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Cell Reports Jun 2024Human CD8 tumor-infiltrating lymphocytes (TILs) with impaired effector functions and PD-1 expression are categorized as exhausted. However, the exhaustion-like features...
Human CD8 tumor-infiltrating lymphocytes (TILs) with impaired effector functions and PD-1 expression are categorized as exhausted. However, the exhaustion-like features reported in TILs might stem from their activation rather than the consequence of T cell exhaustion itself. Using CRISPR-Cas9 and lentiviral overexpression in CD8 T cells from non-cancerous donors, we show that the T cell receptor (TCR)-induced transcription factor interferon regulatory factor 4 (IRF4) promotes cell proliferation and PD-1 expression and hampers effector functions and expression of nuclear factor κB (NF-κB)-regulated genes. While CD8 TILs with impaired interferon γ (IFNγ) production exhibit activation markers IRF4 and CD137 and exhaustion markers thymocyte selection associated high mobility group box (TOX) and PD-1, activated T cells in patients with COVID-19 do not demonstrate elevated levels of TOX and PD-1. These results confirm that IRF4 TILs are exhausted rather than solely activated. Our study indicates, however, that PD-1 expression, low IFNγ production, and active cycling in TILs are all influenced by IRF4 upregulation after T cell activation.
PubMed: 38943641
DOI: 10.1016/j.celrep.2024.114401 -
Nigerian Journal of Clinical Practice Jun 2024Exercise or exercise capacity is a vital physiological function. It is known that certain cytokines support muscle function during exercise and, as a result, increase...
BACKGROUND
Exercise or exercise capacity is a vital physiological function. It is known that certain cytokines support muscle function during exercise and, as a result, increase exercise capacity.
AIMS
In this study, the effect of metformin administered in combination with exercise on osteocalcin (OCN), insulin, and interleukin-6 (IL-6) levels in rats was investigated.
METHODS
Forty-two male Wistar rats were used in this study. The animals were randomly divided into six groups: control (CONT), only exercise (EXE), metformin_100 mg/kg (Met100), metformin_200 mg/kg (Met200), metformin_100 mg/kg+exercise (Met100+EXE), and metformin_200 mg/kg+exercise (Met200+EXE). A 10-week intervention was conducted, excluding exercise training. During the experiment, the groups receiving metformin application (100 or 200 mg/kg) were administered with metformin. At the end of the study, serum samples were collected from the rats to determine the levels of osteocalcin, insulin, and IL-6 using the enzyme-linked immunosorbent assay method. In addition, glucose levels and body weights were evaluated. GraphPad Prism was used for the analyses.
RESULTS
The OCN and insulin levels of the Met100+EXE and Met200+EXE groups were found to be higher compared to the CONT, Met100, and Met200 groups (P < 0.05). The IL-6 level of the EXE group was determined to be higher than that of the CONT, Met100, and Met200 groups (P < 0.01). It was observed that both exercise and the individual or combined application of metformin resulted in lower blood glucose levels compared to the CONT group. The mean body weight of the EXE group was higher than that of the other groups.
CONCLUSION
The combined application of metformin and exercise has increased osteocalcin and insulin levels compared to metformin application alone.
Topics: Animals; Metformin; Interleukin-6; Osteocalcin; Rats, Wistar; Male; Rats; Physical Conditioning, Animal; Insulin; Hypoglycemic Agents; Blood Glucose; Body Weight
PubMed: 38943302
DOI: 10.4103/njcp.njcp_884_23 -
BMC Pharmacology & Toxicology Jun 2024Chalcones and dihydrochalcones (DHCs) are important bioactive natural products (BNPs) isolated from traditional Chinese medicine. In this study, 13 chalcones were...
