-
Frontiers in Endocrinology 2024The involvement of ATP and cAMP in sperm function has been extensively documented, but the understanding of the role of adenosine and adenosine receptors remains...
BACKGROUND
The involvement of ATP and cAMP in sperm function has been extensively documented, but the understanding of the role of adenosine and adenosine receptors remains incomplete. This study aimed to examine the presence of adenosine A2A receptor (A2AR) and study the functional role of A2AR in human sperm.
METHODS
The presence and localization of A2AR in human sperm were examined by western blotting and immunofluorescence assays. The functional role of A2AR in sperm was assessed by incubating human sperm with an A2AR agonist (regadenoson) and an A2AR antagonist (SCH58261). The sperm level of A2AR was examined by western blotting in normozoospermic and asthenozoospermic men to evaluate the association of A2AR with sperm motility and fertilization (IVF) outcomes.
RESULTS
A2AR with a molecular weight of 43 kDa was detected in the tail of human sperm. SCH58261 decreased the motility, penetration ability, intracellular Ca concentration, and CatSper current of human sperm. Although regadenoson did not affect these sperm parameters, it alleviated the adverse effects of SCH58261 on these parameters. In addition, the mean level of A2AR in sperm from asthenozoospermic men was lower than that in sperm from normozoospermic men. The sperm level of A2AR was positively correlated with progressive motility. Furthermore, the fertilization rate during IVF was lower in men with decreased sperm level of A2AR than in men with normal sperm level of A2AR.
CONCLUSIONS
These results indicate that A2AR is important for human sperm motility and is associated with IVF outcome.
Topics: Humans; Male; Sperm Motility; Receptor, Adenosine A2A; Spermatozoa; Fertilization in Vitro; Adult; Asthenozoospermia; Female; Pyrazoles; Adenosine A2 Receptor Agonists; Adenosine A2 Receptor Antagonists; Pyrimidines; Triazoles
PubMed: 38872963
DOI: 10.3389/fendo.2024.1410370 -
Journal of Cancer Research and Clinical... Jun 2024With the development of immunotherapy research, the role of immune checkpoint blockade (ICB) in the treatment of cervical cancer has been emphasized, but many patients...
PURPOSE
With the development of immunotherapy research, the role of immune checkpoint blockade (ICB) in the treatment of cervical cancer has been emphasized, but many patients still can't receive long-term benefits from ICB. Poly ADP ribose polymerase inhibitor (PARPi) has been proved to exert significant antitumor effects in multiple solid tumors. Whether cervical cancer patients obtain better benefits from the treatment regimen of PARPi combined with ICB remains unclear.
METHODS
The alteration of PD-L1 expression induced by niraparib in cervical cancer cells and its underlying mechanism were assessed by western blot and immunofluorescence and quantitative real-time polymerase chain reaction (qRT-PCR).The regulation of PTEN by KDM5A was confirmed using Chromatin immunoprecipitation (ChIP) assay and RNA interference. Analyzing the relationship between PD-L1 and immune effector molecules through searching online databases. Therapeutic efficacy of niraparib, PD-L1 blockade or combination was assessed in syngeneic tumor model. The changes of immune cells and cytokines in vivo was detected by immunohistochemistry (IHC) and qRT-PCR.
RESULTS
We found that niraparib upregulated PD-L1 expression and potentiated the antitumor effects of PD-L1 blockade in a murine cervical cancer model. Niraparib inhibited the Pten expression by increasing the abundance of KDM5A, which expanded PD-L1 abundance through activating the PI3K-AKT-S6K1 pathway. PD-L1 was positively correlated with immune effector molecules including TNF-α, IFN-γ, granzyme A and granzyme B based on biological information analysis. Niraparib increased the infiltration of CD8 T cells and the level of IFN-γ, granzyme B in vivo.
CONCLUSION
Our findings demonstrates the regulation of niraparib on local immune microenvironment of cervical cancer, and provides theoretical basis for supporting the combination of PARPi and PD-L1 blockade as a potential treatment for cervical cancer.
