Dynamic Changes of Regulatory T Cells/CD4⁺ T Cells in Peripheral Blood of Adult Kidney Transplant Recipients: A Comparison of Pediatric and Adult Kidney Donors.

BACKGROUND Inducing transplantation tolerance and monitoring the recipient's immune status to improve allograft survival remains the main goal for kidney transplantation (KTx). MATERIAL AND METHODS A total of 53 renal transplantation patients and 20 healthy individuals were assigned to the post-transplantation and healthy groups, respectively; 10 recipients with stable renal function for 2 years after kidney transplantation were assigned to Group C. Eleven kidney transplantation recipients were hospitalized due to lung infection. Flow cytometry was used to measure levels of Tregs/CD4⁺ T cells. RESULTS The Tregs/CD4⁺ T cells ratio reached homeostasis 6 months after KTx, with no significant difference between Group D (healthy control group) and pre-surgery or Group C (2 years after KTx group). The pediatric donor group and the adult donor group reached immune homeostasis 3 months after the operation. Immune homeostasis is maintaining a balance between immune tolerance and immunogenicity. There was no significant difference in graft function between the pediatric and adult donor groups before surgery, 1 day after surgery, 1 week after surgery, 2 weeks after surgery, and 1 month after surgery; however, graft function was significantly better in the pediatric donor group compared with the adult donor group at 3 mouths (eGFR: 51.7 (40.4-66.2) vs 73.0 (55.7-90.2), P=0.008<0.05) and 6 months (eGFR: 52.2 (37.5-62.8) vs 80.5 (64.1-90.4), P<0.001) after surgery. Pediatric donor kidneys reached immune homeostasis 3 months after surgery, with better graft function at this time compared with adult donor kidneys. The proportion of Tregs/CD4⁺ T cells in recipients with a pulmonary infection after KTx was lower than in those with infection recovery. CONCLUSIONS Expanding the use of pediatric kidneys should be further explored by the transplantation community. The proportion of Tregs/CD4⁺ T cells in recipients with a pulmonary infection after KTx was lower than in those with infection recovery.

Erratum: PRMT4 promotes hepatocellular carcinoma progression by activating AKT/mTOR signaling and indicates poor prognosis: Erratum.

[This corrects the article DOI: 10.7150/ijms.62467.].

Curculigoside mitigates hepatic ischemia/reperfusion-induced oxidative stress, inflammation, and apoptosis via activation of the Nrf-2/HO-1 pathway.

Curculigoside has been shown to decrease oxidative stress and inflammatory reactions in many disorders, but its effects during hepatic ischemia-reperfusion injury (IRI) remain unknown. This research aims to determine the protective role and the potential mechanism of action of curculigoside in hepatic IRI. Here, a well-established rat model of partial warm IRI was constructed; serum ALT/AST and H&E staining were employed to assay the extent of liver injury; the superoxide dismutase, malondialdehyde, IL-6, and TNF-α contents were determined using the corresponding kits; the apoptosis index was evaluated by TUNEL staining; and the expression of Nrf-2, HO-1, and apoptosis-associated proteins was detected by qRT-PCR and Western blotting. The results showed that curculigoside pretreatment effectively mitigated hepatic IRI, as demonstrated by decreases in the levels of serum aminotransferases, hepatocellular necrosis and apoptosis, oxidative stress markers, infiltration of inflammatory cells, and secretion of proinflammatory cytokines. Mechanistically, the expression of Nrf-2 and HO-1 was greatly suppressed by hepatic IRI and reactivated by curculigoside. Furthermore, cotreatment with ML-385, an inhibitor of Nrf-2, counteracted the protective effect of curculigoside against hepatic IRI. The results of our study show that curculigoside plays a protective role in hepatic IRI by inhibiting oxidative stress, inflammation, and apoptosis and that its effects may be associated with activation of the Nrf-2/HO-1 pathway.

Intake of Dietary Fiber From Grains and the Risk of Hypertension in Late Midlife Women: Results From the SWAN Study.

