-
European Journal of Medical Research Jul 2024So far, high-density lipoprotein cholesterol (HDL-C) levels and mortality were shown to have a U-shaped relationship. Additionally, high HDL-C levels increase the risk...
BACKGROUND
So far, high-density lipoprotein cholesterol (HDL-C) levels and mortality were shown to have a U-shaped relationship. Additionally, high HDL-C levels increase the risk of developing a variety of diseases. However, a paucity of data exists regarding the characteristics of people with high HDL-C levels. The aim of this study was to assess the demographics and characteristics of patients with high HDL-C levels and compare their features with normal and low HDL-C groups.
METHODS
As a cross-sectional, matched case-control study, a total of 510 patients with type 2 diabetes (T2D) were enrolled in the study and categorized into three matched groups according to their HDL-C concentrations. The studied groups were matched by their age and gender. Restricted cubic spline (RCS) curves were designed to evaluate the relationship between height, blood pressure, triglyceride, and vitamin D concentrations with the probability of having high HDL-C levels. Furthermore, violin plots were conducted to illustrate the distribution of continuous variables within each group.
RESULTS
This study showed that having high HDL-C (more than 70 mg/dL) compared to having low HDL-C (less than 40 mg/dL in men and 50 mg/dL in women) was significantly associated with height (OR 0.918, 95% CI 0.866-0.974), systolic blood pressure (SBP) (0.941, 0.910-0.972), vitamin D (0.970, 0.941-0.999), and triglyceride (0.992, 0.987-0.998) serum concentrations. Further analysis investigated that having high HDL-C levels compared to desired HDL-C levels (40 ≤ HDL-C levels < 70 in men and 50 ≤ HDL-C levels < 70 in women) was inversely associated with having SPB values greater than 130 mmHg. Besides, sufficient vitamin D levels (above 20 ng/ml) could 0.349 times decrease the odds of having high HDL-C versus normal HDL-C levels.
CONCLUSION
Sufficient vitamin D levels, SPB values higher than 130 mmHg, as well as increased triglyceride levels, were inversely associated with having high HDL levels. However, higher height values were associated with a decreased likelihood of having high HDL.
Topics: Humans; Diabetes Mellitus, Type 2; Male; Female; Cholesterol, HDL; Cross-Sectional Studies; Middle Aged; Case-Control Studies; Aged; Triglycerides; Risk Factors; Adult
PubMed: 38956709
DOI: 10.1186/s40001-024-01950-0 -
Trials Jul 2024Norepinephrine and phenylephrine are commonly used vasoactive drugs to treat hypotension during the perioperative period. The increased release of endogenous...
Effect of norepinephrine and phenylephrine on prothrombotic response in patients undergoing cesarean section under spinal anesthesia: protocol for a randomized, double-blind, controlled study.
BACKGROUND
Norepinephrine and phenylephrine are commonly used vasoactive drugs to treat hypotension during the perioperative period. The increased release of endogenous norepinephrine elicits prothrombotic changes, while parturients are generally in a hypercoagulable state. Therefore, this trial aims to investigate whether there is a disparity between equivalent doses of prophylactic norepinephrine infusion and phenylephrine infusion on prothrombotic response in patients undergoing cesarean section under spinal anesthesia.
METHODS
Sixty-six eligible parturients will be recruited for this trial and randomly assigned to the norepinephrine or phenylephrine group. The "study drug" will be administered at a rate of 15 ml/h starting from the intrathecal injection. The primary outcome are plasma coagulation factor VIII activity (FVIII: C), fibrinogen, and D-dimer levels. The secondary outcomes include hemodynamic variables and umbilical artery blood pH value.
DISCUSSION
Our study is the first trial comparing the effect of norepinephrine and phenylephrine on prothrombotic response in patients undergoing cesarean section under spinal anesthesia. Positive or negative results will all help us better understand the impact of vasoactive drugs on patients. If there are any differences, this trial will provide new evidence for maternal choice of vasoactive medications in the perioperative period.