Topics: Uterine Cervical Neoplasms; Female; Humans; Animals; Piperidines; B7-H1 Antigen; Indazoles; Mice; Immune Checkpoint Inhibitors; Poly(ADP-ribose) Polymerase Inhibitors; Cell Line, Tumor
PubMed: 38869633
DOI: 10.1007/s00432-024-05819-x -
BMJ Open Jun 2024Knee osteoarthritis (KOA) is one of the most common osteoarthritis, imposing substantial economic and medical burdens on both individuals and society. In China, Tuina...
Tuina on knee pain and functional decline of lower limbs for patients with mild-to-moderate knee osteoarthritis in Shanghai: protocol for a multicentre, assessor-blinded, randomised controlled trial.
INTRODUCTION
Knee osteoarthritis (KOA) is one of the most common osteoarthritis, imposing substantial economic and medical burdens on both individuals and society. In China, Tuina has been selected as a complementary and alternative therapy to relieve knee pain and dysfunction symptoms. However, the current evidence is insufficient to support the efficacy of Tuina therapy in addressing knee pain and improving physical function. The trial aims to compare the effectiveness of Tuina with celecoxib, which is considered as the standard treatment, and to assess its potential as an alternative therapy through changes in outcome measures.
METHODS AND ANALYSIS
A total of 360 KOA patients aged between 40 and 70 years and classified as Kellgren and Lawrence grades I-II will be recruited from eight subcentral hospitals. The participants will be randomly assigned to either the treatment group (Tuina, Biw) or the control group (celecoxib, Qd), with both groups undergoing a 4-week intervention phase followed by an 8-week follow-up phase. The primary outcome is the change in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale at week 4 compared with baseline. Secondary outcomes including WOMAC stiffness and function subscales, WOMAC total score, 36-item Short-Form Health Survey, Timed Up and Go test, Short Physical Performance Battery, gait analysis parameters and pain medication records will be assessed at weeks 4, 8 and 12. Any adverse events that occur during the trial will be promptly recorded.
ETHICS AND DISSEMINATION
This study has been approved by the Ethics Committee of Shanghai Municipal Hospital of Traditional Chinese Medicine (2023SHL-KY-16-01, 2023SHL-KY-16-02). Written informed consent will be obtained from all participants. Study results will be disseminated through peer-reviewed journals and conference presentations.
TRIAL REGISTRATION NUMBER
ChiCTR2300069416.
Topics: Humans; Osteoarthritis, Knee; China; Middle Aged; Aged; Randomized Controlled Trials as Topic; Male; Pain Measurement; Female; Celecoxib; Multicenter Studies as Topic; Adult; Treatment Outcome; Arthralgia
PubMed: 38866576
DOI: 10.1136/bmjopen-2023-083440 -
Brain Communications 2024Intracellular pH is a valuable index for predicting neuronal damage and injury. However, no PET probe is currently available for monitoring intracellular pH . In this...
Intracellular pH is a valuable index for predicting neuronal damage and injury. However, no PET probe is currently available for monitoring intracellular pH . In this study, we developed a new approach for visualizing the hydrolysis rate of monoacylglycerol lipase, which is widely distributed in neurons and astrocytes throughout the brain. This approach uses PET with the new radioprobe [C]QST-0837 (1,1,1,3,3,3-hexafluoropropan-2-yl-3-(1-phenyl-1-pyrazol-3-yl)azetidine-1-[C]carboxylate), a covalent inhibitor containing an azetidine carbamate skeleton for monoacylglycerol lipase. The uptake and residence of this new radioprobe depends on the intracellular pH gradient, and we evaluated this with , and assessments. Molecular dynamics simulations predicted that because the azetidine carbamate moiety is close to that of water molecules, the compound containing azetidine carbamate would be more easily hydrolyzed following binding to monoacylglycerol lipase than would its analogue containing a piperidine carbamate skeleton. Interestingly, it was difficult for monoacylglycerol lipase to hydrolyze the azetidine carbamate compound under weakly acidic (pH 6) conditions because of a change in the interactions with water molecules on the carbamate moiety of their complex. Subsequently, an assessment using rat brain homogenate to confirm the molecular dynamics simulation-predicted behaviour of the azetidine carbamate compound showed that [C]QST-0837 reacted with monoacylglycerol lipase to yield an [C]complex, which was hydrolyzed to liberate CO as a final product. Additionally, the CO liberation rate was slower at lower pH. Finally, to indicate the feasibility of estimating how the hydrolysis rate depends on intracellular pH , we performed a PET study with [C]QST-0837 using ischaemic rats. In our proposed compartment model, the clearance rate of radioactivity from the brain reflected the rate of [C]QST-0837 hydrolysis (clearance through the production of CO) in the brain, which was lower in a remarkably hypoxic area than in the contralateral region. In conclusion, we indicated the potential for visualization of the intracellular pH gradient in the brain using PET imaging, although some limitations remain. This approach should permit further elucidation of the pathological mechanisms involved under acidic conditions in multiple CNS disorders.
