Esophageal cancer is a highly invasive malignancy. Neoadjuvant chemoradiotherapy not only increases the rate of complete resection but also improves the median survival. However, a sensitive biomarker is urgently needed in clinical practice. 60 esophageal squamous cell carcinoma (ESCC) patients undergoing neoadjuvant chemoradiotherapy (NCRT) were enrolled at the People's Hospital Affiliated to Jiangsu University. Patients were grouped according to tumor regression grade (TRG) criteria from the College of American Pathologists (CAP). The correlation between TRG groups, clinicopathologic characteristics, and prognosis was analyzed. Differential gene expression analysis was performed on ESCC patients before and after NCRT using the public database (GSE43519). MMP9, NFIX, and GPR56 were identified as candidate genes, and their expression and correlation with prognosis were evaluated by immunohistochemical analysis. Among 60 ESCC patients who underwent surgery after NCRT, the pathological complete response (pCR) rate was 35.0% (21/60), and the major pathological response (MPR) rate was 60.0% (36/60). Poor tumor differentiation and neural or vascular invasion were associated with inadequate tumor regression grade and were independent factors influencing TRG. ESCC patients were divided into effective (TRG 0 + 1) and ineffective (TRG 2 + 3) groups. Higher TRG was significantly associated with shorter overall survival (OS). Our study also identified TRG as an independent prognostic factor through univariate and multivariate Cox regression analyses (P < 0.05). The differentially expressed genes GPR56, MMP9, and NFIX selected from the GSE43519 dataset were significantly downregulated after NCRT (P < 0.001). Immunohistochemistry showed that GPR56 was highly expressed in ESCC, while it was negatively expressed in paracancerous tissues. There was a significant difference in expression between cancerous and paracancerous tissues. GPR56 expression was consistent with the public dataset, and patients with high GPR56 expression had significantly shorter OS (P < 0.05). In addition, patients with inadequate MPR and high GPR56 expression had shorter OS (P < 0.05). The findings suggest that TRG serves as an independent prognostic factor for ESCC following NCRT. High GPR56 expression is found to be associated with a poor prognosis of ESCC. Downregulation of GPR56 suggests a potential significant predictive value in conjunction with MPR analysis.
The timing of meals has been suggested to play an important role in circadian regulation and metabolic health. Three meals a day is a well-established human feeding habit, which in today's lifestyle may or may not be followed. The aim of this study was to test whether the absence of breakfast or supper significantly affects the circadian system and physiological function. The authors developed a rat model for their daily three meals study, whereby animals were divided into three groups (three meals, TM; no first meal, NF; no last meal, NL) all fed with the same amount of food every day. Rats in the NF group displayed significantly decreased levels of plasma triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and glucose in the activity phase, accompanied by delayed circadian phases of hepatic peripheral clock and downstream metabolic genes. Rats in the NL group showed lower concentration of plasma TC, HDL-C, and glucose in the rest phase, plus reduced adipose tissue accumulation and body weight gain. Real-time polymerase chain reaction (PCR) analysis indicated an attenuated rhythm in the food-entraining pathway, including down-regulated expression of the clock genes Per2, Bmal1, and Rev-erbα, which may further contribute to the delayed and decreased expression of FAS in lipogenesis in this group. Our findings are consistent with the conclusion that the daily first meal determines the circadian phasing of peripheral clocks, such as in the liver, whereas the daily last meal tightly couples to lipid metabolism and adipose tissue accumulation, which suggests differential physiological effects and function of the respective meal timings. (Author correspondence: azwfu2003@yahoo.com.cn)
SUMMARY Dec1 and Dec2 are regulators of the mammalian molecular clock that show robust circadian rhythms in the suprachiasmatic nucleus and various peripheral tissues. Although the expression of Dec1 and Dec2 is altered by multiple stimuli in different organs, their transcriptional regulatory mechanisms have not been fully elucidated for the kidney. In the present study, we describe for the first time significant dissociation of expression patterns with arrhythmic expression of Dec1 and rhythmic expression of Dec2 in rat kidney under a normal light–dark (LD) cycle. Daytime restricted feeding (RF) significantly altered the expression patterns of these two clock genes, and even induced circadian expression of Dec1 with an amplitude of 2.2 on day 3 and 4.2 on day 7. However, when a reversed feeding schedule was coupled with a reversed LD cycle, the expression of Dec1 but not Dec2 reverted to being arrhythmic. Moreover, exogenous injection of the glucocorticoid analogue dexamethasone (Dex) at certain times of the day resulted in rhythmic expression of Dec1, which was similar to that seen following RF for 7 days. In contrast, endogenous disruption of glucocorticoids by adrenalectomy abolished RF-induced rhythmic expression of Dec1 in the kidney. These observations suggest the existence of a glucocorticoid gating mechanism in the circadian expression of Dec1 in rat kidney.
