Huang-Lian-Jie-Du Decoction (HLJDD), traditional Chinese medicine (TCM), is proven to have ameliorative effects on learning and memory deficits of Alzheimer's disease (AD). The current study aims to reveal the underlying mechanism of HLJDD in the treatment of AD by simultaneous determination on the regulation of HLJDD on oxidative stress, neurotransmitters, and AMPK-SIRT1 pathway in AD. AD model rat was successfully established by injection of D-galactose and Aβ 25-35-ibotenic acid. Morris Water Maze (MWM) test was used to evaluate the success of AD modelling. On this basis, an advanced technique with UPLC-QqQ MS/MS was built up and applied to determine the levels of 8 neurotransmitters in rat plasma. Significant alternation in methionine, glutamine, and tryptophan was observed in AD rats' plasma after the administration of HLJDD, relative to the model group. Meanwhile, HLJDD could upregulate the levels of SOD, GSH-Px, AMPK, and SIRT1 and downregulate the content of MDA in the peripheral system of the AD rats. The underlying therapeutic mechanism of HLJDD for the treatment of AD was associated with alleviating oxidation stress, inflammation, neurotransmitters, and energy metabolism. These data provide solid foundation for the potential use of HLJDD to treat AD.

in current clinical practice, the standard evaluation for axillary lymph node (ALN) status in breast cancer has a low efficiency and is based on an invasive procedure that causes operative-associated complications in many patients. Therefore, we aimed to use machine learning techniques to develop an efficient preoperative magnetic resonance imaging (MRI) radiomics evaluation approach of ALN status and explore the association between radiomics and the tumor microenvironment in patients with early-stage invasive breast cancer.

Resistance to radiotherapy is frequently encountered in clinic, leading to poor prognosis of cancer patients. Long noncoding RNAs (lncRNAs) play important roles in the development of radioresistance due to their functions in regulating the expression of target genes at both transcriptional and posttranscriptional levels. Exploring key lncRNAs and elucidating the mechanisms contributing to radioresistance are crucial for the development of effective strategies to reverse radioresistance, which however remains challenging. Here, actin filament-associated protein 1 antisense RNA1 (lncAFAP1-AS1) is identified as a key factor in inducing radioresistance of triple-negative breast cancer (TNBC) via activating the Wnt/β-catenin signaling pathway. Considering the generation of a high concentration of reduction agent glutathione (GSH) under radiation, a reduction-responsive nanoparticle (NP) platform is engineered for effective lncAFAP1-AS1 siRNA (siAFAP1-AS1) delivery. Systemic delivery of siAFAP1-AS1 with the reduction-responsive NPs can synergistically reverse radioresistance by silencing lncAFAP1-AS1 expression and scavenging intracellular GSH, leading to a dramatically enhanced radiotherapy effect in both xenograft and metastatic TNBC tumor models. The findings indicate that lncAFAP1-AS1 can be used to predict the outcome of TNBC radiotherapy and combination of systemic siAFAP1-AS1 delivery with radiotherapy can be applied for the treatment of recurrent TNBC patients.

BACKGROUND Type A AAD, a serious cardiovascular emergency requiring urgent surgery, is the most common and serious AAD. The aim of this study was to investigate the diagnostic value of ADAMTS1 and ADAMTS4 in patients with type A acute aortic dissection (AAD). MATERIAL AND METHODS Immunohistochemistry and qRT-PCR were used to evaluate the protein and mRNA expression levels of ADAMTS1 and ADAMTS4 in 14 type A acute aortic dissection (AAD) tissues and 10 control aortic tissues. Serum ADAMTS1 and ADAMTS4 expression levels in 74 patients with type A AAD, 36 patients with hypertension (HPT), and 34 healthy donors were examined by ELISA. The diagnostic value of serum ADAMTS1 and ADAMTS4 were determined by receiver operator characteristic curve (ROC). Furthermore, the dynamic change of serum ADAMTS1, ADAMTS4, D-dimer, and CRP were detected before and after surgery at different time-points in 14 patients with type A AAD. RESULTS ADAMTS1 and ADAMTS4 protein and mRNA expression levels were found to be significantly higher in 14 type A AAD tissues (p<0.0001) compared with 10 control tissues. Serum ADAMTS1 and ADAMTS4 levels were significant higher in patients with type A AAD than those in the HPT and HD group (p<0.0001 for both). The AUC value, sensitivity, and specificity of ADAMTS1 were 0.9710 (95% CI: 0.9429 to 0.9991), 87.84%, and 97.06%, respectively, and those of ADAMTS4 were 0.9893 (95% CI: 0.9765 to 1.002), 94.59%, and 97.06%, respectively. In addition, serum ADAMTS4 level was gradually decreased with the time extension after surgery, similar to D-dimer change. CONCLUSIONS These data suggest that measurement of serum ADAMTS1 and ADAMTS4 levels could be potential diagnostic biomarkers for type A AAD, and ADAMTS4 might be a risk factor associated with type A AAD.