PubMed: 38863573
DOI: 10.1093/braincomms/fcae172 -
Scientific Reports Jun 2024This review used traditional and network meta-analyses (NMA) to conduct a comprehensive study of antithrombotic therapies in children with thromboembolic disease. We... (Meta-Analysis)
Meta-Analysis
This review used traditional and network meta-analyses (NMA) to conduct a comprehensive study of antithrombotic therapies in children with thromboembolic disease. We searched the PubMed, Embase, Cochrane Library, Web of Science and ClinicalTrials.gov databases from their inception to 26 February, 2023. And we finally included 16 randomized controlled trials. In the prevention of thromboembolic events (TEs), the use of anticoagulants had a low risk of TEs (relative risk (RR) 0.73, 95% CI 0.56 to 0.94) and a high risk of minor bleeding (RR 1.43, 95% CI 1.09 to 1.86) compared with no anticoagulants. In the treatment of TEs, direct oral anticoagulants (DOACs) were not inferior to standard anticoagulation in terms of efficacy and safety outcomes. In NMA, rivaroxaban and apixaban showed the lowest risk for TEs and major or clinically relevant nonmajor bleeding. According to the overall assessment of efficacy and safety, dabigatran may be the best choice for children with thromboembolic disease. The results of our study will provide references and suggestions for clinical drug selection.
Topics: Humans; Child; Thromboembolism; Fibrinolytic Agents; Hemorrhage; Anticoagulants; Treatment Outcome; Pyrazoles; Dabigatran; Rivaroxaban; Randomized Controlled Trials as Topic; Pyridones
PubMed: 38862574
DOI: 10.1038/s41598-024-64334-8 -
Journal For Immunotherapy of Cancer Jun 2024A combination of axitinib and immune checkpoint inhibitors (ICIs) demonstrated promising efficacy in the treatment of advanced renal cell carcinoma (RCC). This study...
BACKGROUND
A combination of axitinib and immune checkpoint inhibitors (ICIs) demonstrated promising efficacy in the treatment of advanced renal cell carcinoma (RCC). This study aims to prospectively evaluate the safety, efficacy, and biomarkers of neoadjuvant toripalimab plus axitinib in non-metastatic clear cell RCC.
METHODS
This is a single-institution, single-arm phase II clinical trial. Patients with non-metastatic biopsy-proven clear cell RCC (T2-T3N0-1M0) are enrolled. Patients will receive axitinib 5 mg twice daily combined with toripalimab 240 mg every 3 weeks (three cycles) for up to 12 weeks. Patients then will receive partial (PN) or radical nephrectomy (RN) after neoadjuvant therapy. The primary endpoint is objective response rate (ORR). Secondary endpoints include disease-free survival, safety, and perioperative complication rate. Predictive biomarkers are involved in exploratory analysis.