Chalcones and dihydrochalcones (DHCs) are important bioactive natural products (BNPs) isolated from traditional Chinese medicine. In this study, 13 chalcones were designed with the inspiration of Loureirin, a DHC extracted from Resina Draconis, and synthesized by classical Claisen-Schmidt reactions. Afterwards the reduction reactions were carried out to obtain the corresponding DHCs. Cytotoxicity assay indicated chalcones and DHCs possessed selective cytotoxicity against colorectal cancer (CRC) cells. The preliminary structure-activity relationships (SAR) of these compounds suggested the α, β-unsaturated ketone of the chalcones were crucial for the anticancer activity. Interestingly, compounds 3d and 4c exhibited selective anticancer activity against CRC cell line HCT116 with IC of 8.4 and 17.9 μM but not normal cell. Moreover, 4c could also inhibit the migration and invasion of CRC cells. Mechanism investigations showed 4c could induce cell cycle G2/M arrest by regulating cell cycle-associated proteins and could also up-regulate Fas cell surface death receptor. The virtual docking further pointed out that compounds 3d and 4c could nicely bind to the Fas/FADD death domain complex (ID: 3EZQ). Furthermore, silencing of Fas significantly enhanced the proliferation of CRC cells and attenuated the cytotoxicity induced by 4c. These results suggested 4c exerted its anticancer activity possibly regulating cell cycle and Fas death receptor. In summary, this study investigated the anticancer activity and mechanism of Loureirin analogues in CRC, suggesting these compounds may warrant further investigation as promising anticancer drug candidates for the treatment of CRC.
Topics: Humans; Colorectal Neoplasms; Chalcones; Antineoplastic Agents; fas Receptor; Structure-Activity Relationship; HCT116 Cells; Molecular Docking Simulation; Cell Movement; Cell Cycle; Cell Line, Tumor
PubMed: 38943212
DOI: 10.1186/s40360-024-00758-2 -
Cancer Cell International Jun 2024Despite effective strategies, resistance in EGFR mutated lung cancer remains a challenge. Metabolic reprogramming is one of the main mechanisms of tumor drug resistance....
BACKGROUND
Despite effective strategies, resistance in EGFR mutated lung cancer remains a challenge. Metabolic reprogramming is one of the main mechanisms of tumor drug resistance. A class of drugs known as "statins" inhibit lipid cholesterol metabolism and are widely used in patients with cardiovascular diseases. Previous studies have also documented its ability to improve the therapeutic impact in lung cancer patients who receive EGFR-TKI therapy. Therefore, the effect of statins on targeted drug resistance to lung cancer remains to be investigated.
METHODS
Prolonged exposure to gefitinib resulted in the emergence of a resistant lung cancer cell line (PC9GR) from the parental sensitive cell line (PC9), which exhibited a traditional EGFR mutation. The CCK-8 assay was employed to assess the impact of various concentrations of pitavastatin on cellular proliferation. RNA sequencing was conducted to detect differentially expressed genes and their correlated pathways. For the detection of protein expression, Western blot was performed. The antitumor activity of pitavastatin was evaluated in vivo via a xenograft mouse model.
RESULTS
PC9 gefitinib resistant strains were induced by low-dose maintenance. Cell culture and animal-related studies validated that the application of pitavastatin inhibited the proliferation of lung cancer cells, promoted cell apoptosis, and restrained the acquired resistance to EGFR-TKIs. KEGG pathway analysis showed that the hippo/YAP signaling pathway was activated in PC9GR cells relative to PC9 cells, and the YAP expression was inhibited by pitavastatin administration. With YAP RNA interference, pAKT, pBAD and BCL-2 expression was decreased, while BAX expression as increased. Accordingly, YAP down-regulated significantly increased apoptosis and decreased the survival rate of gefitinib-resistant lung cancer cells. After pAKT was increased by SC79, apoptosis of YAP down-regulated cells induced by gefitinib was decreased, and the cell survival rate was increased. Mechanistically, these effects of pitavastatin are associated with the YAP pathway, thereby inhibiting the downstream AKT/BAD-BCL-2 signaling pathway.
CONCLUSION
Our study provides a molecular basis for the clinical application of the lipid-lowering drug pitavastatin enhances the susceptibility of lung cancer to EGFR-TKI drugs and alleviates drug resistance.
PubMed: 38943199
DOI: 10.1186/s12935-024-03416-z -
BMC Research Notes Jun 2024Numerous studies confirm the effectiveness of cognitive training in older adults. However, there is limited evidence of the transfer occurrence. The part of the study...
Limited training and transfer effects in older and young adults who participated in 12 sessions of process-based working memory training. A three-armed pretest-posttest design study.
OBJECTIVE
Numerous studies confirm the effectiveness of cognitive training in older adults. However, there is limited evidence of the transfer occurrence. The part of the study presented here tested the effect of 12 process-based working memory training sessions on the performance of the trained task (training effect) and other cognitive tasks (transfer effect). A pretest-posttest study design with one experimental group and two control (passive and active) groups. The sample comprised three groups of older adults: experimental (n = 25), passive control (n = 22), active control (n = 7), and young adults: experimental (n = 25), passive control (n = 25), and active control (n = 12). The study was registered after completion with a ClinicalTrials.gov Identifier: NCT06235840 on 31 January 2024.