Background: Integrated Chinese and Western medicine (integrated medicine) is routinely used in the treatment of coronavirus disease 2019 (COVID-19) in China. In this study, we undertook a systematic review and meta-analysis of published randomized controlled trials (RCTs) to evaluate the efficacy of integrated medicine therapy for patients with COVID-19. Methods: In this meta-analysis, we searched PubMed, Embase, Web of Science, SinoMed, China National Knowledge Infrastructure (CNKI), Chongqing VIP (CQVIP), and Wanfang databases from inception to April 12, 2021, to identify RCTs of integrated medicine in the treatment of COVID-19. The quality of RCTs was assessed by the Cochrane risk of bias tool. RevMan v5.3 and Stata software packages were used for statistical analysis. Results: Nineteen RCTs involving 1,853 patients met our inclusion criteria. Compared with patients treated by conventional Western medicine (CWM), patients treated by integrated medicine have a higher overall effective rate [ RR = 1.17, 95% CI: (1.10, 1.26), p < 0.00001], fever disappearance rate [ RR = 1.25, 95% CI: (1.04, 1.50), p = 0.02], fatigue disappearance rate [ RR = 1.28, 95% CI: (1.00, 1.63), p = 0.05], and chest CT improvement rate [ RR = 1.24, 95% CI: (1.14, 1.34), p < 00001]. Beneficial effects of the integrated medicine therapy were also seen in C-reactive protein (CRP) level [ WMD = −4.14, 95% CI: (−6.38, −1.91), p = 0.0003] and white blood cell (WBC) count [WMD = 0.35, 95% CI: (0.11, 0.58), p = 0.004]. Subgroup analyses showed that, when the treatment time is <2 weeks, the effect of integrated medicine treatment is more obvious in improving the overall effective rate, clinical symptoms (fever, fatigue, and cough), the CRP level, and WBC count compared with that of the CWM treatment. For patients with severe and non-severe COVID-19, integrated medicine is more effective in improving fever and cough symptoms and WBC count than using CWM alone. Conclusion: The results of the current meta-analysis suggested that the integrated medicine can improve the clinical symptoms, chest CT and infection indicators of COVID-19 patients. Even if the treatment time is <2 weeks, the effect of integrated medicine in improving symptoms is more obvious compared with the treatment of CWM. However, the results should be interpreted cautiously due to the heterogeneity among the studies.
Patients with early-onset preeclampsia (EOPE) have a most severe disease state. a2-macroglobulin (A2M) play a crucial role in the pathogenesis of EOPE, but its molecular basis and therapeutic potential remain unclear. This study aimed to elucidate the mechanisms of A2M in EOPE progression and explore the potential of A2M in the treatment of EOPE. A2M-Low Density Lipoprotein Receptor-Related Protein 1 (LRP1) blocker Receptor-associated protein (RAP) were utilized to alleviate the disease symptom of lipopolysaccharide (LPS) induced preeclampsia rat model. RNA-seq data sourced from public databases and morphological experiments were utilized to examine the relationship between the main fate of smooth muscle cell (SMC) during uterine spiral artery remodeling (SPA-REM) and A2M. Proteomic sequencing analysis of A2M overexpression rat placenta was used to identify the underlying mechanism. Further, LC-MS/MS analysis combined with Co-immunoprecipitation (Co-IP) was used to examine the interacting between A2M and underlying mechanism. Single-cell analysis and morphological experimental results suggest that SMC phenotype switching disorder is the main fate of SMC in the pathological of SPA-REM disorder, and A2M has a causal relationship with this process. Proteomic sequencing data suggest that A2M participates in this process through the RhoA-GTPase pathway, further experimental data provide evidences that A2M can directly upregulate RhoA-GTPase. Cytological and explant experiments suggest that RAP has better efficacy than A2M knockdown AAV vector, finally the efficacy of RAP was verified in the rat model of preeclampsia. SMC A2M promotes the progression of preeclampsia by directly upregulating RhoA-GTPase. Our findings also reveal that A2M serve as a potential target for EOPE and provide a preliminary therapy for inhibit the combination of A2M-LRP1.
Diabetic retinopathy(DR) and diabetic nephropathy(DN) are the most common complications of diabetes, and the main causes of death and disability of diabetes. Clinical reports showed that Fufang Xueshuantong capsule(FXT) had effective curative effect on DR and DN, but there was no report on the distribution of chemical compounds of FXT in beagle dog eyes and kidneys. In this study, FXT was given by gavage administration in Beagle dogs for 3 days, and then their eyeballs and kidneys were taken. The chemical compounds in beagle dog eyes and kidneys were detected by HPLC LTQ-Orbitrap technology. Furthermore, by comparing with the data from retrieving literature and references, the chemical compounds were identified by the accurate mass, retention time (tR), and MS/MS. Fourteen and 19 types of notoginsenosides were respectively identified in eyeballs and kidneys in this study, and these results could lay foundation for clarifying the effective ingredients of FXT in treatment of DR and DN.
Thyroid disease and gestational diabetes mellitus (GDM) are frequent complications during pregnancy. We observed the relationship between thyroid indicators and blood glucose to analyze whether thyroid function is associated with the development of GDM. We enrolled a total of 575 pregnant women diagnosed with GDM and 573 pregnant women without GDM. The correlation between thyroid indicators and blood glucose levels was established through correlation analysis. In addition, stratified analysis and restricted cubic spline curves were employed to describe the association between thyroid indicators and the incidence of GDM. We found no significant difference in urine iodine levels between the GDM and non-GDM groups throughout the second trimester. The levels of free triiodothyronine (FT3) and both fasting blood glucose and post-load blood glucose showed a robust positive connection. Thyroid-stimulating hormone (TSH) and free thyroxine (FT4), on the other hand, showed a weakly positive connection with these glucose values. A nonlinear correlation between FT3 and the risk of GDM was also found (pNonlinear=0.0007, p<0.0001). Particularly, those in the top quartile of FT3 had a 6.99-fold greater risk than those in the lowest. Notably, FT3 levels below 4.04 pmol/l were linked to a decreased chance of developing GDM, but levels over 4.04 pmol/l were linked to a greater risk. Our study successfully established the correlation between thyroid indicators and the risk of GDM. Notably, we discovered a non-linear association between FT3 levels and GDM. The study suggests that ensuring optimal thyroid function during pregnancy may decrease the likelihood of developing GDM.
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