Simvastatin suppresses the DNA replication licensing factor MCM7 and inhibits the growth of tamoxifen-resistant breast cancer cells

Acquired tamoxifen resistance (TamR) remains a major challenge in breast cancer endocrine therapy. The mechanism of acquiring tamoxifen resistance remains elusive, and no effective drugs are available. In this investigation, we determined that the expression of the DNA damage marker γH2AX is upregulated under minichromosome maintenance protein 7 (MCM7) knockdown in phospho Ser807/811-retinoblastoma protein (p-Rb) defect cells. In addition, the expression of p-Rb was lower in TamR cells than in parental cells, and the expression of γH2AX was significantly upregulated when MCM7 was knocked down in TamR cells. Simvastatin, an agent for hypercholesterolemia treatment, activated the MCM7/p-RB/γH2AX axis and induced DNA damage in TamR cells, especially when combined with tamoxifen. Finally, in vitro and in vivo experiments demonstrated that simvastatin combined with tamoxifen increased TamR cell apoptosis and inhibited xenograft growth. In conclusion, simvastatin may suppress TamR cell growth by inhibiting MCM7 and Rb and subsequently inducing DNA damage

Simvastatin and Atorvastatin inhibit DNA replication licensing factor MCM7 and effectively suppress RB-deficient tumors growth

Loss or dysfunction of tumor suppressor retinoblastoma (RB) is a common feature in various tumors, and contributes to cancer cell stemness and drug resistance to cancer therapy. However, the strategy to suppress or eliminate Rb-deficient tumor cells remains unclear. In the present study, we accidentally found that reduction of DNA replication licensing factor MCM7 induced more apoptosis in RB-deficient tumor cells than in control tumor cells. Moreover, after a drug screening and further studies, we demonstrated that statin drug Simvastatin and Atorvastatin were able to inhibit MCM7 and RB expressions. Further study showed that Simvastatin and Atorvastatin induced more chromosome breaks and gaps of Rb-deficient tumor cells than control tumor cells. In vivo results showed that Simvastatin and Atorvastatin significantly suppressed Rb-deficient tumor growth than control in xenograft mouse models. The present work demonstrates that ‘old' lipid-lowering drugs statins are novel weapons against RB-deficient tumors due to their effects on suppressing MCM7 protein levels

Probiotics partially attenuate the severity of acute kidney injury through an immunomodulatory effect

Background A healthy microbiome helps maintain the gut barrier and mucosal immune tolerance. Previously, we demonstrated that acute kidney injury (AKI) provoked dysbiosis, gut inflammation, and increased permeability. Here, we investigated the renoprotective effects of the probiotic Bifidobacterium bifidum BGN4 and the underlying mechanisms thereof. Methods C57BL/6 mice were subjected to bilateral renal ischemia-reperfusion injury (IRI) or sham operation. In the probiotic-treated group, BGN4 was administered by gavage once daily, starting 2 weeks before injury. Results Administration of BGN4 significantly increased gut microbiome diversity and prevented expansion of the Enterobacteriaceae and Bacteroidetes that were the hallmarks of AKI-induced dysbiosis. Further, BGN4 administration also significantly reduced other IRI-induced changes in the colon microenvironment, including effects on permeability, apoptosis of colon epithelial cells, and neutrophil and proinflammatory macrophage infiltration. Mononuclear cells co-cultured with BGN4 expressed significantly increased proportions of CD103+/CD11c+ and CD4+ CD25+ Treg cells, suggesting a direct immunomodulatory effect. BGN4 induced Treg expansion in colon, mesenteric lymph nodes (MNL), and kidney. BGN4 also reduced CX3CR1intermediateLy6Chigh monocyte infiltration and interleukin (IL)-17A suppression in the small intestine, which may have attenuated AKI severity, kidney IL-6 messenger RNA expression, and AKI-induced liver injury. Conclusion Prior supplementation with BGN4 significantly attenuated the severity of IRI and secondary liver injury. This renoprotective effect was associated with increased Foxp3 and reduced IL-17A expression in the colon, MNL, and kidney, suggesting that BGN4-induced immunomodulation might contribute to its renoprotective effects. Probiotics may therefore be a promising strategy to reduce AKI severity and/or remote organ injury

Altered gut microbiome plays an important role in AKI to CKD transition in aged mice