RESULTS
A total of 20 patients were enrolled in the study, with 19 of them undergoing surgery. One patient declined surgery. The primary endpoint ORR was 45%. The posterior distribution of πORR had a mean of 0.44 (95% credible intervals: 0.24-0.64), meeting the predefined primary endpoint with an ORR of 32%. Tumor shrinkage was observed in 95% of patients prior to nephrectomy. Furthermore, four patients achieved a pathological complete response. Grade ≥3 adverse events occurred in 25% of patients, including hypertension, hyperglycemia, glutamic pyruvic transaminase/glutamic oxaloacetic transaminase (ALT/AST) increase, and proteinuria. Postoperatively, one grade 4a and eight grade 1-2 complications were noted. In comparison to patients with stable disease, responders exhibited significant differences in immune factors such as Arginase 1(ARG1), Melanoma antigen (MAGEs), Dendritic Cell (DC), TNF Superfamily Member 13 (TNFSF13), Apelin Receptor (APLNR), and C-C Motif Chemokine Ligand 3 Like 1 (CCL3-L1). The limitation of this trial was the small sample size.
CONCLUSION
Neoadjuvant toripalimab combined with axitinib shows encouraging activity and acceptable toxicity in locally advanced clear cell RCC and warrants further study.
TRIAL REGISTRATION NUMBER
clinicaltrials.gov, NCT04118855.
Topics: Humans; Carcinoma, Renal Cell; Axitinib; Male; Female; Kidney Neoplasms; Middle Aged; Neoadjuvant Therapy; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Adult; Prospective Studies; Nephrectomy
PubMed: 38862251
DOI: 10.1136/jitc-2023-008475 -
Cancer Biology & Therapy Dec 2024Chronic stress can induce stress-related hormones; norepinephrine (NE) is considered to have the highest potential in cancer. NE can stimulate the expression of...
BACKGROUND
Chronic stress can induce stress-related hormones; norepinephrine (NE) is considered to have the highest potential in cancer. NE can stimulate the expression of hypoxia-inducible factor-1α (HIF-1α), which is associated with vascular endothelial growth factor (VEGF) secretion and tumor angiogenesis. However, the underlying mechanisms are poorly understood.
METHODS
Tumor-bearing mice were subjected to chronic restraint stress and treated with normal saline, human monoclonal VEGF-A neutralizing antibody bevacizumab, or β-adrenergic receptor (β-AR) antagonist (propranolol). Tumor growth and vessel density were also evaluated. Human colorectal adenocarcinoma cells were treated with NE, propranolol, or the inhibitor of transforming growth factor-β (TGF-β) receptor Type I kinase (Ly2157299) . TGF-β1 in mouse serum and cell culture supernatants was quantified using ELISA. The expression of HIF-1α was measured using Real time-PCR and western blotting. Cell migration and invasion were tested.
RESULTS
Chronic restraint stress attenuated the efficacy of bevacizumab and promoted tumor growth and angiogenesis in a colorectal tumor model. Propranolol blocked this effect and inhibited TGF-β1 elevation caused by chronic restraint stress or NE. NE upregulated HIF-1α expression, which was reversed by propranolol or Ly2157299. Propranolol and Ly2157199 blocked NE-stimulated cancer cell migration and invasion.
CONCLUSIONS
Our results demonstrate the effect of NE on tumor angiogenesis and the critical role of TGF-β1 signaling during this process. In addition, β-AR/TGF-β1 signaling/HIF-1α/VEGF is a potential signaling pathway. This study also indicates that psychosocial stress might be a risk factor which weakens the efficacy of anti-angiogenic therapy.
Topics: Animals; Colorectal Neoplasms; Humans; Neovascularization, Pathologic; Mice; Transforming Growth Factor beta1; Hypoxia-Inducible Factor 1, alpha Subunit; Signal Transduction; Bevacizumab; Propranolol; Cell Line, Tumor; Vascular Endothelial Growth Factor A; Male; Cell Movement; Norepinephrine; Stress, Psychological; Adrenergic beta-Antagonists; Angiogenesis; Pyrazoles; Quinolines
PubMed: 38857055
DOI: 10.1080/15384047.2024.2366451 -
Ticks and Tick-borne Diseases Sep 2024A promising alternative approach to conventional vector and rodent control practices is the use of a bait containing a rodenticide and acaricide in controlling vectors...