Background: The possible effects of dietary fiber intake on hypertension have not been clarified fully. The association of dietary fiber intake with hypertension risk in midlife women was analyzed in this study. Methods: Baseline data were obtained from the Study of Women's Health Across the Nation (SWAN). Smooth curve, linear regression, and logistic regression analyses were performed to investigate the associations of four indices of daily dietary estimate (DDE) of dietary fiber (dietary fiber intake, dietary fiber intake from beans, dietary fiber intake from vegetables/fruit, and dietary fiber intake from grains) with blood pressure in midlife women. For this research purpose, diastolic blood pressure (DBP) ≥90 mmHg was defined as diastolic hypertension, and systolic blood pressure (SBP) ≥140 mmHg was defined as systolic hypertension. Results: This study included 2,519 participants with an average age of 46. The smooth curve showed approximate negative correlations between three fiber indices (DDE dietary fiber, DDE fiber from vegetables/fruit, and DDE fiber from grains) and blood pressure, including DBP and SBP (all P < 0.005). There were also approximate negative correlations between two fiber indices (DDE dietary fiber and DDE fiber from grains) and the risk of diastolic hypertension and systolic hypertension (all P < 0.05). Furthermore, multiple linear regression analysis suggested that DDE dietary fiber (Sß = -0.057, 95% CI -0.194 - -0.012, P = 0.027), DDE fiber from vegetables/fruit (Sß = -0.046, 95% CI -0.263 - -0.007, P = 0.039), and DDE fiber from grains (Sß = -0.073, 95% CI -0.600 - -0.099, P = 0.006, Model 4) were still negatively correlated with DBP after adjusting for confounding factors. Only DDE fiber from grains was independently and negatively associated with SBP (Sß = -0.060, 95% CI -0.846 - -0.093, P = 0.015) after these same confounding factors were adjusted for. Importantly, multiple logistic regression analysis suggested that only higher DDE fiber from grains was independently associated with a reduced risk of diastolic hypertension (OR = 0.848, 95% CI 0.770-0.934, P = 0.001, Model 4) and systolic hypertension (OR = 0.906, 95% CI 0.826-0.993, P = 0.034, Model 4) after the adjustments were made for confounding factors. Conclusions: We found that dietary fiber intake, especially DDE fiber from grains, contributes to a lower risk of systolic hypertension and diastolic hypertension in midlife women.

PRMT4 promotes hepatocellular carcinoma progression by activating AKT/mTOR signaling and indicates poor prognosis.

Background: Protein arginine methyltransferase 4 (PRMT4) has been reported to play a role in several common cancers; however, the function and mechanism of PRMT4 in hepatocellular carcinoma (HCC) are not fully understood. This study aimed to investigate the role and mechanism of PRMT4 in the progression of HCC. Methods: PRMT4 expression and clinicopathological characteristics were investigated using an HCC tissue microarray (TMA) consisting of 140 patient samples analyzed by immunohistochemistry. CCK-8, crystal violet and Transwell assays were used to determine cell proliferation, colony formation, migration, and invasion of HCC cell lines in which PRMT4 was overexpressed or downregulated. The underlying mechanism of PRMT4 function was explored by Western blot assays. Results: PRMT4 was highly expressed in HCC tumor tissues compared to adjacent nontumor tissues. PRMT4 expression was significantly associated with alpha-fetoprotein levels, tumor size, satellite nodules, and microvascular invasion. Patients with higher PRMT4 expression had a shorter survival time and higher recurrence rate. Functional studies demonstrated that PRMT4 overexpression promoted HCC cell proliferation, migration, and invasion in vitro, while knocking down PRMT4 inhibited these malignant behaviors. Additional results revealed that PRMT4 promoted the progression of HCC cells via activation of the AKT/mTOR signaling pathway. Furthermore, inhibition of the AKT/mTOR signaling by MK2206 or rapamycin significantly attenuated PRMT4-mediated malignant phenotypes. Conclusions: This study suggests that PRMT4 may promote the progression of HCC cells by activating the AKT/mTOR signaling pathway, which may be a valuable biomarker and potential target for HCC.

Long non-coding RNA VCAN-AS1 promotes the malignant behaviors of breast cancer by regulating the miR-106a-5p-mediated STAT3/HIF-1α pathway.