IntroductionThis study investigated the role of renal-intestinal crosstalk in the transition from acute kidney injury (AKI) to chronic kidney disease (CKD) in elderly individuals.MethodsUsing young and aged mice, we induced bilateral ischemia-reperfusion injury (IRI) and compared intestinal and kidney inflammation over 28 days. To determine the role of the microbiome in gut–kidney crosstalk, we analyzed the microbiome of fecal samples of the young vs. aged mice and examined the effects of probiotic supplementation.ResultsIn the post-IRI recovery phase, prolonged intestinal and renal inflammation along with dysbiosis were evident in aged vs. younger mice that was associated with severe renal dysfunction and fibrosis progression in aged mice. Probiotic supplementation with Bifidobacterium bifidum BGN4 and Bifidobacterium longum BORI alleviated intestinal inflammation but not intestinal leakage, characterized by decreased inflammatory cytokine levels and decreased infiltration of macrophages, neutrophils, and Th17 cells. This was associated with improved M1-dominant renal inflammation and ultimately improved renal function and fibrosis, suggesting that renal–intestinal crosstalk in aged mice contributes to the transition from AKI to CKD.DiscussionOur study findings suggest that exacerbation of chronic inflammation through the gut–kidney axis might be an important mechanism in the transition from AKI to CKD in the elderly

Effects of pH on nitrogen transformations in media-based aquaponics

International audience•Aquaponics could tolerate a wide range of pH from 6.0 to 9.0.•Higher nitrogen utilization efficiency and N2O emission were achieved at pH 6.0.•Denitrification accounted for 75.2–78.5% of N2O emission from aquaponics.•Unfavorable conditions for denitrifiers led to higher N2O emission at pH 6.0. To investigate the effects of pH on performance and nitrogen transformations in aquaponics, media-based aquaponics operated at pH 6.0, 7.5 and 9.0 were systematically examined and compared in this study. Results showed that nitrogen utilization efficiency (NUE) reached its maximum of 50.9% at pH 6.0, followed by 47.3% at pH 7.5 and 44.7% at pH 9.0. Concentrations of nitrogen compounds (i.e., TAN, NO2−-N and NO3−-N) in three pH systems were all under tolerable levels. pH had significant effect on N2O emission and N2O conversion ratio decreased from 2.0% to 0.6% when pH increased from 6.0 to 9.0, mainly because acid environment would inhibit denitrifiers and lead to higher N2O emission. 75.2–78.5% of N2O emission from aquaponics was attributed to denitrification. In general, aquaponics was suggested to maintain pH at 6.0 for high NUE, and further investigations on N2O mitigation strategy are needed

Pregnancy‐related knowledge in women with epilepsy in childbearing age: A pilot questionnaire survey from China

Abstract Purpose We aim to understand the knowledge of and attitudes toward pregnancy issues among women with epilepsy (WWE) and their caregivers and analyze the answers from the questionnaire to expose topics that require educational activities; thus, WWE experiences pregnancy better. Methods WWE at their childbearing age and/or their caregivers who entered the Fourth Affiliated Hospital of Zhejiang University for treatment of their condition were invited to fill out a questionnaire between March 1 and November 31, 2022. Results A combined total of 205 WWE and 142 caregivers completed the questionnaires. Among the surveyed WWE, a majority (63.74%) reported experiencing at least one miscarriage or induced abortion. However, a significant proportion (84.62%) of these WWE were still able to successfully give birth to at least one child. Furthermore, the offspring of these WWE showed no significant differences compared to the offspring of women without epilepsy, as reported by 93.51% of the participants. The participants’ knowledge regarding the impact of epilepsy on pregnancy was found to be comparable, with average scores of 7.74 and 7.84, respectively. The participants exhibited a limited comprehension of antiseizure medications (ASMs)‐related knowledge, specifically pertaining to ASMs adjustment during pregnancy (17.56% vs. 16.90%) and offspring outcomes (30.24% vs. 26.06%). Statistical analysis revealed significant correlations between the overall score and education level (p < .001), as well as epilepsy duration (p = .008). Regarding the source of knowledge, participants acknowledged primarily relying on neurologists, who remained their preferred choice for consultation. Conclusion In our study, the understanding of pregnancy‐related knowledge did not differ from WWE and their caregivers, both are far from satisfactory in certain areas. It is urgent for WWE and their caregivers to improve their pregnancy‐related knowledge of epilepsy. As their primary access is from knowledgeable health care professionals like neurologists, well‐trained neurologists in epilepsy management during pregnancy are in need