A rodent and tick bait for controlling white-footed mice (Peromyscus leucopus) and blacklegged ticks (Ixodes scapularis), the respective pathogen host and vector of the Lyme disease spirochetes.
A promising alternative approach to conventional vector and rodent control practices is the use of a bait containing a rodenticide and acaricide in controlling vectors and pathogen reservoirs concurrently. In the United States, Lyme disease continues to be the most prevalent vector-borne disease with approximately 500,000 Lyme disease cases estimated each year. Previous research has demonstrated the usefulness of a low dose fipronil bait in controlling Ixodes scapularis larvae feeding on white-footed mice. However, considering white-footed mice can be an unwanted species because of their association with tick-borne disease and hantaviruses, a combination rodent and tick bait (RTB) might provide a useful alternative to encourage additional community participation in integrated tick management (ITM) efforts. The purpose of this research was to evaluate the use of RTB (0.025 % warfarin, 0.005 % fipronil) in controlling white-footed mice and I. scapularis larvae. Studies were designed in part based on Environmental Protection Agency (EPA) guidelines. A laboratory choice test was conducted to evaluate the use of RTB in controlling white-footed mice over 15-day exposure when they were exposed to an alternative diet. Mice were observed every day for mortality and signs of warfarin toxicity. A simulated field test was conducted to evaluate the use of RTB, presented in the presence of an alternative diet, in controlling I. scapularis parasitizing white-footed mice over 4-day exposure. Mice were fitted with capsules and manually infested with I. scapularis larvae. The inside of each capsule was observed to evaluate tick attachment. Replete larvae detaching from each mouse were collected. Blood was collected from all treatment group mice via cardiac puncture to determine the fipronil sulfone concentration in plasma for each animal. Results indicated that RTB would be adequately consumed in the presence of an alternative diet under laboratory and simulated field conditions. Treatment with RTB resulted in 100 % mortality of white-footed mice during 15-day exposure and prevented 100 % larvae from feeding to repletion during 4-day exposure. All mice succumbing to RTB showed signs of warfarin toxicity. All mice parasitized with ticks that were exposed to RTB had fipronil sulfone detectable in plasma, with even the lowest concentration detected (8.1 parts per billion) controlling 100 % parasitizing I. scapularis larvae. The results suggest that RTB could be a useful means of rodent and tick control for use in ITM programs.
Topics: Animals; Ixodes; Peromyscus; Lyme Disease; Tick Control; Tick Infestations; Larva; Rodenticides; Acaricides; Pyrazoles; Female; Arachnid Vectors
PubMed: 38852539
DOI: 10.1016/j.ttbdis.2024.102362 -
Scientific Reports Jun 2024Protein kinase dysregulation induces cancer cell aggressiveness leading to rapid tumor progression and poor prognosis in TNBC patients. Many small-molecule kinase...
Protein kinase dysregulation induces cancer cell aggressiveness leading to rapid tumor progression and poor prognosis in TNBC patients. Many small-molecule kinase inhibitors have been tested in clinical trials to treat TNBC patients. In the previous study, we found that N-phenylpyrazoline small molecule acts as a protein kinase inhibitor in cervical cancer cells. However, there remains unknown about N-phenyl pyrazoline potency as a kinase inhibitor and its anti-cancer activity in TNBC cells. In this study, we investigated the activity of N-phenyl pyrazoline against TNBC cells via tyrosine kinase inhibition. Based on the MTT assay, the IC50 values for the N-phenyl pyrazoline 2, 5, A, B, C, and D against Hs578T were 12.63 µM, 3.95 µM, not available, 18.62 µM, 30.13 µM, and 26.79 µM, respectively. While only P5 exhibited the IC50 against MDA MB 231 (21.55 µM). Further, N-phenyl pyrazoline 5 treatment significantly inhibited the cell proliferation rate of Hs578T and MDA MB 231 cells. The migration assay showed that treatment with the compound N-phenyl pyrazoline 5 with 4 µM concentration significantly reduced cell migration of Hs578T cells. N-phenyl pyrazoline 5 treatment at 1 µM and 2 µM was able to reduce the tumorsphere size of Hs578t cells. A combination treatment of P5 and paclitaxel showed a synergistic effect with a combination index score > 1 in both TNBC cells. Further, the P5 predictively targeted the protein kinases that significantly correlated to breast cancer prognosis. The GSEA analysis result shows that receptor tyrosine kinase, Notch3, Notch4, and Ephrin signaling pathways were targeted by P5. The P5 treatment reduced the EGFR expression level and activation in TNBC cells.