An accumulating number of studies have found that long noncoding RNAs (lncRNAs) participate in breast cancer (BC) development. LncRNA VCAN-AS1, a novel lncRNA, has been confirmed to regulate the progression of gastric cancer, while its role in BC is elusive. Here, our results illustrate that VCAN-AS1 is overexpressed in BC tissues and cells, while miR-106a-5p was downregulated and negatively correlated with VCAN-AS1. In addition, high VCAN-AS1 expression and low miR-106a-5p expression were closely correlated with poor overall survival in BC patients. Functional experiments confirmed that VCAN-AS1 overexpression notably accelerated BC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) and enhanced tumor cell growth while also suppressing cell apoptosis. However, overexpression of miR-106a-5p had the opposite effects. In addition, rescue experiments confirmed that overexpression of VCAN-AS1 inhibited the tumor-suppressive effects mediated by miR-106a-5p. Mechanistically, through bioinformatics analysis, we found that VCAN-AS1 functions as a competitive endogenous RNA (ceRNA) of miR-106a-5p, which targets the 3' untranslated region (UTR) of signal transducer and activator of transcription 3 (STAT3). Further experiments indicated that miR-106a-5p downregulated the STAT3/hypoxia-inducible factor-1alpha (HIF-1α) pathway, while activating the STAT3 pathway reversed miR-106a-5p-mediated antitumor effects. Collectively, our data suggest that VCAN-AS1 is upregulated in breast cancer and promotes its progression by regulating the miR-106a-5p-mediated STAT3/HIF-1α pathway. This study provides a new target for BC therapy.

Hypoxia-inducible factor-1alpha protects the liver against ischemia-reperfusion injury by regulating the A2B adenosine receptor.

Hepatic ischemia-reperfusion injury (IRI) is an inevitable complication associated with liver surgical procedures, and its pathological process remains elusive. Therefore, the present study investigated the role and mechanism of hypoxia-inducible factor-1alpha (HIF-1α) in hepatic IRI. Here, we constructed rat models with hepatic IRI and BRL-3A cell models with hypoxia/reoxygenation (H/R) insult. The extent of liver injury was assayed by measuring serum ALT/AST levels and performing H&E staining; the levels of SOD, MDA, MPO, IL-6 and TNF-α were determined using commercial kits; apoptosis was detected using the TUNEL assay and flow cytometry; and the expression of HIF-1α/A2BAR signaling-related molecules and apoptosis-associated indicators was detected using Western blotting or qRT-PCR. The expression level of HIF-1α was significantly upregulated in the liver of rats subjected to IRI, as well as in BRL-3A cells treated with H/R. HIF-1α overexpression exerted a protective effect on hepatic IRI or H/R insult by reducing serum aminotransferase levels and hepatic necrosis, inhibiting inflammation and apoptosis of hepatocytes, and alleviating oxidative stress. In contrast, inhibition of HIF-1α expression exacerbated hepatic injury induced by IR or H/R. Mechanistically, the expression level of A2BAR was markedly increased during hepatic IRI or H/R insult. Moreover, A2BAR expression increased with HIF-1α upregulation and decreased with HIF-1α downregulation. Importantly, inhibition of A2BAR signaling abolished HIF-1α overexpression-mediated hepatoprotection. Taken together, HIF-1α exerts protective effects on hepatic IRI by attenuating liver necrosis, the inflammatory response, oxidative stress and apoptosis, and its mechanism may be related to the upregulation of A2BAR signaling.

Negative Plant-Soil Feedback Driven by Re-assemblage of the Rhizosphere Microbiome With the Growth of Panax notoginseng.

There is a concerted understanding of the accumulation of soil pathogens as the major driving factor of negative plant-soil feedback (NPSF). However, our knowledge of the connection between plant growth, pathogen build-up and soil microbiome assemblage is limited. In this study, significant negative feedback between the soil and sanqi (Panax notoginseng) was found, which were caused by the build-up of the soil-borne pathogens Fusarium oxysporum, F. solani, and Monographella cucumerina. Soil microbiome analysis revealed that the rhizospheric fungal and bacterial communities were changed with the growth of sanqi. Deep analysis of the phylum and genus levels corroborated that rhizospheric fungal Ascomycota, including the soil-borne pathogens F. oxysporum, F. solani, and especially M. cucumerina, were significantly enriched with the growth of sanqi. However, the bacteria Firmicutes and Acidobacteria, including the genera Pseudomonas, Bacillus, Acinetobacter and Burkholderia, were significantly suppressed with the growth of sanqi. Using microbial isolation and in vitro dual culture tests, we found that most isolates derived from the suppressed bacterial genera showed strong antagonistic ability against the growth of sanqi soil-borne pathogens. Interestingly, inoculation of these suppressed isolates in consecutively cultivated soil could significantly alleviate NPSF. In summary, sanqi growth can suppress antagonistic bacteria through re-assemblage of the rhizosphere microbiome and cause the accumulation of soil-borne pathogens, eventually building negative feedback loops between the soil and plants.