Poly-(ADP-ribose) polymerase inhibitors (PARPi) selectively kill breast and ovarian cancers with defects in homologous recombination (HR) caused by BRCA1/2 mutations. There is also clinical evidence ...for the utility of PARPi in breast and ovarian cancers without BRCA mutations, but the underlying mechanism is not clear. Here, we report that the deubiquitylating enzyme USP15 affects cancer cell response to PARPi by regulating HR. Mechanistically, USP15 is recruited to DNA double-strand breaks (DSBs) by MDC1, which requires the FHA domain of MDC1 and phosphorylated Ser678 of USP15. Subsequently, USP15 deubiquitinates BARD1 BRCT domain, and promotes BARD1-HP1γ interaction, resulting in BRCA1/BARD1 retention at DSBs. USP15 knockout mice exhibit genomic instability in vivo. Furthermore, cancer-associated USP15 mutations, with decreased USP15-BARD1 interaction, increases PARP inhibitor sensitivity in cancer cells. Thus, our results identify a novel regulator of HR, which is a potential biomarker for therapeutic treatment using PARP inhibitors in cancers.
To systematically analyze the damage caused by bedrock and overburden layer slope under seismic action, a set of large-scale shaking table test was designed and completed. Interpolation of the ...acceleration amplification coefficient, Hilbert-Huang transform and transfer function was adopted. The damage mechanisms of the bedrock and overburden layer slopes under seismic action are systematically summarized in terms of slope displacement, acceleration field, vibration amplitude, energy, vibration frequency, and damage level. The results show a significant acceleration amplification effect within the slope under seismic action and a localized amplification effect at the top and trailing edges of the slope. With an increase in the input seismic intensity, the difference in the vibration amplitude between the overburden layer and bedrock increased, low-frequency energy of the overburden layer was higher than that of the bedrock, and the vibration frequency of the overburden layer was smaller than that of the bedrock. These differences cause the interface to experience cyclic loading continuously, resulting in the damage degree of the overburden layer at the interface being larger than that of the bedrock, reduction of the shear strength, and eventual formation of landslides. The displacement in the middle of the overburden is always greater than that at the top. Therefore, under the action of an earthquake and gravity, the damage mode of the bedrock and overburden layer slope is such that the leading edge of the critical part pulls and slides at the trailing edge, and multiple tensile cracks are formed on the slope surface.
Gellan gum is a naturally occurring polymer that can cross-link in the presence of divalent cations to form biocompatible hydrogels. However, physically cross-linked gellan gum hydrogels lose their ...stability under physiological conditions, thus restricting the applications of these hydrogels in vivo. To improve the mechanical strength of the gels, we incorporated methacrylate into the gellan gum and chemically cross-linked the hydrogel through three polymerization methods: step growth through thiol–ene photoclick chemistry, chain-growth via photopolymerization, and mixed model in which both mechanisms were employed. Methacrylation was confirmed and quantified by proton nuclear magnetic resonance (1H NMR) and Fourier transform infrared spectroscopy. The mechanical properties and chemistry of the cross-linked gels were systematically altered by varying the reaction conditions. The compression moduli of the resulting hydrogels ranged between 6.4 and 17.2 kPa. The swelling ratios of the hydrogels were correlated with the compression moduli and affected by the addition of calcium. In vitro enzymatic degradation rate was found to depend on the degree of methacrylation. NIH/3T3 fibroblast cell proliferation and morphology were related to substrate stiffness, with a high stiffness leading generally to higher proliferation. The proliferation is further affected by the thiol–ene ratio. These results suggest that a hydrogel platform based on the gellan gum can offer versatile chemical modifications and tunable mechanical properties. The influence of these substrates on cell behavior suggests that the gellan gum hydrogels have the flexibility to be engineered for a variety of biomaterials applications.
Background
Recent clinical and animal studies have shown that renal denervation (RDN) improves insulin sensitivity and endothelial dysfunction. However, the specific mechanism remains incompletely ...understood. The purpose of this study is to investigate the effects of RDN on endothelial dysfunction of type 2 diabetes mellitus (T
2
DM) rat models with insulin resistance and to explore the underlying molecular mechanisms.
Methods
Male Sprague–Dawley rats were fed with or without high-fat diet allocated in different groups, combined with low-dose streptozotocin which induces a rat model to develop T
2
DM with insulin resistance. RDN was conducted 1 week after the rat models fully developed T
2
DM. The animals were sub-divided into four groups randomly: control group (CON,
n
= 6), diabetic group (T
2
DM,
n
= 6), diabetic with sham surgery group (Sham,
n
= 6) and diabetic with RDN group (RDN,
n
= 6). Rats in all groups were studied at baseline, both preoperatively and 4 weeks after RDN, respectively. Western blot was used to detect the expression of angiotensin-converting enzyme 2 (ACE2) protein and the expression of autophagy-related proteins Beclin1, LC3 and p62 and autophagy signaling pathway AMPK/mTOR proteins and apoptosis-related protein caspase-3 in the aorta endothelial cells. In addition, the effects of ACE2 on autophagy of human umbilical vein insulin resistance endothelial cell culture in vitro were also studied.