Both primary thyroid lymphoma (PTL) and diffuse sclerosing variant of papillary thyroid carcinoma (DSVPTC) are two rare malignant tumours with different therapies and prognoses. This study compared their clinical features.

The recurrent aphthous stomatitis (RAS) frequently affects patient quality of life as a result of long lasting and recurrent episodes of burning pain. However, there were temporarily few available effective medical therapies currently. Drug target identification was the first step in drug discovery, was usually finding the best interaction mode between the potential target candidates and probe small molecules. Therefore, elucidating the molecular mechanism of RAS pathogenesis and exploring the potential molecular targets of medical therapies for RAS was of vital importance.

An anti-cancer campaign might not be easily achieved through a single therapeutic modality. Collaboration of multimodal therapies and diagnosis could be vital to win the battle against cancer. In this context, we synthesized a multifunctional theranostic nanocomposite (UCNP-BPNS) from upconversion nanoparticles (UCNP) and black phosphorus nanosheets (BPNS) for synergistic photothermal/photodynamic therapies in vitro and dual modal imaging. Core-shell UCNP (NaYF4:Yb,Er@NaGdF4) and BPNS were synthesized using solvo-thermal and liquid exfoliation methods, respectively, and then covalently conjugated after UCNP was modified with polyacrylic acid and BPNS with methoxypolyethylene glycol amine. The experimental results validate that the nanocomposite exhibited a good photothermal therapy (PTT) effect under 808 nm laser irradiation, endorsing the apparent heat conversion effect of BPNS. Besides, a very good photodynamic therapy (PDT) effect was achieved under 980 nm laser irradiation of the nanocomposite due to Förster resonance energy transfer from UCNP to BPNS that generated singlet oxygen (1O2). The synergistic PTT/PDT therapeutic effect provided by UCNP-BPNS under simultaneous 808 and 980 nm laser irradiation was significantly higher than either PTT or PDT alone. Furthermore, due to the merit of the outer shell coated on the surface of the core of UCNP, the nanocomposite exhibited good potential for magnetic resonance and upconversion luminescence imaging. These results demonstrated that our multifunctional nanocomposite has promising theranostic efficacy under near infrared laser irradiation.

At present, donkey meat in the market shows an imbalance between supply and demand, and there is an urgent need to cultivate a meat-type Dezhou donkey breed. On the one hand, it can improve the imbalance in the market, and on the other hand, it can promote the rapid development of the donkey industry. This study aimed to reveal significant genetic variation in the NK1 homeobox 2 gene (NKX1-2) of Dezhou donkeys and investigate the association between genotype and body size in Dezhou donkeys.

Osteosarcoma is a primary bone malignancy with a high rate of recurrence and poorer prognosis. Therefore, it is of vital importance to explore novel prognostic molecular biomarkers and targets for more effective therapeutic approaches. Previous studies showed that histone demethylase KDM5A can increase the proliferation and metastasis of several cancers. However, the function of KDM5A in the carcinogenesis of osteosarcoma is not clear. In the current study, KDM5A was highly expressed in osteosarcoma than adjacent normal tissue. Knockdown of KDM5A suppressed osteosarcoma cell proliferation and induced apoptosis. Moreover, knockdown of KDM5A could increase the expression level of P27 (cell-cycle inhibitor) and decrease the expression of Cyclin D1. Furthermore, after knockout of KDM5A in osteosarcoma cells by CRISPR/Cas9 system, the tumor size and growth speed were inhibited in tumor-bearing nude mice. RNA-Seq of KDM5A-KO cells indicated that interferon, epithelial-mesenchymal transition (EMT), IL6/JAK/STAT3, and TNF-α/NF-κB pathway were likely involved in the regulation of osteosarcoma cell viability. Taken together, our research established a role of KDM5A in osteosarcoma tumorigenesis and progression.

