirrhosis and complications. Clinical markers were significantly correlated with the gut microbiota and metabolites.Conclusions: Cirrhosis-dependent gut microbiota and metabolites present unique signatures that can be used as noninvasive biomarkers for the diagnosis of cirrhosis and its complications.
Crucial role for sensory nerves and Na/H exchanger inhibition in dapagliflozin- and empagliflozin-induced arterial relaxation
Authors: Elizabeth A Forrester, Miguel Benítez-Angeles, Kaitlyn E Redford, Tamara Rosenbaum, Geoffrey W Abbott, Vincenzo Barrese, Kim Dora, Anthony P Albert, Johs Dannesboe, Isabelle Salles-Crawley, Thomas A Jepps, Iain A Greenwood
Journal: Cardiovascular Research (2024)

Abstract Aims Sodium/glucose transporter 2 (SGLT2 or SLC5A2) inhibitors lower blood glucose and are also approved treatments for heart failure independent of raised glucose. Various studies have showed that SGLT2 inhibitors relax arteries, but the underlying mechanisms are poorly understood and responses variable across arterial beds. We speculated that SGLT2 inhibitor-mediated arterial relaxation is dependent upon calcitonin gene-related peptide (CGRP) released from sensory nerves independent of glucose transport. Methods and results The functional effects of SGLT1 and 2 inhibitors (mizagliflozin, dapagliflozin, and empagliflozin) and the sodium/hydrogen exchanger 1 (NHE1) blocker cariporide were determined on pre-contracted resistance arteries (mesenteric and cardiac septal arteries) as well as main renal conduit arteries from male Wistar rats using wire myography. SGLT2, CGRP, TRPV1, and NHE1 expression was determined by western blot and immunohistochemistry. Kv7.4/5/KCNE4 and TRPV1 currents were measured in the presence and absence of dapagliflozin and empagliflozin. All SGLT inhibitors (1–100 µM) and cariporide (30 µM) relaxed mesenteric arteries but had negligible effect on renal or septal arteries. Immunohistochemistry with TRPV1 and CGRP antibodies revealed a dense innervation of sensory nerves in mesenteric arteries that were absent in renal and septal arteries. Consistent with a greater sensory nerve component, the TRPV1 agonist capsaicin relaxed mesenteric arteries more effectively than renal or septal arteries. In mesenteric arteries, relaxations to dapagliflozin, empagliflozin, and cariporide were attenuated by the CGRP receptor antagonist BIBN-4096, depletion of sensory nerves with capsaicin, and blockade of TRPV1 or Kv7 channels. Neither dapagliflozin nor empagliflozin activated heterologously expressed TRPV1 channels or Kv7 channels directly. Sensory nerves also expressed NHE1 but not SGLT2 and cariporide pre-application as well as knockdown of NHE1 by translation stop morpholinos prevented the relaxant response to SGLT2 inhibitors. Conclusion SGLT2 inhibitors relax mesenteric arteries by promoting the release of CGRP from sensory nerves in a NHE1-dependent manner.
Impact of C-reactive protein point-of-care testing on antibiotic prescriptions for children and adults with suspected respiratory tract infections in primary care: a French patient-level randomized controlled superiority trial
Authors: Camille Jung, Corinne Levy, Stéphane Béchet, Philippe Aegerter, Robert Cohen, Robert Touitou, Touitou Robert, Batsch Esther, Casadevall Marion, Chevillard Marie, Denantes Mady, Djen David, Gasman Yaël, Janody Valérie, Lancelot Anne, Laplante Alice, Levy Dora, Madi-Rezgui Saskia, Myara François, Pinto Emmanuel, Trincard Blandine, Yacoubovitch Jacques, Nureni-Banafunzi Ismaël, Lachine Nastassja, Dardel Nicole, Faure David, Chefdebien Marine, Rozenfeld Richard, Lion-Altmayer Juliette, Gaisne-Joly Marine, Zaghdoun David, Gely Florence
Journal: Clinical Microbiology and Infection (2024)

The value of C-reactive protein point-of-care testing (CRP POCT) to guide antibiotic prescriptions in adults has previously been emphasized. The aim of this study was to assess the impact of CRP POCT on antibiotic prescriptions by general practitioners (GPs) for suspected lower respiratory tract infections in children ≥3 years old and in adults.