Results
RDN decreased plasma and renal tissue norepinephrine levels. The Von Willebrand factor level was also decreased, while the plasma level of nitric oxide (NO) was significantly increased after RDN. Compared with the T
2
DM group and the Sham group, the endothelium-dependent and endothelium-independent diastolic function of the RDN group was improved significantly, the expression of Beclin1, LC3, ACE2 and eNOS proteins was higher, and the level of p62 protein was decreased. Furthermore, we found that RDN can activate the expression of p-AMPK and inhibit the expression of p-mTOR. In cell culture experiment, ACE2 activated p-AMPK and inhibited p-mTOR, thus promoting autophagy.
Conclusions
RDN may not only increase the expression of ACE2 in the vascular endothelium, but also can via ACE2 activate p-AMPK and inhibit p-mTOR, thus promoting autophagy and improving endothelial dysfunction.
High voltage direct current (HVDC) transmission technology has incomparable advantages in long‐distance and large‐capacity transmission. With the development of HVDC transmission technology, ...transmission lines inevitably pass through some densely populated and economically developed areas. Due to environmental considerations, the space electric field around the buildings that are adjacent to HVDC transmission lines has aroused increasing attention. However, it is hard to be predicted by simulation because of the calculation complexity. This paper proposed a new calculated method to obtain the composite electric field around HVDC transmission lines with adjacent residential buildings, and the validity and correctness of the method are verified by the experimental results. Then, the distortion of the electric field around the building and its impact on the design of the safe corridor width of the HVDC transmission line is analyzed. The proposed method, unlike existing methods, can be used to predict the space composite electric field distribution around HVDC transmission lines and their adjacent residences, which are of arbitrary material, shape, and size. It can provide guide for the optimal design of transmission line corridors.
The acquisition of resistance is a major obstacle to the clinical use of platinum drugs for ovarian cancer treatment. Increase of DNA damage response is one of major mechanisms contributing to ...platinum-resistance. However, how DNA damage response is regulated in platinum-resistant ovarian cancer cells remains unclear. Using quantitative high throughput combinational screen (qHTCS) and RNA-sequencing (RNA-seq), we show that dual oxidase maturation factor 1 (DUOXA1) is overexpressed in platinum-resistant ovarian cancer cells, resulting in over production of reactive oxygen species (ROS). Elevated ROS level sustains the activation of ATR-Chk1 pathway, leading to resistance to cisplatin in ovarian cancer cells. Moreover, using qHTCS we identified two Chk1 inhibitors (PF-477736 and AZD7762) that re-sensitize resistant cells to cisplatin. Blocking this novel pathway by inhibiting ROS, DUOXA1, ATR or Chk1 effectively overcomes cisplatin resistance in vitro and in vivo. Significantly, the clinical studies also confirm the activation of ATR and DOUXA1 in ovarian cancer patients, and elevated DOUXA1 or ATR-Chk1 pathway correlates with poor prognosis. Taken together, our findings not only reveal a novel mechanism regulating cisplatin resistance, but also provide multiple combinational strategies to overcome platinum-resistance in ovarian cancer.
•Providing multiple potential approaches for treatment of platinum resistant ovarian cancer.•Integrating qHTCS, RNA-seq and clinical studies to elucidate cisplatin resistant mechanism.•DUOXA1-mediated activation of ATR-Chk1 regulates cisplatin resistance in ovarian cancer.
The JAK2/STAT pathway is hyperactivated in many cancers, and such hyperactivation is associated with a poor clinical prognosis and drug resistance. The mechanism regulating JAK2 activity is complex. ...Although translocation of JAK2 between nucleus and cytoplasm is an important regulatory mechanism, how JAK2 translocation is regulated and what is the physiological function of this translocation remain largely unknown. Here, we found that protease SENP1 directly interacts with and deSUMOylates JAK2, and the deSUMOylation of JAK2 leads to its accumulation at cytoplasm, where JAK2 is activated. Significantly, this novel SENP1/JAK2 axis is activated in platinum-resistant ovarian cancer in a manner dependent on a transcription factor RUNX2 and activated RUNX2/SENP1/JAK2 is critical for platinum-resistance in ovarian cancer. To explore the application of anti-SENP1/JAK2 for treatment of platinum-resistant ovarian cancer, we found SENP1 deficiency or treatment by SENP1 inhibitor Momordin Ic significantly overcomes platinum-resistance of ovarian cancer. Thus, this study not only identifies a novel mechanism regulating JAK2 activity, but also provides with a potential approach to treat platinum-resistant ovarian cancer by targeting SENP1/JAK2 pathway.
