The senescence of renal tubular epithelial cells (RTECs) is crucial in the progression of diabetic kidney disease (DKD). Accumulating evidence suggests a close association between insufficient ...mitophagy and RTEC senescence. Yeast mitochondrial escape 1-like 1 (YME1L), an inner mitochondrial membrane metalloprotease, maintains mitochondrial integrity. Its functions in DKD remain unclear. Here, we investigated whether YME1L can prevent the progression of DKD by regulating mitophagy and cellular senescence.
We analyzed YME1L expression in renal tubules of DKD patients and mice, explored transcriptomic changes associated with YME1L overexpression in RTECs, and assessed its impact on RTEC senescence and renal dysfunction using an HFD/STZ-induced DKD mouse model. Tubule-specific overexpression of YME1L was achieved through the use of recombinant adeno-associated virus 2/9 (rAAV 2/9). We conducted both in vivo and in vitro experiments to evaluate the effects of YME1L overexpression on mitophagy and mitochondrial function. Furthermore, we performed LC-MS/MS analysis to identify potential protein interactions involving YME1L and elucidate the underlying mechanisms.
Our findings revealed a significant decrease in YME1L expression in the renal tubules of DKD patients and mice. However, tubule-specific overexpression of YME1L significantly alleviated RTEC senescence and renal dysfunction in the HFD/STZ-induced DKD mouse model. Moreover, YME1L overexpression exhibited positive effects on enhancing mitophagy and improving mitochondrial function both in vivo and in vitro. Mechanistically, our LC-MS/MS analysis uncovered a crucial mitophagy receptor, BCL2-like 13 (BCL2L13), as an interacting partner of YME1L. Furthermore, YME1L was found to promote the phosphorylation of BCL2L13, highlighting its role in regulating mitophagy.
This study provides compelling evidence that YME1L plays a critical role in protecting RTECs from cellular senescence and impeding the progression of DKD. Overexpression of YME1L demonstrated significant therapeutic potential by ameliorating both RTEC senescence and renal dysfunction in the DKD mice. Moreover, our findings indicate that YME1L enhances mitophagy and improves mitochondrial function, potentially through its interaction with BCL2L13 and subsequent phosphorylation. These novel insights into the protective mechanisms of YME1L offer a promising strategy for developing therapies targeting DKD.
Brassica rapa includes several important leafy vegetable crops with the potential for high cadmium (Cd) accumulation, posing a risk to human health. This study aims to understand the genetic basis ...underlying the variation in Cd accumulation among B. rapa vegetables. Cd uptake and translocation in 64 B. rapa accessions were compared. The role of the heavy metal ATPase gene BrHMA3 in the variation of Cd accumulation was investigated. BrHMA3 encodes a tonoplast-localized Cd transporter. Five full-length and four truncated haplotypes of the BrHMA3 coding sequence were identified, explaining >80% of the variation in the Cd root to shoot translocation among the 64 accessions and in F2 progeny. Truncated BrHMA3 haplotypes had a 2.3 and 9.3 times higher shoot Cd concentration and Cd translocation ratio, respectively, than full-length haplotypes. When expressed in yeast and Arabidopsis thaliana, full-length BrHMA3 showed activity consistent with a Cd transport function, whereas truncated BrHMA3 did not. Variation in the BrHMA3 promoter sequence had little effect on Cd translocation. Variation in the BrHMA3 coding sequence is a key determinant of Cd translocation to and accumulation in the leaves of B. rapa. Strong alleles of BrHMA3 can be used to breed for B. rapa vegetables that are low in Cd in their edible portions.
Abstract Multiple myeloma (MM) is a plasma cell disorder accounting for approximately 10% of hematologic malignancies. There is limited epidemiological evidence regarding the long-term trends and ...disparities in MM in the US. We conducted a multiple time point cross-sectional study using MM incidence rate data from the Surveillance, Epidemiology, and End Results (SEER) database and mortality data from the CDC Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) Underlying Cause of Death database between 1999 and 2020. During this period, MM incidence has steadily increased, while MM mortality has steadily decreased, with substantial racial and ethnic disparities. Non-Hispanic Black individuals exhibited the highest incidence rates, which consistently rose from 12.02 (95% CI 10.54, 13.64) in 1999 to 14.20 (95% CI 12.93, 15.55) per 100,000 population by 2020. Non-Hispanic American Indian/Native Alaskans and Asian/Pacific Islanders demonstrated the lowest incidence rates of 5.59 (95% CI 2.69, 10.04) and 3.56 (95% CI 2.94, 4.27) per 100,000 population in 1999 to 5.76 (95% CI 3.49, 8.90) and 3.92 (95% CI 3.46, 4.42) per 100,000 population, respectively, by 2020. Disparities by gender, age, US census region, and rurality were observed, underscoring the importance of targeted, equity-centered interventions and MM screening initiatives for at-risk populations.