TRIAL REGISTRATION
Chinese Clinical Trial Registry ChiCTR2300077164. Registered on 1 November 2023. https://www.chictr.org.cn/ .
Topics: Humans; Cesarean Section; Anesthesia, Spinal; Female; Norepinephrine; Double-Blind Method; Pregnancy; Phenylephrine; Vasoconstrictor Agents; Randomized Controlled Trials as Topic; Anesthesia, Obstetrical; Adult; Fibrin Fibrinogen Degradation Products; Factor VIII; Treatment Outcome; Blood Coagulation; Hemodynamics
PubMed: 38956697
DOI: 10.1186/s13063-024-08255-x -
Radiation Oncology (London, England) Jul 2024Radiotherapy is essential in the treatment of prostate cancer. An alternative to conventional photon radiotherapy is the application of carbon ions, which provide a...
BACKGROUND
Radiotherapy is essential in the treatment of prostate cancer. An alternative to conventional photon radiotherapy is the application of carbon ions, which provide a superior intratumoral dose distribution and less induced damage to adjacent healthy tissue. A common characteristic of prostate cancer cells is their dependence on androgens which is exploited therapeutically by androgen deprivation therapy in the advanced prostate cancer stage. Here, we aimed to analyze the transcriptomic response of prostate cancer cells to irradiation by photons in comparison to carbon ions, focusing on DNA damage, DNA repair and androgen receptor signaling.
METHODS
Prostate cancer cell lines LNCaP (functional TP53 and androgen receptor signaling) and DU145 (dysfunctional TP53 and androgen receptor signaling) were irradiated by photons or carbon ions and the subsequent DNA damage was assessed by immuno-cytofluorescence. Furthermore, the cells were treated with an androgen-receptor agonist. The effects of irradiation and androgen treatment on the gene regulation and the transcriptome were investigated by RT-qPCR and RNA sequencing, followed by bioinformatic analysis.
RESULTS
Following photon or carbon ion irradiation, both LNCaP and DU145 cells showed a dose-dependent amount of visible DNA damage that decreased over time, indicating occurring DNA repair. In terms of gene regulation, mRNAs involved in the TP53-dependent DNA damage response were significantly upregulated by photons and carbon ions in LNCaP but not in DU145 cells, which generally showed low levels of gene regulation after irradiation. Both LNCaP and DU145 cells responded to photons and carbon ions by downregulation of genes involved in DNA repair and cell cycle, partially resembling the transcriptome response to the applied androgen receptor agonist. Neither photons nor carbon ions significantly affected canonical androgen receptor-dependent gene regulation. Furthermore, certain genes that were specifically regulated by either photon or carbon ion irradiation were identified.
CONCLUSION
Photon and carbon ion irradiation showed a significant congruence in terms of induced signaling pathways and transcriptomic responses. These responses were strongly impacted by the TP53 status. Nevertheless, irradiation mode-dependent distinct gene regulations with undefined implication for radiotherapy outcome were revealed. Androgen receptor signaling and irradiations shared regulation of certain genes with respect to DNA-repair and cell-cycle.
Topics: Humans; Male; Prostatic Neoplasms; Receptors, Androgen; Tumor Suppressor Protein p53; Photons; Transcriptome; Signal Transduction; DNA Damage; Heavy Ion Radiotherapy; DNA Repair; Gene Expression Regulation, Neoplastic; Cell Line, Tumor; Carbon
PubMed: 38956684
DOI: 10.1186/s13014-024-02480-z -
Human Genomics Jul 2024Knockout of GAS2 (growth arrest-specific protein 2), causes disorganization and destabilization of microtubule bundles in supporting cells of the cochlear duct, leading...