Linear and non-linear dynamics of ecosystem services supply, demand, and mismatches across a rapidly urbanizing region

Achieving the sustainability of coupled human-nature systems requires matching the ecosystem services (ES) provided by nature to the needs of society. However, most of the current studies on ES supply–demand relationships focus on spatial mismatches and rarely consider their temporal dynamics. In this study, the year-by-year dynamics (2001–2020) of 12 ESs at multiple spatial scales were investigated by using space–time interaction (STI) analysis, fuzzy C-mean clustering, and emerging hotspot analysis. We found that (1) three forms of temporal dynamics of ES indicators can be identified, including linear dynamics, fluctuating dynamics, and regime shift dynamics. (2) Temporal dynamic patterns of the same ES were not consistent across all counties, showing great spatial heterogeneity. The temporal dynamics of each ES type at each county were spatially explicitly clustered into linear dynamics, fluctuating dynamics, and regime shift dynamics with different means. (3) The ES supply–demand relationships can shift between supply–demand balance, excess supply, and excess demand when the temporal dynamics of ES supply do not match with that of ES demand. Our results suggest that temporal dynamic analysis in ecological restoration effectiveness assessment can help to avoid erroneous results compared to considering only pre- and post-policy ES changes. The identified emerging hotspots of excess supply and excess demand can help decision-makers more accurately identify priority locations for management

Perturbation of Circadian Rhythm Is Associated with Increased Prevalence of Chronic Kidney Disease: Results of the Korean Nationwide Population-Based Survey

Disturbances in circadian rhythms cause several health problems, such as psychosis, metabolic syndrome, and cancer; however, their effect on kidney disease remains unclear. This study aimed to evaluate the association between chronic kidney disease (CKD) and sleep disturbance in a Korean adult population. A total of 17,408 participants who completed the National Health and Nutrition Examination Survey from 2016 to 2018 were assessed for their sleep patterns and renal function. CKD was defined as an estimated glomerular filtration rate &le; 60 mL/min/1.73 m&sup2; or a positive dipstick urinalysis. Sleep onset time and sleep duration showed significant differences between the control and CKD groups (p &lt; 0.001). After adjusting for the covariates, sleep onset time rather than sleep duration was independently associated with incidence of CKD, and this association was more significant in people who were older, in women, and in those with low body mass index and no comorbidities. When comparing the prevalence of newly diagnosed CKD according to sleep onset time in a population with no CKD risk factors or no history of CKD, the early bedtime group showed an independent association with incidence of new CKD (odds ratio (OR), 1.535; 95% confidence interval (CI), 1.011&ndash;2.330) even after adjusting for covariates. Impaired circadian rhythm along with sleep disturbance could be associated with CKD development; therefore, sleep disturbance might be an important therapeutic target for CKD

Study on environmental factors affecting the quality of codonopsis radix based on MaxEnt model and all-in-one functional factor

Abstract Owing to the increasing market demand of Codonopsis Radix, the cropper blindly cultivates to expand planting area for economic benefits, which seriously affects the quality of Codonopsis Radix. Therefore, this study synthesized 207 batches of Codonopsis Radix and 115 ecological factors, and analyzed the suitable planting areas of Codonopsis pilosula under current and future climate change based on Geographic Information System (GIS) and MaxEnt model. Secondly, we evaluated the quality of Codonopsis Radix based on the all-in-one functional factor including chromatographic fingerprint, the index components, the effective compounds groups, the nutritional components, and the nutritional elements, and the quality regionalization of Codonopsis Radix was analyzed. Finally, the ecological factors affecting the accumulation of effective components of Codonopsis Radix were analyzed. This study found for the first time that the highly suitable area of Codonopsis pilosula was mainly distributed in the Weihe River system and the Bailongjiang River system in Gansu Province. There were differences in the quality of Codonopsis Radix from different ecologically suitable areas based on the all-in-one functional factors, and the comprehensive high-quality area of Codonopsis Radix was mainly distributed in Longnan and Longxi district of Gansu Province. The precipitation, temperature and altitude play a key role in the accumulation of chemical components in the 10 ecological factors affecting the distribution of Codonopsis pilosula. Under future climatic conditions, the highly suitable area of Codonopsis pilosula is decreased