The development of a biodegradable and shape-adaptable bioscaffold that can enhance local cytokine retention and bioactivity is essential for the application of immunotherapy in periodontal diseases. ...Here, we report a biodegradable, anti-inflammatory, and osteogenic ILGel that uses a physically cross-linked DNA hydrogel as a soft bioscaffold for the long-term sustained release of cytokine interleukin-10 (IL-10) to accelerate diabetic alveolar bone rebuilding. Porous microstructures of ILGel favored the encapsulation of IL-10 and maintained IL-10 bioactivity for at least 7 days. ILGel can be gradually degraded or hydrolyzed under physiological conditions, avoiding the potential undesired side effects on dental tissues. Long-term sustained release of bioactive IL-10 from ILGel not only promoted M2 macrophage polarization and attenuated periodontal inflammation but also triggered osteogenesis of mesenchymal stem cells (MSCs), leading to accelerated alveolar bone formation and healing of alveolar bone defects under diabetic conditions in vivo. ILGel treatment significantly accelerated the defect healing rate of diabetic alveolar injury up to 93.42 ± 4.6% on day 21 post treatment compared to that of free IL-10 treatment (63.30 ± 7.39%), with improved trabecular architectures. Our findings imply the potential application of the DNA hydrogel as the bioscaffold for cytokine-based immunotherapy in diabetic alveolar bone injury and other periodontal diseases.
Background
The interleukin-1 pathway has been linked to pancreatic diseases. We applied the Mendelian randomization approach to explore whether higher interleukin-1 receptor antagonist (IL-1RA) ...levels reduce the risk of acute and chronic pancreatitis and pancreatic cancer.
Methods
Genetic variants associated with blood IL-1RA levels at the genome-wide significance level and located 5MB downstream or upstream of the
IL1RN
gene were extracted from a genome-wide meta-analysis of 21,758 participants. After pruning, genetic variants without linkage disequilibrium were used as genetic instrument for IL-1RA. Summary-level data on acute and chronic pancreatitis and pancreatic cancer were obtained from the UK Biobank and FinnGen studies. The associations were meta-analyzed for one outcome from two sources.
Results
Genetically predicted higher levels of IL-1RA were associated with a lower risk of acute and chronic pancreatitis and pancreatic cancer. In the meta-analysis of UK Biobank and FinnGen, the combined odds ratio was 0.87 (95% confidence interval CI 0.77-0.97,
P
=0.003) for acute pancreatitis, 0.73 (95% CI 0.65-0.82,
P
=2.93×10
-8
) for chronic pancreatitis, and 0.86 (95% CI 0.77-0.96,
P
=0.009) for pancreatic cancer per one standard deviation increment in genetically predicted levels of IL-1RA.
Conclusion
This study suggests a protective role of IL-1RA in three major pancreatic diseases, which hints the therapeutic potentials of IL-1RA in pancreatic diseases.
We conducted a two-sample Mendelian randomization (MR) study to assess the associations of genetically predicted circulating vitamin C levels with cardiovascular diseases (CVDs).
Ten lead ...single-nucleotide polymorphisms associated with plasma vitamin C levels at the genome-wide significance level were used as instrumental variables. Summary-level data for 15 CVDs were obtained from corresponding genetic consortia, the UK Biobank study, and the FinnGen consortium. The inverse-variance-weighted method was the primary analysis method, supplemented by the weighted median and MR-Egger methods. Estimates for each CVD from different sources were combined. Genetically predicted vitamin C levels were not associated with any CVD after accounting for multiple testing. However, there were suggestive associations of higher genetically predicted vitamin C levels (per 1 standard deviation increase) with lower risk of cardioembolic stroke odds ratio, 0.79; 95% confidence interval (CI), 0.64, 0.99; P = 0.038 and higher risk of atrial fibrillation (odds ratio, 1.09; 95% CI, 1.00, 1.18; P = 0.049) in the inverse-variance-weighted method and with lower risk of peripheral artery disease (odds ratio, 0.76, 95% CI, 0.62, 0.93; P = 0.009) in the weighted median method.
We found limited evidence with MR techniques for an overall protective role of vitamin C in the primary prevention of CVD. The associations of vitamin C levels with cardioembolic stroke, atrial fibrillation, and peripheral artery disease need further study.
Epidemiological studies have demonstrated a high association of inorganic arsenic exposure with vascular diseases. Recent research has also linked this vascular damage to impairment of endothelial ...nitric oxide synthase (eNOS) function by arsenic exposure. However, the role of eNOS in regulating the arsenite-induced vascular dysfunction still remains to be clarified. In our present study, we investigated the effect of arsenite on Akt1 and eNOS and its involvement in cytotoxicity of vascular endothelial cells. Our study demonstrated that arsenite decreased the protein levels of both Akt1 and eNOS accompanied with increased levels of ubiquitination of total cell lysates. We found that inhibition of the ubiquitin–proteasome pathway by MG-132 could partially protect Akt1 and eNOS from degradation by arsenite together with a proportional protection from the arsenite-induced cytoxicity. Moreover, up-regulation of eNOS protein expression significantly attenuated the arsenite-induced cytotoxicity and eNOS activity could be significantly inhibited after incubation with arsenite for 24 h in a cell-free system. Our study indicated that endothelial eNOS activity could be attenuated by arsenite via the ubiquitin–proteasome-mediated degradation of Akt1/eNOS as well as via direct inhibition of eNOS activity. Our study also demonstrated that eNOS actually played a protective role in arsenite-induced cytoxicity. These observations supported the hypothesis that the impairment of eNOS function by arsenite is one of the mechanisms leading to vascular changes and diseases.