Knockout of GAS2 (growth arrest-specific protein 2), causes disorganization and destabilization of microtubule bundles in supporting cells of the cochlear duct, leading to hearing loss in vivo. However, the molecular mechanism through which GAS2 variant results in hearing loss remains unknown. By Whole-exome sequencing, we identified a novel heterozygous splicing variant in GAS2 (c.616-2 A > G) as the only candidate mutation segregating with late-onset and progressive nonsyndromic hearing loss (NSHL) in a large dominant family. This splicing mutation causes an intron retention and produces a C-terminal truncated protein (named GAS2mu). Mechanistically, the degradation of GAS2mu via the ubiquitin-proteasome pathway is enhanced, and cells expressing GAS2mu exhibit disorganized microtubule bundles. Additionally, GAS2mu further promotes apoptosis by increasing the Bcl-xS/Bcl-xL ratio instead of through the p53-dependent pathway as wild-type GAS2 does, indicating that GAS2mu acts as a toxic molecule to exacerbate apoptosis. Our findings demonstrate that this novel variant of GAS2 promotes its own protein degradation, microtubule disorganization and cellular apoptosis, leading to hearing loss in carriers. This study expands the spectrum of GAS2 variants and elucidates the underlying pathogenic mechanisms, providing a foundation for future investigations of new therapeutic strategies to prevent GAS2-associated progressive hearing loss.
Topics: Humans; Male; Female; Pedigree; Deafness; Mutation; Apoptosis; Adult; Asian People; Middle Aged; Exome Sequencing; Genes, Dominant; Microtubules; East Asian People
PubMed: 38956677
DOI: 10.1186/s40246-024-00628-2 -
Acta Neuropathologica Communications Jul 2024The genetic architecture of Parkinson's disease (PD) is complex and multiple brain cell subtypes are involved in the neuropathological progression of the disease. Here...
The genetic architecture of Parkinson's disease (PD) is complex and multiple brain cell subtypes are involved in the neuropathological progression of the disease. Here we aimed to advance our understanding of PD genetic complexity at a cell subtype precision level. Using parallel single-nucleus (sn)RNA-seq and snATAC-seq analyses we simultaneously profiled the transcriptomic and chromatin accessibility landscapes in temporal cortex tissues from 12 PD compared to 12 control subjects at a granular single cell resolution. An integrative bioinformatic pipeline was developed and applied for the analyses of these snMulti-omics datasets. The results identified a subpopulation of cortical glutamatergic excitatory neurons with remarkably altered gene expression in PD, including differentially-expressed genes within PD risk loci identified in genome-wide association studies (GWAS). This was the only neuronal subtype showing significant and robust overexpression of SNCA. Further characterization of this neuronal-subpopulation showed upregulation of specific pathways related to axon guidance, neurite outgrowth and post-synaptic structure, and downregulated pathways involved in presynaptic organization and calcium response. Additionally, we characterized the roles of three molecular mechanisms in governing PD-associated cell subtype-specific dysregulation of gene expression: (1) changes in cis-regulatory element accessibility to transcriptional machinery; (2) changes in the abundance of master transcriptional regulators, including YY1, SP3, and KLF16; (3) candidate regulatory variants in high linkage disequilibrium with PD-GWAS genomic variants impacting transcription factor binding affinities. To our knowledge, this study is the first and the most comprehensive interrogation of the multi-omics landscape of PD at a cell-subtype resolution. Our findings provide new insights into a precise glutamatergic neuronal cell subtype, causal genes, and non-coding regulatory variants underlying the neuropathological progression of PD, paving the way for the development of cell- and gene-targeted therapeutics to halt disease progression as well as genetic biomarkers for early preclinical diagnosis.
Topics: Humans; Parkinson Disease; Neurons; Gene Regulatory Networks; Male; Female; alpha-Synuclein; Aged; YY1 Transcription Factor; Genome-Wide Association Study; Transcriptome; Single-Cell Analysis; Temporal Lobe; Middle Aged; Gene Expression Regulation; Multiomics
PubMed: 38956662
DOI: 10.1186/s40478-024-01803-1 -
Journal of Orthopaedic Surgery and... Jul 2024Spinal cord injury (SCI) is a severe condition with an extremely high disability rate. It is mainly manifested as the loss of motor, sensory and autonomic nerve...