Abstract Cyclin-dependent kinases 4 and 6 (CDK4/6) play a pivotal role in cell cycle and cancer development. Targeting CDK4/6 has demonstrated promising effects against breast cancer. However, ...resistance to CDK4/6 inhibitors (CDK4/6i), such as palbociclib, remains a substantial challenge in clinical settings. Using high-throughput combinatorial drug screening and genomic sequencing, we find that the microphthalmia-associated transcription factor (MITF) is activated via O-GlcNAcylation by O-GlcNAc transferase (OGT) in palbociclib-resistant breast cancer cells and tumors. Mechanistically, O-GlcNAcylation of MITF at Serine 49 enhances its interaction with importin α/β, thus promoting its translocation to nuclei, where it suppresses palbociclib-induced senescence. Inhibition of MITF or its O-GlcNAcylation re-sensitizes resistant cells to palbociclib. Moreover, clinical studies confirm the activation of MITF in tumors from patients who are palbociclib-resistant or undergoing palbociclib treatment. Collectively, our studies shed light on the mechanism regulating palbociclib resistance and present clinical evidence for developing therapeutic approaches to treat CDK4/6i-resistant breast cancer patients.
Allergic rhinitis (AR) is a widespread allergic airway disease that results from a complex interplay between genetic and environmental factors and affects approximately 10%-40% of the global ...population. Pollen is a common allergen, and exposure to pollen can cause epigenetic changes. However, the mechanism underlying pollen-induced DNA methylation changes and their potential effects on the allergic march are still unclear. The purpose of this study was to explore the methylation-driven mechanisms of AR during the pollen and non-pollen seasons using bioinformatics analysis and to investigate their relationship with asthma.
We downloaded DNA methylation and gene expression data from the GEO database (GSE50387: GSE50222, GSE50101) and identified differentially methylated positions (DMPs) and differentially expressed genes (DEGs) during the pollen and non-pollen seasons using the CHAMP and limma packages. Through correlation analysis, we identified methylation-driven genes and performed pathway enrichment analysis to annotate their functions. We incorporated external data on AR combined with asthma (GSE101720) for analysis to identify key CpGs that promote the transformation of AR to asthma. We also utilized external data on olive pollen allergy (GSE54522) for analysis to validate the methylation-driven genes. Weighted correlation network analysis (WGCNA) was employed to identify gene modules significantly correlated with pollen allergy. We extracted genes related to the key methylation-driven gene
from the significant module and performed pathway intelligent clustering using KOBAS-i. We also utilized gene set enrichment analysis to explore the potential function of
.
We identified 20 and 24 CpG-Gene pairings during the pollen and non-pollen seasons. After incorporating external data from GSE101720, we found that
is a key gene that may facilitate the transformation of AR into asthma during the pollen season. This finding was further validated in another external dataset, GSE54522, which is associated with pollen allergy. WGCNA identified 17 modules, among which the blue module showed significant correlation with allergies.
was located in the blue module. We performed pathway analysis on the genes correlated with
extracted from the blue module and identified a prominent cluster of pathways in the KOBAS-i results, including Toll-like receptor (
) family,
,
, and oxidative stress. Gene set enrichment analysis around
(paired with
) also indicated its potential involvement in initiating and modulating allergic inflammation from the perspective of
and
signaling.
We identified methylation-driven genes and their related pathways during the pollen and non-pollen seasons in patients with AR and identified key CpGs that promote the transformation of AR into asthma due to pollen exposure. This study provides new insights into the underlying molecular mechanisms of the transformation of AR to asthma.
Background:
Diabetic cardiomyopathy is a multifaceted complication of diabetes that lacks effective treatments. Berberine (BBR), a bioactive compound from
Rhizoma coptidis
, has potential therapeutic ...implications, but its precise role in diabetic cardiomyopathy remains to be defined.
Methods:
In this study, a diabetic cardiomyopathy model was established by administration of a high-fat diet and streptozotocin injection to C57BL/6J mice. Concurrently, the mice received BBR treatment daily for a duration of 8 weeks. After the treatment period, myocardial injury, cardiac function, and the levels of oxidative stress and apoptosis were assessed.
Results:
BBR significantly ameliorated cardiac dysfunction and histopathological damage caused by diabetic cardiomyopathy. This treatment also elevated serum superoxide dismutase levels while decreasing malondialdehyde levels. The anti-apoptotic activity of BBR was evidenced by a decrease in TUNEL-positive cells and the percentage of apoptotic cells, as determined by flow cytometry, in conjunction with diminished levels of BCL2-associated X protein/B cell lymphoma 2 (BAX/BCL2) in heart tissues. Mechanistically, BBR was found to ameliorate diabetic cardiomyopathy by upregulating the expression of myocardial methionine sulfoxide reductase A (MsrA) and concurrently suppressing cardiac CaMKII oxidation.
Conclusions:
BBR alleviates diabetic cardiomyopathy by inhibiting myocardial apoptosis and oxidative stress through the MsrA and CaMKII signaling pathways.
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