The precise measurement of the spectrum of protons, the most abundant component of the cosmic radiation, is necessary to understand the source and acceleration of cosmic rays in the Milky Way. This ...work reports the measurement of the cosmic ray proton fluxes with kinetic energies from 40 GeV to 100 TeV, with 2
/
years of data recorded by the DArk Matter Particle Explorer (DAMPE). This is the first time that an experiment directly measures the cosmic ray protons up to ~100 TeV with high statistics. The measured spectrum confirms the spectral hardening at ~300 GeV found by previous experiments and reveals a softening at ~13.6 TeV, with the spectral index changing from ~2.60 to ~2.85. Our result suggests the existence of a new spectral feature of cosmic rays at energies lower than the so-called knee and sheds new light on the origin of Galactic cosmic rays.
Purpose: In a previous genome-wide gene expression profiling analysis using an invasion cancer cell lines model, we have identified
Slug as selectively overexpressed in the highly invasive cancer ...cells. Here, we investigated the clinical significance of Slug in lung adenocarcinoma and the role of Slug in the process of cancer cell invasion and metastasis.
Experimental Design: Real-time quantitative reverse transcription-PCR was used to investigate Slug mRNA in surgically resected lung adenocarcinoma of 54 patients and its correlation with survival. We overexpressed Slug in a lung adenocarcinoma cell line with very low Slug levels and investigated the in vitro and in vivo effects of Slug expression.
Results: High expression of Slug mRNA in lung cancer tissue was significantly associated with postoperative relapse ( P = 0.03) and shorter patient survival ( P < 0.001). The overexpression of Slug enhanced xenograft tumor growth and increased microvessel counts in angiogenesis assay. Both inducible and constitutive overexpression
of Slug suppressed the expression of E-cadherin and increased the in vitro invasive ability. Zymography revealed increased matrix metalloproteinase-2 activity in Slug overexpressed cells. ELISA, reverse transcription-PCR, and immunohistochemistry confirmed the increase of matrix metalloproteinase-2
proteins and mRNA in Slug overexpressed cells and xenograft tumors.
Conclusions: Slug expression can predict the clinical outcome of lung adenocarcinoma patients. Slug is a novel invasion-promoting gene in lung adenocarcinoma.
In this prospective study, Han Chinese subjects who were candidates for carbamazepine therapy were screened for the HLA-B*1502 allele because of its association with the Stevens–Johnson syndrome and ...toxic epidermal necrolysis.
The Stevens–Johnson syndrome (SJS) and its related disease, toxic epidermal necrolysis (TEN), are two of the most serious adverse reactions caused by drugs. SJS is characterized by high fever, malaise, and a rapidly developing, blistering exanthema of macular papules and target-like lesions, accompanied by mucosal involvement. This condition is associated with a rate of death of approximately 5%. TEN has a similar presentation, with even more extensive skin detachment and a death rate of 25 to 35%.
1
Carbamazepine, an anticonvulsant and specific analgesic agent for trigeminal neuralgia, is the most common cause of SJS–TEN in Southeast Asian countries.
2
We previously . . .
Evidence on the associations of lifestyle factors with venous thromboembolism (VTE) is inconsistent. We aimed to investigate the associations of modifiable lifestyle factors with VTE in women and ...men.
We used data from two cohorts comprising 30,137 women and 36,193 men aged over 45 years and free of cancer and VTE. Information on lifestyle factors was collected in 1997 via a self-administrated questionnaire. VTE cases were ascertained by linkage with the National Patient Register until the end of 2019.
During a mean of 16.9-years follow-up, 1784 women and 2043 men were diagnosed with VTE. Compared with individuals with <10 min/day of physical activity, the multivariable hazard ratios (HRs) of VTE were 0.67 (95% confidence interval (CI), 0.58, 0.79) and 0.78 (95% CI, 0.67, 0.92) in women and men with >60 min/day, respectively. Compared with individuals with the lowest adherence to a modified Dietary Approaches to Stop Hypertension diet, the multivariable HRs of VTE were 0.87 (95% CI, 0.75, 0.99) and 0.88 (95% CI, 0.80, 1.00) for women and men with the highest adherence. In women, the multivariable HRs of VTE were 1.16 (95% CI, 1.03, 1.29) for past smoker and 1.28 (95% CI, 1.14, 1.45) for current smoker compared with never smoker. Alcohol and coffee consumption were not associated with VTE.
This study suggests that being physically active and adhering to a healthy diet may lower the risk of VTE in women and men. Cigarette smoking was positively associated with VTE in women.
•Physical activity and diet quality appear to be important modifiable factors for venous thromboembolism in both men and women.•Cigarette smoking may increase the risk of venous thromboembolism in women.•Alcohol and coffee consumption was not associated with venous thromboembolism risk.
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