RESULTS
Under the influence of training, the performance of the trained task improved significantly, but only in young adults. Transfer of WM training effects was not revealed. Among young adults, a testing effect was observed for the indicator of attentional focus and psychomotor speed. Moreover, the obtained results suggest the transfer from practice in multi-domain training, implemented in the active control group, to tasks that require the use of fluid intelligence. However, this finding should be interpreted with great caution due to the small size of active control groups.
Topics: Humans; Memory, Short-Term; Male; Female; Transfer, Psychology; Adult; Young Adult; Aged; Middle Aged; Cognition; Attention; Learning; Psychomotor Performance; Cognitive Training
PubMed: 38943197
DOI: 10.1186/s13104-024-06844-2 -
Trials Jun 2024Isolated REM sleep behavior disorder (iRBD) is an early α-synucleinopathy often accompanied by incipient cognitive impairment. As executive dysfunctions predict earlier...
Cognitive training and promoting a healthy lifestyle for individuals with isolated REM sleep behavior disorder: study protocol of the delayed-start randomized controlled trial CogTrAiL-RBD.
BACKGROUND
Isolated REM sleep behavior disorder (iRBD) is an early α-synucleinopathy often accompanied by incipient cognitive impairment. As executive dysfunctions predict earlier phenotypic conversion from iRBD to Parkinson's disease and Lewy body dementia, cognitive training focusing on executive functions could have disease-modifying effects for individuals with iRBD.
METHODS
The study CogTrAiL-RBD investigates the short- and long-term effectiveness and the feasibility and underlying neural mechanisms of a cognitive training intervention for individuals with iRBD. The intervention consists of a 5-week digital cognitive training accompanied by a module promoting a healthy, active lifestyle. In this monocentric, single-blinded, delayed-start randomized controlled trial, the intervention's effectiveness will be evaluated compared to an initially passive control group that receives the intervention in the second, open-label phase of the study. Eighty individuals with iRBD confirmed by polysomnography will be consecutively recruited from the continuously expanding iRBD cohort at the University Hospital Cologne. The evaluation will focus on cognition and additional neuropsychological and motor variables. Furthermore, the study will examine the feasibility of the intervention, effects on physical activity assessed by accelerometry, and interrogate the intervention's neural effects using magnetic resonance imaging and polysomnography. Besides, a healthy, age-matched control group (HC) will be examined at the first assessment time point, enabling a cross-sectional comparison between individuals with iRBD and HC.
DISCUSSION
This study will provide insights into whether cognitive training and psychoeducation on a healthy, active lifestyle have short- and long-term (neuro-)protective effects for individuals with iRBD.
TRIAL REGISTRATION
The study was prospectively registered in the German Clinical Trial Register (DRKS00024898) on 2022-03-11, https://drks.de/search/de/trial/DRKS00024898 .
PROTOCOL VERSION
V5 2023-04-24.
Topics: Humans; Single-Blind Method; REM Sleep Behavior Disorder; Healthy Lifestyle; Randomized Controlled Trials as Topic; Executive Function; Cognition; Time Factors; Polysomnography; Treatment Outcome; Cognitive Behavioral Therapy; Male; Germany; Middle Aged; Exercise; Female; Aged; Feasibility Studies; Cognitive Training
PubMed: 38943191
DOI: 10.1186/s13063-024-08265-9 -
Veterinary Research Jun 2024Migratory birds are important vectors for virus transmission, how migratory birds recognize viruses and viruses are sustained in birds is still enigmatic. As an animal...