Topics: Humans; Triple Negative Breast Neoplasms; Paclitaxel; Cell Line, Tumor; Cell Proliferation; Pyrazoles; Female; Cell Movement; Protein Kinase Inhibitors; Drug Synergism; Antineoplastic Agents
PubMed: 38851778
DOI: 10.1038/s41598-024-63778-2 -
Ecotoxicology and Environmental Safety Jul 2024The aim of this study is to investigate the role of estrogen receptor β (ERβ) in nonylphenol (NP) - induced depression - like behavior in rats and its impact on the...
The aim of this study is to investigate the role of estrogen receptor β (ERβ) in nonylphenol (NP) - induced depression - like behavior in rats and its impact on the regulation of the TPH2/5-HT pathway. In the in vitro experiment, rat basophilic leukaemia cells (RBL-2H3) cells were divided into the four groups: blank group, NP group (20 μM), ERβ agonist group (0.01 μM), and NP+ERβ agonist group (20 μM+0.01 μM). For the in vivo experiment, 72 adult male Sprague-Dawley rats were randomly divided into following six groups: the Control, NP (40 mg/kg) group, ERβ agonist (2 mg/kg, Diarylpropionitrile (DPN)) group, ERβ inhibitor (0.1 mg/kg, 4-(2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl) phenol (PHTPP)) group, NP+ERβ agonist (40 mg/kg NP + 2 mg/kg DPN) group, and NP+ERβ inhibitor (40 mg/kg NP + 0.1 mg/kg PHTPP) group, with 12 rats in each group. Each rat in drug group were given NP by gavage and/or received a single intraperitoneal injection of DPN 2 mg/kg or PHTPP 0.1 mg/kg. Both in vivo and in vitro, NP group showed a decrease in the expression levels of ERβ, tryptophan hydroxylase (TPH1), and tryptophan hydroxylase-2 (TPH2) genes and proteins, and reduced levels of DA, NE, and 5-hydroxytryptophan (5-HT) neurotransmitters. RBL-2H3 cells showed signs of cell shrinkage, with rounded cells, increased suspension and more loosely arranged cells. The effectiveness of the ERβ agonist stimulation exhibited an increase exceeding 60% in RBL-2H3 cells. The application of ERβ agonist resulted in an alleviation the aforementioned alterations. ERβ agonist activated the TPH2/5-HT signaling pathways. Compared to the control group, the NP content in the brain tissue of the NP group was significantly increased. The latency to eat for the rats was longer and the amount of food consumed was lower, and the rats had prolonged immobility time in the behavioral experiment of rats. The expression levels of ERβ, TPH1, TPH2, 5-HT and 5-HITT proteins were decreased in the NP group, suggesting NP-induced depression-like behaviours as well as disturbances in the secretion of serum hormones and monoamine neurotransmitters. In the NP group, the midline raphe nucleus showed an elongated nucleus with a dark purplish-blue colour, nuclear atrophy, displacement and pale cytoplasm. ERβ might ameliorate NP-induced depression-like behaviors, and secretion disorders of serum hormones and monoamine neurotransmitters via activating TPH2/5-HT signaling pathways.
Topics: Animals; Tryptophan Hydroxylase; Estrogen Receptor beta; Phenols; Male; Rats, Sprague-Dawley; Rats; Serotonin; Depression; Neurotransmitter Agents; Signal Transduction; Cell Line, Tumor; Nitriles; Propionates; Pyrazoles; Pyrimidines
PubMed: 38850708
DOI: 10.1016/j.ecoenv.2024.116521