5-10% of patients are diagnosed with metastatic breast cancer (MBC) at the initial diagnosis. This study aimed to develop a nomogram to predict the overall survival (OS) of these patients.
de novo ...MBC patients diagnosed in 2010-2016 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. They were randomly divided into a training and a validation cohort with a ratio of 2:1. The best subsets of covariates were identified to develop a nomogram predicting OS based on the smallest Akaike Information Criterion (AIC) value in the multivariate Cox models. The discrimination and calibration of the nomogram were evaluated using the Concordance index, the area under the time-dependent receiver operating characteristic curve (AUC) and calibration curves.
In this study, we included 7986 patients with de novo MBC. The median follow-up time was 36 months (range: 0-83 months). Five thousand three-hundred twenty four patients were allocated into the training cohort while 2662 were allocated into the validation cohort. In the training cohort, age at diagnosis, race, marital status, differentiation grade, subtype, T stage, bone metastasis, brain metastasis, liver metastasis, lung metastasis, surgery and chemotherapy were selected to create the nomogram estimating the 1-, 3- and 5- year OS based on the smallest AIC value in the multivariate Cox models. The nomogram achieved a Concordance index of 0.723 (95% CI, 0.713-0.733) in the training cohort and 0.719 (95% CI, 0.705-0.734) in the validation cohort. AUC values of the nomogram indicated good specificity and sensitivity in the training and validation cohort. Calibration curves showed a favorable consistency between the predicted and actual survival probabilities.
The developed nomogram reliably predicted OS in patients with de novo MBC and presented a favorable discrimination ability. While further validation is needed, this may be a useful tool in clinical practice.
Gallbladder cancer (GBC) is the most prevalent and invasive biliary tract malignancy. As a GTPase-activating protein, Neurofibromin 1 (NF1) is a tumor suppressor that negatively regulates the RAS ...signaling pathway, and its abnormality leads to neurofibromatosis type 1 (NF-1) disease. However, the role of NF1 playing in GBC and the underlying molecular mechanism has not been defined yet.
A combination of NOZ and EH-GB1 cell lines as well as nude mice, were utilized in this study. mRNA expression and protein levels of NF1 and YAP1 were evaluated by quantitative real-time PCR (qRT-PCR), western blot (WB), and immunohistochemistry (IHC). In vitro and in vivo assays were performed to explore the biological effects of NF1 in NOZ and EH-GB1 cells via siRNA or lv-shRNA mediated knockdown. Direct interaction between NF1 and YAP1 was detected by confocal microscopy and co-immunoprecipitation (Co-IP), and further confirmed by GST pull-down assay and isothermal titration calorimetry assay (ITC). The stability of proteins was measured by western blot (WB) in the presence of cycloheximide.
This study showed that a higher level of NF1 and YAP1 was found in GBC samples than in normal tissues and associated with worse prognoses. The NF1 knockdown impaired the proliferation and migration of NOZ in vivo and in vitro by downregulating YAP1 expression. Moreover, NF1 co-localized with YAP1 in NOZ and EH-GB1 cells, and the WW domains of YAP1 specifically recognized the PPQY motif of NF1. The structural modeling also indicated the hydrophobic interactions between YAP1 and NF1. On the other hand, YAP1 knockdown also impaired the proliferation of NOZ in vitro, phenocopying the effects of NF1 knockdown. Overexpression of YAP1 can partially rescue the impaired proliferation in NF1 stably knockdown cells. In mechanism, NF1 interacted with YAP1 and increased the stability of YAP1 by preventing ubiquitination.
Our findings discovered a novel oncogenic function of NF1 by directly interacting with YAP1 protein and stabilizing YAP1 to protect it from proteasome degradation in NOZ cells. NF1 may serve as a potential therapeutic target in GBC.
The accumulation of cadmium in rice (
L.) and wheat (
L.) is a serious threat to the safe use of farmland and to the health of the human diet that has attracted extensive attention from researchers. ...In this review, a bibliometric analysis was performed using a VOS viewer (1.6.18, Netherlands) to investigate the status of cadmium contamination in rice and wheat growing systems, human health risks, mechanisms of Cd uptake and transport, and the corresponding research hotspots. It has a certain reference value for the prevention and control of cadmium pollution in rice and wheat planting systems in China and abroad. The results showed that the Cd content in rice and wheat planting systems in the Yangtze River Basin was significantly higher than that in other areas of China, and the Cd content in rice and wheat grains and the hazard quotient (
) in Hunan Province was the highest. The average Cd concentration exceeded the recommended limit by about 62% for rice and 81% for wheat. The main reasons for the high Cd pollution in rice and wheat growing areas in Hunan are mining activities, phosphate fertilizer application, sewage irrigation, and electronic equipment manufacturing. In this review, we demonstrate that cadmium toxicity reduces the uptake and transport of essential elements in rice and wheat. Cadmium stress seriously affected the growth and morphology of plant roots. In the shoots, Cd toxicity was manifested by a series of physiological injuries, such as decreased photosynthesis, soluble protein, sugar, and antioxidant enzyme activity. Cadmium that accumulates in the shoots is transferred to grains and then passes up the food chain to people and animals. Therefore, methods for reducing cadmium content in grains of rice and wheat are urgently needed, especially in Cd-contaminated soil. Current research on Cd pollution in rice and wheat planting systems focuses on the bioavailability of Cd, soil rhizosphere changes in wheat and rice, and the role of antioxidant enzyme systems in alleviating heavy metal stress in rice and wheat.