Migratory birds are important vectors for virus transmission, how migratory birds recognize viruses and viruses are sustained in birds is still enigmatic. As an animal model for waterfowl among migratory birds, studying and dissecting the antiviral immunity and viral evasion in duck cells may pave a path to deciphering these puzzles. Here, we studied the mechanism of antiviral autophagy mediated by duck STING in DEF cells. The results collaborated that duck STING could significantly enhance LC3B-II/I turnover, LC3B-EGFP puncta formation, and mCherry/EGFP ratio, indicating that duck STING could induce autophagy. The autophagy induced by duck STING is not affected by shRNA knockdown of ATG5 expression, deletion of the C-terminal tail of STING, or TBK1 inhibitor BX795 treatment, indicating that duck STING activated non-classical selective autophagy is independent of interaction with TBK1, TBK1 phosphorylation, and interferon (IFN) signaling. The STING R235A mutant and Sar1A/B kinase mutant abolished duck STING induced autophagy, suggesting binding with cGAMP and COPII complex mediated transport are the critical prerequisite. Duck STING interacted with LC3B through LIR motifs to induce autophagy, the LIR 4/7 motif mutants of duck STING abolished the interaction with LC3B, and neither activated autophagy nor IFN expression, indicating that duck STING associates with LC3B directed autophagy and dictated innate immunity activation. Finally, we found that duck STING mediated autophagy significantly inhibited duck plague virus (DPV) infection via ubiquitously degraded viral proteins. Our study may shed light on one scenario about the control and evasion of diseases transmitted by migratory birds.
Topics: Animals; Ducks; Autophagy; Signal Transduction; Mardivirus; Interferons; Alphaherpesvirinae; Immunity, Innate; Membrane Proteins; Poxviridae Infections
PubMed: 38943190
DOI: 10.1186/s13567-024-01338-2 -
Particle and Fibre Toxicology Jun 2024Today, nanomaterials are broadly used in a wide range of industrial applications. Such large utilization and the limited knowledge on to the possible health effects have...
BACKGROUND
Today, nanomaterials are broadly used in a wide range of industrial applications. Such large utilization and the limited knowledge on to the possible health effects have raised concerns about potential consequences on human health and safety, beyond the environmental burden. Given that inhalation is the main exposure route, workers exposed to nanomaterials might be at risk of occurrence of respiratory morbidity and/or reduced pulmonary function. However, epidemiological evidence regarding the association between cumulative exposure to nanomaterials and respiratory health is still scarce. This study focused on the association between cumulative exposure to nanomaterials and pulmonary function among 136 workers enrolled in the framework of the European multicentric NanoExplore project.
RESULTS
Our findings suggest that, independently of lifelong tobacco smoking, ethnicity, age, sex, body mass index and physical activity habits, 10-year cumulative exposure to nanomaterials is associated to worse FEV and FEF, which might be consistent with the involvement of both large and small airway components and early signs of airflow obstruction. We further explored the hypothesis of a mediating effect via airway inflammation, assessed by interleukin (IL-)10, IL-1β and Tumor Necrosis Factor alpha (TNF-α), all quantified in the Exhaled Breath Condensate of workers. The mediation analysis results suggest that IL-10, TNF-α and their ratio (i.e., anti-pro inflammatory ratio) may fully mediate the negative association between cumulative exposure to nanomaterials and the FEV/FVC ratio. This pattern was not observed for other pulmonary function parameters.
CONCLUSIONS
Safeguarding the respiratory health of workers exposed to nanomaterials should be of primary importance. The observed association between cumulative exposure to nanomaterials and worse pulmonary function parameters underscores the importance of implementing adequate protective measures in the nanocomposite sector. The mitigation of harmful exposures may ensure that workers can continue to contribute productively to their workplaces while preserving their respiratory health over time.
Topics: Humans; Male; Nanostructures; Female; Occupational Exposure; Adult; Inhalation Exposure; Middle Aged; Lung; Pneumonia; Forced Expiratory Volume; Respiratory Function Tests; Cytokines; Air Pollutants, Occupational; Europe
PubMed: 38943182
DOI: 10.1186/s12989-024-00589-3 -
Journal of Orthopaedic Surgery and... Jun 2024Tendon stem/progenitor cell (TSPC) senescence contributes to tendon degeneration and impaired tendon repair, resulting in age-related tendon disorders. Ferroptosis, a...
Platelet-derived exosomes alleviate tendon stem/progenitor cell senescence and ferroptosis by regulating AMPK/Nrf2/GPX4 signaling and improve tendon-bone junction regeneration in rats.
BACKGROUND
Tendon stem/progenitor cell (TSPC) senescence contributes to tendon degeneration and impaired tendon repair, resulting in age-related tendon disorders. Ferroptosis, a unique iron-dependent form of programmed cell death, might participate in the process of senescence. However, whether ferroptosis plays a role in TSPC senescence and tendon regeneration remains unclear. Recent studies reported that Platelet-derived exosomes (PL-Exos) might provide significant advantages in musculoskeletal regeneration and inflammation regulation. The effects and mechanism of PL-Exos on TSPC senescence and tendon regeneration are worthy of further study.
