Biomedical Journal最新文献

This issue of the Biomedical Journal delves into the multifaceted roles of NOD-like receptors (NLRs) in immunity, examining their subfamilies and functions within innate and adaptive immunity, autoimmune and inflammatory conditions, and mitophagy regulation. In this issue the dynamics of mRNA vaccines are explored, as well as the synergistic effects of a ketogenic diet with anti-tumor therapies, the roles of curcumin and RANKL in osteoclastogenesis, and the validation of a rapid diagnostic test for an oral cancer biomarker. Additionally, advancements in ocular care are highlighted, featuring a novel prodrug targeting corneal neovascularization, and discussing the efficacy of dexamethasone implants against macular edema. Concluding, further insights into the impact of sweetened foods on child development are given.

Background

Evidence reveals frequent sugar consumption worsens cognition in animal models, and similar effects on child development are probable. We aimed to investigate the influence of sweetened foods (SFs) on child developmental trajectories.

Methods

The prospective cohort recruited 3-month-old children in Taiwan from 1st April 2016 to 30th June 2017. Developmental inventories including cognitive, language, and motor domains, were measured at the age of 3-,12-, 24-, and 36 months old via in-person interviews. We constructed latent growth models with covariates to estimate the influence of SFs on child development.

Results

Ultimately, 4782 children (50.7% boys) were included in the statistical analysis. In the cognitive domain, consumption at one year of age significantly affected the intercept, but not the linear slope and quadratic term (intercept: estimate = −0.054, p < .001); consumption at two years of age significantly affected the intercept and quadratic term (intercept: estimate = −0.08, p < .001; quadratic term: estimate = −0.093, p = .026), but not the linear slope. In the language domain, only consumption at two years of age significantly affected the intercept (estimate = −0.054, p < .001). In the motor domain, consumption at two years of age significantly affected the linear slope and quadratic term (estimate = 0.080, p = .011 and estimate = −0.082, p = .048, respectively).

Conclusion

We found SFs exposure at different times has different negative effects on child development. Early exposure to SFs harmed children's cognitive function. Relatively late exposure to SFs not only deteriorated children's cognitive and language abilities but also decelerated developmental velocity in cognitive and motor domains.

Background

Curcumin ameliorates bone loss by inhibiting osteoclastogenesis. Curcumin inhibits RANKL-promoted autophagy in osteoclast precursors (OCPs), which mediates its anti-osteoclastogenic effect. But the role of RANKL signaling in curcumin-regulated OCP autophagy is unknown. This study aimed to explore the relationship between curcumin, RANKL signaling, and OCP autophagy during osteoclastogenesis.

Methods

We investigated the role of curcumin in RANKL-related molecular signaling in OCPs, and identified the significance of RANK-TRAF6 signaling in curcumin-treated osteoclastogenesis and OCP autophagy using flow sorting and lentiviral transduction. Tg-hRANKL mice were used to observe the in vivo effects of curcumin on RANKL-regulated bone loss, osteoclastogenesis, and OCP autophagy. The significance of JNK-BCL2-Beclin1 pathway in curcumin-regulated OCP autophagy with RANKL was explored via rescue assays and BCL2 phosphorylation detection.

Results

Curcumin inhibited RANKL-related molecular signaling in OCPs, and repressed osteoclast differentiation and autophagy in sorted RANK⁺ OCPs but did not affect those of RANK⁻ OCPs. Curcumin-inhibited osteoclast differentiation and OCP autophagy were recovered by TRAF6 overexpression. But curcumin lost these effects under TRAF6 knockdown. Furthermore, curcumin prevented the decrease in bone mass and the increase in trabecular osteoclast formation and autophagy in RANK⁺ OCPs in Tg-hRANKL mice. Additionally, curcumin-inhibited OCP autophagy with RANKL was reversed by JNK activator anisomycin and TAT-Beclin1 overexpressing Beclin1. Curcumin inhibited BCL2 phosphorylation at Ser70 and enhanced protein interaction between BCL2 and Beclin1 in OCPs.

Conclusions

Curcumin suppresses RANKL-promoted OCP autophagy by inhibiting signaling pathway downstream of RANKL, contributing to its anti-osteoclastogenic effect. Moreover, JNK-BCL2-Beclin1 pathway plays an important role in curcumin-regulated OCP autophagy.

Background

Methods

Results

Conclusions

Background

There is currently no well-accepted consensus on the association between gut microbiota and the response to treatment of immune checkpoint inhibitors (ICIs) in patients with advanced cancer.