Biodetoxification fungus selectively degrades toxic inhibitors generated from pretreatment of lignocellulose without consuming fermentable sugars. However, one barrier for practical application is ...the sustained cell viability in the consequent fermentation step to compete the fermentable sugars with fermenting strains, resulting in sugar loss and reduced target product yield. This study investigated the competitive growth property between the biodetoxification fungus
Paecilomyces variotii
FN89 and the L-lactic acid bacterium
Pediococcus acidilactici
ZY271 under varying temperature and lactic acid osmatic stress. The results show that the L-lactic acid bacterium
Ped. acidilactici
ZY271 showed less thermotolerance to
Pae. variotii
FN89 at high temperature of 45 °C to 50 °C in both synthetic medium and wheat straw hydrolysate. In the higher temperature environment, the growth of the biodetoxification strian failed to compete with the lactic acid fermentation strain and was quickly eliminated from the fermentation system. The high temperature fermentation facilitated a fast transition from the detoxification stage to the fermentation stage for higher production of L-lactic acid.
Both genetic and environmental factors are implicated in type 1 diabetes (T1D). Because environmental factors can trigger epigenetic changes, we hypothesized that variations in histone ...post-translational modifications (PTMs) at the promoter/enhancer regions of T1D susceptible genes may be associated with T1D. We therefore evaluated histone PTM variations at known T1D susceptible genes in blood cells from T1D patients versus healthy nondiabetic controls, and explored their connections to T1D. We used the chromatin immunoprecipitation-linked to microarray approach to profile key histone PTMs, including H3-lysine 4 trimethylation (H3K4me3), H3K27me3, H3K9me3, H3K9 acetylation (H3K9Ac), and H4K16Ac at genes within the T1D susceptible loci in lymphocytes, and H3K4me3, H3K9me2, H3K9Ac, and H4K16Ac at the insulin-dependent diabetes mellitus 1 region in monocytes of T1D patients and healthy controls separately. We screened for potential variations in histone PTMs using computational methods to compare datasets from T1D and controls. Interestingly, we observed marked variations in H3K9Ac levels at the upstream regions of HLA-DRB1 and HLA-DQB1 within the insulin-dependent diabetes mellitus 1 locus in T1D monocytes relative to controls. Additional experiments with THP-1 monocytes demonstrated increased expression of HLA-DRB1 and HLA-DQB1 in response to interferon-γ and TNF-α treatment that were accompanied by changes in H3K9Ac at the same promoter regions as that seen in the patient monocytes. These results suggest that the H3K9Ac status of HLA-DRB1 and HLA-DQB1, two genes highly associated with T1D, may be relevant to their regulation and transcriptional response toward external stimuli. Thus, the promoter/enhancer architecture and chromatin status of key susceptible loci could be important determinants in their functional association to T1D susceptibility.
Both genetic and epigenetic factors are implicated in Type 1 diabetes (T1D).
Variations in histone H3-lysine 9 acetylation are detected around the promoter/enhancer regions of key T1D susceptible genes in monocytes of T1D subjects versus normals.
The chromatin status of this key region is altered in T1D.
Epigenetic variations at T1D susceptible genes may be functionally important.
The Fufang Danshen formula is a clinically important anti-atherosclerotic preparation in traditional Chinese medicine. However, its anti-atherosclerotic effect is not well recognized, and the ...mechanisms of its combined active ingredients, namely Ginsenoside Rg1-Notoginsenoside R1-Protocatechuic aldehyde (RRP), remain unclear. The purpose of this study was to investigate the anti-atherosclerotic effects and potential mechanism of RRP in ApoE
mice and in low-shear stress-injured vascular endothelial cells.
ApoE
mice were randomly divided into three groups: model group, rosuvastatin group, and RRP group, with C57BL/6J mice as the control group. Oil-red O, hematoxylin and eosin, Masson, and Movat staining were utilized for the observation of aortic plaque. Changes in the blood lipid indexes were observed with an automatic biochemistry analyzer. ET-1, eNOS, TXA
, and PGI
levels were analyzed by enzyme-linked immunosorbent assay.
, a fluid shear stress system was used to induce cell injury. Piezo1 expression in HUVECs was silenced using siRNA. Changes in morphology, proliferation, migration, and tube formation activity of cells were observed after RRP treatment. Quantitative Real-Time PCR and western blot analysis were employed to monitor mRNA and protein expression.
RRP treatment reduced the atherosclerotic area and lipid levels and improved endothelial function in ApoE
mice. RRP significantly repaired cell morphology, reduced excessive cell proliferation, and ameliorated migration and tube formation activity. In addition, RRP affected the FAK-PI3K/Akt signaling pathway. Importantly, Piezo1 silencing abolished the protective effects of RRP.
RRP has anti-atherosclerotic effects and antagonizes endothelial cell damage via modulating the FAK-PI3K/Akt signaling pathway. Piezo1 is a possible target of RRP in the treatment of atherosclerosis. Thus, RRP has promising therapeutic potential and broad application prospect for atherosclerosis.
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