METHODS
Herein, we examined the role of ferroptosis in the pathogenesis of TSPC senescence. PL-Exos were isolated and determined by TEM, particle size analysis, western blot and mass spectrometry identification. We investigated the function and underlying mechanisms of PL-Exos in TSPC senescence and ferroptosis via western blot, real-time quantitative polymerase chain reaction, and immunofluorescence analysis in vitro. Tendon regeneration was evaluated by HE staining, Safranin-O staining, and biomechanical tests in a rotator cuff tear model in rats.
RESULTS
We discovered that ferroptosis was involved in senescent TSPCs. Furthermore, PL-Exos mitigated the aging phenotypes and ferroptosis of TSPCs induced by t-BHP and preserved their proliferation and tenogenic capacity. The in vivo animal results indicated that PL-Exos improved tendon-bone healing properties and mechanical strength. Mechanistically, PL-Exos activated AMPK phosphorylation and the downstream nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) signaling pathway, leading to the suppression of lipid peroxidation. AMPK inhibition or GPX4 inhibition blocked the protective effect of PL-Exos against t-BHP-induced ferroptosis and senescence.
CONCLUSION
In conclusion, ferroptosis might play a crucial role in TSPC aging. AMPK/Nrf2/GPX4 activation by PL-Exos was found to inhibit ferroptosis, consequently leading to the suppression of senescence in TSPCs. Our results provided new theoretical evidence for the potential application of PL-Exos to restrain tendon degeneration and promote tendon regeneration.
Topics: Animals; Ferroptosis; Exosomes; NF-E2-Related Factor 2; Cellular Senescence; Rats; Signal Transduction; Phospholipid Hydroperoxide Glutathione Peroxidase; Regeneration; AMP-Activated Protein Kinases; Stem Cells; Tendons; Male; Blood Platelets; Rats, Sprague-Dawley; Rotator Cuff Injuries; Disease Models, Animal
PubMed: 38943181
DOI: 10.1186/s13018-024-04869-8 -
Journal of Orthopaedic Surgery and... Jun 2024Our study aims to assess the effectiveness of multicomponent supervised tele-rehabilitation compared to home-based self-rehabilitation management in patients following... (Comparative Study)
Comparative Study Randomized Controlled Trial
Multicomponent supervised tele-rehabilitation versus home-based self-rehabilitation management after anterior cruciate ligament reconstruction: a study protocol for a randomized controlled trial.
INTRODUCTION
Our study aims to assess the effectiveness of multicomponent supervised tele-rehabilitation compared to home-based self-rehabilitation management in patients following anterior cruciate ligament reconstruction (ACLR).
METHODS
The current study is designed as a single-center, single-blinded, randomized controlled, two-arm trial. Participants will be randomized and allocated at a 1:1 ratio into either a multicomponent supervised tele-rehabilitation group or a home-based self-rehabilitation group. All participants receive uniform preoperative education through the HJT software. Participants in the intervention group undergo multicomponent supervised tele-rehabilitation, while those in the control group follow a home-based self-rehabilitation program. All the participants were assessed and measured for the included outcomes at the outpatient clinic before the procedure, and in 2, 4, 8, 12, and 24 weeks after ACLR by two assessors. The primary outcome was the percentage of patients who achieve a satisfactory active ROM at the 12 weeks following the ACLR. The satisfactory active ROM was also collected at 2, 4, 8, and 24 weeks after ACLR. The secondary outcomes were active and passive range of motion (ROM), pain, muscle strength, and function results.
REGISTRATION DETAILS
Ethical approval has been obtained from the West China Hospital Ethics Committee (approval number 2023-1929, December 2023). The trial has been registered on ClinicalTrials.gov (registration number NCT06232824, January 2024).
Topics: Humans; Anterior Cruciate Ligament Reconstruction; Telerehabilitation; Single-Blind Method; Range of Motion, Articular; Treatment Outcome; Adult; Male; Female; Young Adult; Home Care Services; Randomized Controlled Trials as Topic; Anterior Cruciate Ligament Injuries; Muscle Strength; Adolescent
PubMed: 38943178
DOI: 10.1186/s13018-024-04871-0