Prognostic stratification of sepsis through DNA damage response based RiskScore system: insights from single-cell RNA-sequencing and transcriptomic profiling.

Background: A novel risk scoring system, predicated on DNA damage response (DDR), was developed to enhance prognostic predictions and potentially inform the creation of more effective therapeutic protocols for sepsis. Methods: To thoroughly delineate the expression profiles of DDR markers within the context of sepsis, an analytical approach utilizing single-cell RNA-sequencing (scRNA-seq) was implemented. Our study utilized single-cell analysis techniques alongside weighted gene co-expression network analysis (WGCNA) to pinpoint the genes that exhibit the most substantial associations with DNA damage response (DDR). Through Cox proportional hazards LASSO regression, we distinguished DDR-associated genes and established a risk model, enabling the stratification of patients into high- and low-risk groups. Subsequently, we carried out an analysis to determine our model's predictive accuracy regarding patient survival. Moreover, we examined the distinct biological characteristics, various signal transduction routes, and immune system responses in sepsis patients, considering different risk categories and outcomes related to survival. Lastly, we conducted experimental validation of the identified genes through in vivo and in vitro assays, employing RT-PCR, ELISA, and flow cytometry. Results: Both single-cell RNA sequencing (scRNA-seq) and bulk transcriptomic analyses have demonstrated a strong correlation between DNA damage response (DDR) levels and sepsis prognosis. Specific cell subtypes, including monocytes, megakaryocytes, CD4+ T cells, and neutrophils, have shown elevated DDR activity. Cells with increased DDR scores exhibited more robust and numerous interactions with other cell populations. The weighted gene co-expression network analysis (WGCNA) and single-cell analyses revealed 71 DDR-associated genes. We developed a four-gene risk scoring system using ARL4C, CD247, RPL7, and RPL31, identified through univariate COX, LASSO COX regression, and log-rank (Mantel-Cox) tests. Nomograms, calibration plots, and decision curve analyses (DCA) regarding these specific genes have provided significant clinical benefits for individuals diagnosed with sepsis. The study suggested that individuals categorized as lower-risk demonstrated enhanced infiltration of immune cells, upregulated expression of immune regulators, and a more prolific presence of immune-associated functionalities and pathways. RT-qPCR analyses on a sepsis rat model revealed differential gene expression predominantly in the four targeted genes. Furthermore, ARL4C knockdown in sepsis model in vivo and vitro caused increased inflammatory response and a worse prognosis. Conclusion: The delineated DDR expression landscape offers insights into sepsis pathogenesis, whilst our riskScore model, based on a robust four-gene signature, could underpin personalized sepsis treatment strategies.

Widowed status increases the risk of death in vulvar cancer.

AIM: To evaluate the effect of marital status on survival of patients with vulvar cancer. MATERIALS & METHODS: A total of 4001 patients with vulvar cancer were included from the SEER database. Statistical analyses were performed using χ2 test, Kaplan-Meier method, Cox regression proportional hazards and a 1:1 propensity score-matching. RESULTS: The 8-year vulvar cancer-related survival in married, divorced, single and widowed patients were 78.6, 82.2, 78.9 and 61.6%, respectively (p < 0.001). In multivariate analysis, widows patients had significantly worse vulvar cancer survival than the nonwidowed counterparts in unmatched and matched populations. CONCLUSION: Being widowed is associated with greater risk of vulvar cancer mortality than the nonwidowed counterparts.

Tetrahydrocurcumin Provides Neuroprotection in Experimental Traumatic Brain Injury and the Nrf2 Signaling Pathway as a Potential Mechanism.

The protective effect of tetrahydrocurcumin (THC) after experimental traumatic brain injury (TBI) has been demonstrated, as demonstrated by the inhibition of oxidative stress, mitochondrial dysfunction, and apoptosis. However, the mechanisms underlying this effect are still not well understood. This study was to investigate the neuroprotective effects of THC, and its potential mechanisms, in a rat model of TBI. To this end, rats were divided into 4 groups: the sham group, the TBI group, the TBI + vehicle (V) group, and the TBI + THC group. THC or V was administered via intraperitoneal injection to rats in the TBI + V and TBI + THC groups 30 min after TBI. After euthanasia (24 h after TBI), neurological scores, brain water content, and neuronal cell death in the cerebral cortex were recorded. Brain samples were collected after neurological scoring for further analysis. THC treatment alleviated brain edema, attenuated TBI-induced neuronal cell apoptosis, and improved neurobehavioral function. In addition, NFE2-related factor 2 (Nrf2) expression was upregulated following TBI. These results suggest that THC improves neurological outcome after TBI, possibly by activating the Nrf2 signaling pathway.

Preparation and evaluation of dl-praeruptorin A microemulsion based hydrogel for dermal delivery.

The purpose of the present investigation was to develop and optimize the microemulsion (ME) as a transdermal system for Pd-Ia, a poor water soluble and low bioavailable drug. The pseudo-ternary phase diagrams were constructed for various ME formulations including oleic acid as the oil phase, Cremophor RH40 as the surfactant, ethanol as the cosurfactant, and water. The maximum cumulative amount permeated through rat abdominal skins per unit area in 32 h (Q32), and the maximum flux were evaluated using the Franz diffusion cell in order to optimize the ME formulation. The results indicated that the optimized ME formulation was composed of oleic acid (5%, W/W), Cremophor RH40 (13.33%, W/W), ethanol (26.67%, W/W), and water (55%, W/W); the maximum cumulative amount of Pd-Ia was 354.330 ± 12.006 µg cm(-2), the maximum flux was 11.467 ± 0.500 µg cm(-2)h(-1). ME-gel was administered transdermally to rats. The mean plasma concentration of Pd-Ia following transdermal application of ME-gel could be maintained for 32 h at least and the half-life was evidently prolonged. It shows that the ME-gel could be a promising vehicle for dermal delivery of Pd-Ia.