Spinal cord injury (SCI) is a severe condition with an extremely high disability rate. It is mainly manifested as the loss of motor, sensory and autonomic nerve functions below the injury site. High-frequency transcranial magnetic stimulation, a recently developed neuromodulation method, can increase motor function in mice with spinal cord injury. This study aimed to explore the possible mechanism by which transcranial magnetic stimulation (TMS) restores motor function after SCI. A complete T8 transection model of the spinal cord was established in mice, and the mice were treated daily with 15 Hz high-frequency transcranial magnetic stimulation. The BMS was used to evaluate the motor function of the mice after SCI. Western blotting and immunofluorescence were used to detect the expression of Connexin43 (CX43) and autophagy-related proteins in vivo and in vitro, and correlation analysis was performed to study the relationships among autophagy, CX43 and motor function recovery after SCI in mice. Western blotting was used to observe the effect of magnetic stimulation on the expression of mTOR pathway members. In the control group, the expression of CX43 was significantly decreased, and the expression of microtubule-associated protein 1 A/1b light chain 3 (LC3II) and P62 was significantly increased after 4 weeks of spinal cord transection. After high-frequency magnetic stimulation, the level of CX43 decreased, and the levels of LC3II and P62 increased in primary astrocytes. The BMS of the magnetic stimulation group was greater than that of the control group. High-frequency magnetic stimulation can inhibit the expression of CX43, which negatively regulates autophagic flux. HF-rTMS increased the expression levels of mTOR, p-mTOR and p-S6. Our experiments showed that rTMS can restore hindlimb motor function in mice after spinal cord injury via regulation of the Cx43-autophagy loop and activation of the mTOR signalling pathway.
Topics: Animals; Transcranial Magnetic Stimulation; Spinal Cord Injuries; Recovery of Function; Connexin 43; Autophagy; Mice; TOR Serine-Threonine Kinases; Mice, Inbred C57BL; Motor Activity; Disease Models, Animal; Male; Female
PubMed: 38956661
DOI: 10.1186/s13018-024-04879-6 -
Nutrition & Metabolism Jul 2024Maintaining skeletal muscle mass is important for improving muscle strength and function. Hence, maximizing lean body mass (LBM) is the primary goal for both elite... (Review)
Review
Maintaining skeletal muscle mass is important for improving muscle strength and function. Hence, maximizing lean body mass (LBM) is the primary goal for both elite athletes and fitness enthusiasts. The use of amino acids as dietary supplements is widespread among athletes and physically active individuals. Extensive literature analysis reveals that branched-chain amino acids (BCAA), creatine, glutamine and β-alanine may be beneficial in regulating skeletal muscle metabolism, enhancing LBM and mitigating exercise-induced muscle damage. This review details the mechanisms of these amino acids, offering insights into their efficacy as supplements. Recommended dosage and potential side effects are then outlined to aid athletes in making informed choices and safeguard their health. Lastly, limitations within the current literature are addressed, highlighting opportunities for future research.
PubMed: 38956658
DOI: 10.1186/s12986-024-00820-0 -
Journal of Neuroinflammation Jul 2024Type 2 diabetes mellitus (T2DM) and obstructive sleep apnea (OSA) are mutual risk factors, with both conditions inducing cognitive impairment and anxiety. However,...
BACKGROUND
Type 2 diabetes mellitus (T2DM) and obstructive sleep apnea (OSA) are mutual risk factors, with both conditions inducing cognitive impairment and anxiety. However, whether OSA exacerbates cognitive impairment and anxiety in patients with T2DM remains unclear. Moreover, TREM2 upregulation has been suggested to play a protective role in attenuating microglia activation and improving synaptic function in T2DM mice. The aim of this study was to explore the regulatory mechanisms of TREM2 and the cognitive and anxiety-like behavioral changes in mice with OSA combined with T2DM.