Methods

Fecal samples were collected before ICI treatment. Gut microbiota was analyzed using 16 S ribosomal RNA sequencing. We investigated the relationship between the α-diversity of fecal microbiota and patients’ clinical outcomes. Microbiota profiles from patients and healthy controls were determined. Pre-treatment serum was examined by cytokine array.

Results

We analyzed 74 patients, including 42 with melanoma, 8 with kidney cancer, 13 with lung cancer, and 11 with other cancers. Combination therapy of anti-PD1 and anti-CTLA-4 was used in 14 patients, and monotherapy in the rest. Clinical benefit was observed in 35 (47.3 %) cases, including 2 complete responses, 16 partial responses, and 17 stable diseases according to RECIST criteria. No significant difference in α-diversity was found between the benefiter and non-benefiter groups. However, patients with α-diversity within the range of our healthy control had a significantly longer median overall survival (18.9 months), compared to the abnormal group (8.2 months) (p = 0.041, hazard ratio = 0.546) for all patients. The microbiota composition of the benefiters was similar to that of healthy individuals. Furthermore, specific bacteria, such as Prevotella copri and Faecalibacterium prausnitzii, were associated with a favorable outcome. We also observed that serum IL-18 before treatment was significantly lower in the benefiters, compared to non-benefiters.

Conclusions

The α-diversity of gut microbiota is positively correlated with more prolonged overall survival in cancer patients following ICI therapy.

In Saccharomyces cerevisiae, Ras (RAt Sarcoma) activity plays a central role in mediating the effect of glucose in decreasing stress resistance and longevity, with constitutive Ras activation mutations promoting cell growth and oncogenesis. Here, we used transposon mutagenesis in yeast to identify suppressors of the constitutively active Ras2G19V, orthologue of the KRASG12C mammalian oncogene. We identified mutations in YMR1 (Yeast Myotubularin Related), SJL2 (SynaptoJanin-Like) and SJL3 phosphatases, which target phosphatidylinositol phosphates, as the most potent suppressors of constitutive active Ras, able to reverse its effect on stress sensitization and sufficient to extend longevity. In sjl2 mutants, the staining of Ras-GTP switched from membrane-associated to a diffuse cytoplasmic staining, suggesting that it may block Ras activity by preventing its localization. Whereas expression of the Sjl2 PI 3,4,5 phosphatase mediated stress sensitization in both the Ras2G19V and wild type backgrounds, overexpression of the phosphatidylinositol 3 kinase VPS34 (Vacuolar Protein Sorting), promoted heat shock sensitization only in the Ras2G19V background, suggesting a complex relationship between different phosphatidylinositol and stress resistance. These results provide potential targets to inhibit the growth of cancer cells with constitutive Ras activity and link the glucose-dependent yeast pro-aging Ras signaling pathway to the well-established pro-aging PI3K (PhosphoInositide 3-Kinase) pathway in worms and other species raising the possibility that the conserved longevity effect of mutations in the PI3K-AKT (AK strain Transforming) pathway may involve inhibition of Ras signaling.

Background

Human respiratory sensory gating is a neural process associated with inhibiting the cortical processing of repetitive respiratory mechanical stimuli. While this gating is typically examined in the time domain, the neural oscillatory dynamics, which could offer supplementary insights into respiratory sensory gating, remain unknown. The purpose of the present study was to investigate central neural gating of respiratory sensation using both time- and frequency-domain analyses.

Methods

A total of 37 healthy adults participated in this study. Two transient inspiratory occlusions were presented within one inspiration, while responses in the electroencephalogram (EEG) were recorded. N1 amplitudes and oscillatory activities to the first stimulus (S1) and the second stimulus (S2) were measured. The perceived level of breathlessness and level of unpleasantness elicited by the occlusions were measured after the experiment.

Results

As expected, the N1 peak amplitude to the S1 was significantly larger than to the S2. The averaged respiratory sensory gating S2/S1 ratio for the N1 peak amplitude was 0.71. For both the evoked- and induced-oscillations, time-frequency analysis showed higher theta activations in response to S1 relative to S2. A positive correlation was observed between the perceived unpleasantness and induced theta power.

Conclusions

Our results suggest that theta oscillations, evoked as well as induced, reflect the “gating” of respiratory sensation. Theta oscillation, particularly theta-induced power, may be indicative of the emotional processing of respiratory mechanosensation. The findings of this study serve as a foundation for future investigations into the underlying mechanisms of respiratory sensory gating, particularly in patient populations.