METHODS
A T2DM with OSA model was developed by treating mice with a 60% kcal high-fat diet (HFD) combined with intermittent hypoxia (IH). Spatial learning memory capacity and anxiety in mice were investigated. Neuronal damage in the brain was determined by the quantity of synapses density, the number and morphology of brain microglia, and pro-inflammatory factors. For mechanism exploration, an in vitro model of T2DM combined with OSA was generated by co-treating microglia with high glucose (HG) and IH. Regulation of TREM2 on IFNAR1-STAT1 pathway was determined by RNA sequencing and qRT-PCR.
RESULTS
Our results showed that HFD mice exhibited significant cognitive dysfunction and anxiety-like behavior, accompanied by significant synaptic loss. Furthermore, significant activation of brain microglia and enhanced microglial phagocytosis of synapses were observed. Moreover, IH was found to significantly aggravate anxiety in the HFD mice. The mechanism of HG treatment may potentially involve the promotion of TREM2 upregulation, which in turn attenuates the proinflammatory microglia by inhibiting the IFNAR1-STAT1 pathway. Conversely, a significant reduction in TREM2 in IH-co-treated HFD mice and HG-treated microglia resulted in the further activation of the IFNAR1-STAT1 pathway and consequently increased proinflammatory microglial activation.
CONCLUSIONS
HFD upregulated the IFNAR1-STAT1 pathway and induced proinflammatory microglia, leading to synaptic damage and causing anxiety and cognitive deficits. The upregulated TREM2 inT2DM mice brain exerted a negative regulation of the IFNAR1-STAT1 pathway. Mice with T2DM combined with OSA exacerbated anxiety via the downregulation of TREM2, causing heightened IFNAR1-STAT1 pathway activation and consequently increasing proinflammatory microglia.
Topics: Animals; Mice; Diet, High-Fat; Membrane Glycoproteins; Receptors, Immunologic; Anxiety; Signal Transduction; Hypoxia; Male; Mice, Inbred C57BL; Diabetes Mellitus, Type 2; Receptor, Interferon alpha-beta; Diabetes Mellitus, Experimental; Microglia; STAT1 Transcription Factor; Sleep Apnea, Obstructive
PubMed: 38956653
DOI: 10.1186/s12974-024-03160-1 -
Journal of Translational Medicine Jul 2024CD19-targeted chimeric antigen receptor T (CAR-T) cell therapy stands out as a revolutionary intervention, exhibiting remarkable remission rates in patients with...
BACKGROUND
CD19-targeted chimeric antigen receptor T (CAR-T) cell therapy stands out as a revolutionary intervention, exhibiting remarkable remission rates in patients with refractory/relapsed (R/R) B-cell malignancies. However, the potential side effects of therapy, particularly cytokine release syndrome (CRS) and infections, pose significant challenges due to their overlapping clinical features. Promptly distinguishing between CRS and infection post CD19 target CAR-T cell infusion (CTI) remains a clinical dilemma. Our study aimed to analyze the incidence of infections and identify key indicators for early infection detection in febrile patients within 30 days post-CTI for B-cell malignancies.
METHODS
In this retrospective cohort study, a cohort of 104 consecutive patients with R/R B-cell malignancies who underwent CAR-T therapy was reviewed. Clinical data including age, gender, CRS, ICANS, treatment history, infection incidence, and treatment responses were collected. Serum biomarkers procalcitonin (PCT), interleukin-6 (IL-6), and C-reactive protein (CRP) levels were analyzed using chemiluminescent assays. Statistical analyses employed Pearson's Chi-square test, t-test, Mann-Whitney U-test, Kaplan-Meier survival analysis, Cox proportional hazards regression model, Spearman rank correlation, and receiver operating characteristic (ROC) curve analysis to evaluate diagnostic accuracy and develop predictive models through multivariate logistic regression.
RESULTS
In this study, 38 patients (36.5%) experienced infections (30 bacterial, 5 fungal, and 3 viral) within the first 30 days of CAR T-cell infusion. In general, bacterial, fungal, and viral infections were detected at a median of 7, 8, and 9 days, respectively, after CAR T-cell infusion. Prior allogeneic hematopoietic cell transplantation (HCT) was an independent risk factor for infection (Hazard Ratio [HR]: 4.432 [1.262-15.565], P = 0.020). Furthermore, CRS was an independent risk factor for both infection ((HR: 2.903 [1.577-5.345], P < 0.001) and severe infection (9.040 [2.256-36.232], P < 0.001). Serum PCT, IL-6, and CRP were valuable in early infection prediction post-CAR-T therapy, particularly PCT with the highest area under the ROC curve (AUC) of 0.897. A diagnostic model incorporating PCT and CRP demonstrated an AUC of 0.903 with sensitivity and specificity above 83%. For severe infections, a model including CRS severity and PCT showed an exceptional AUC of 0.991 with perfect sensitivity and high specificity. Based on the aforementioned analysis, we proposed a workflow for the rapid identification of early infection during CAR-T cell therapy.
CONCLUSIONS
CRS and prior allogeneic HCT are independent infection risk factors post-CTI in febrile B-cell malignancy patients. Our identification of novel models using PCT and CRP for predicting infection, and PCT and CRS for predicting severe infection, offers potential to guide therapeutic decisions and enhance the efficacy of CAR-T cell therapy in the future.
Topics: Humans; Female; Male; Middle Aged; Immunotherapy, Adoptive; Adult; Antigens, CD19; Fever; Infections; Aged; ROC Curve; Young Adult; Retrospective Studies
PubMed: 38956649
DOI: 10.1186/s12967-024-05308-2 -
BMC Veterinary Research Jul 2024The neuroimmune network plays a crucial role in regulating mucosal immune homeostasis within the digestive tract. Synaptosome-associated protein 25 (SNAP-25) is a...
BACKGROUND
The neuroimmune network plays a crucial role in regulating mucosal immune homeostasis within the digestive tract. Synaptosome-associated protein 25 (SNAP-25) is a presynaptic membrane-binding protein that activates ILC2s, initiating the host's anti-parasitic immune response.
METHODS
To investigate the effect of Moniezia benedeni (M. benedeni) infection on the distribution of SNAP-25 in the sheep's small intestine, the recombinant plasmid pET-28a-SNAP-25 was constructed and expressed in BL21, yielding the recombinant protein. Then, the rabbit anti-sheep SNAP-25 polyclonal antibody was prepared and immunofluorescence staining was performed with it. The expression levels of SNAP-25 in the intestines of normal and M. benedeni-infected sheep were detected by ELISA.
RESULTS
The results showed that the SNAP-25 recombinant protein was 29.3 KDa, the titer of the prepared immune serum reached 1:128,000. It was demonstrated that the rabbit anti-sheep SNAP-25 polyclonal antibody could bind to the natural protein of sheep SNAP-25 specifically. The expression levels of SNAP-25 in the sheep's small intestine revealed its primary presence in the muscular layer and lamina propria, particularly around nerve fibers surrounding the intestinal glands. Average expression levels in the duodenum, jejunum, and ileum were 130.32 pg/mg, 185.71 pg/mg, and 172.68 pg/mg, respectively. Under conditions of M. benedeni infection, the spatial distribution of SNAP-25-expressing nerve fibers remained consistent, but its expression level in each intestine segment was increased significantly (P < 0.05), up to 262.02 pg/mg, 276.84 pg/mg, and 326.65 pg/mg in the duodenum, jejunum, and ileum, and it was increased by 101.06%, 49.07%, and 89.16% respectively.
CONCLUSIONS
These findings suggest that M. benedeni could induce the SNAP-25 expression levels in sheep's intestinal nerves significantly. The results lay a foundation for further exploration of the molecular mechanism by which the gastrointestinal nerve-mucosal immune network perceives parasites in sheep.
Topics: Animals; Sheep; Sheep Diseases; Intestine, Small; Synaptosomal-Associated Protein 25; Enteric Nervous System; Rabbits
PubMed: 38956647
DOI: 10.1186/s12917-024-04140-6