Venenum Bufonis (VB), also called Chan Su in China, has been extensively used as a traditional Chinese medicine (TCM) for treating heart failure (HF) since ancient time. However, the active components and the potential anti-HF mechanism of VB remain unclear. In the current study, the major absorbed components and metabolites of VB after oral administration in rats were first collected from literatures. A total of 17 prototypes and 25 metabolites were gathered. Next, a feasible network-based pharmacological approach was developed and employed to explore the therapeutic mechanism of VB on HF based on the collected constituents. In total, 158 main targets were screened out and considered as effective players in ameliorating HF. Then, the VB components-main HF putative targets-main pathways network was established, clarifying the underlying biological process of VB on HF. More importantly, the main hubs were found to be highly enriched in adrenergic signalling in cardio-myocytes. After verified by molecular docking studies, four key targets (ATP1A1, GNAS, MAPK1 and PRKCA) and three potential active leading compounds (bufotalin, cinobufaginol and 19-oxo-bufalin) were identified, which may play critical roles in cardiac muscle contraction. This study demonstrated that the integrated strategy based on network pharmacology and molecular docking was helpful to uncover the synergistic mechanism of multiple constituents in TCM.

Toad venom, a dried product of secretion from Bufo bufo gargarizans Cantor or Bufo melanostictus Schneider, has had the therapeutic effects of hepatocellular carcinoma confirmed. Bufalin and cinobufagin were considered as the two most representative antitumor active components in toad venom. However, the underlying mechanisms of this antitumor effect have not been fully implemented, especially the changes in endogenous small molecules after treatment. Therefore, this study was designed to explore the intrinsic mechanism on hepatocellular carcinoma after the cotreatment of bufalin and cinobufagin based on untargeted tumor metabolomics. Ultraperformance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) was performed to identify the absorbed components of toad venom in rat plasma. In vitro experiments were determined to evaluate the therapeutic effects of bufalin and cinobufagin and screen the optimal ratio between them. An in vivo HepG2 tumor-bearing nude mice model was established, and a series of pharmacodynamic indicators were determined, including the body weight of mice, tumor volume, tumor weight, and histopathological examination of tumor. Further, the entire metabolic alterations in tumor after treating with bufalin and cinobufagin were also profiled by UHPLC-MS/MS. Twenty-seven active components from toad venom were absorbed in rat plasma. We found that the cotreatment of bufalin and cinobufagin exerted significant antitumor effects both in vitro and in vivo, which were reflected in inhibiting proliferation and inducing apoptosis of HepG2 cells and thereby causing cell necrosis. After cotherapy of bufalin and cinobufagin for twenty days, compared with the normal group, fifty-six endogenous metabolites were obviously changed on HepG2 tumor-bearing nude mice. Meanwhile, the abundance of α-linolenic acid and phenethylamine after the bufalin and cinobufagin intervention was significantly upregulated, which involved phenylalanine metabolism and α-linolenic acid metabolism. Furthermore, we noticed that amino acid metabolites were also altered in HepG2 tumor after drug intervention, such as norvaline and Leu-Ala. Taken together, the cotreatment of bufalin and cinobufagin has significant antitumor effects on HepG2 tumor-bearing nude mice. Our work demonstrated that the in-depth mechanism of antitumor activity was mainly through the regulation of phenylalanine metabolism and α-Linolenic acid metabolism.

The purpose of this study is to explore the mechanism of the Zhilong Huoxue Tongyu (ZL) capsule in the treatment of intracerebral hemorrhage (ICH) via targeting ferroptosis based on network pharmacology.

Multiferroics, showing the coexistence of two or more ferroic orderings at room temperature, could harness a revolution in multifunctional devices. However, most of the multiferroic compounds known to date are not magnetically and electrically ordered at ambient conditions, so the discovery of new materials is pivotal to allow the development of the field. In this work, we show that BaFe2O4 is a previously unrecognized room temperature multiferroic. X-ray and neutron diffraction allowed to reveal the polar crystal structure of the compound as well as its antiferromagnetic behavior, confirmed by bulk magnetometry characterizations. Piezo force microscopy and electrical measurements show the polarization to be switchable by the application of an external field, while symmetry analysis and calculations based on density functional theory reveal the improper nature of the ferroelectric component. Considering the present findings, we propose BaFe2O4 as a Bi- and Pb-free model for the search of new advanced multiferroic materials.

Tail wagging plays an important role in social interactions, e.g., dogs show asymmetrical tail wagging in response to different social stimuli. However, the effects of social cues on tail wagging and the intrinsic organization of wagging behavior remain largely unknown. Here, we developed a platform using a deep-learning-based motion-tracking technique to extract and analyze the movement trajectory of a dog's tail tip during dog-human interactions. Individual dogs exhibited unique and stable wagging characteristics. We further found that tail wagging developed asymmetry toward the right side over three days of dog-human interactions, suggesting that it is a time-sensitive indicator of social familiarity. In addition, wagging appeared to follow an attractor-like dynamic process consisting of stable states and unstable, transitional states. Together, these results revealed sophisticated characteristics and organization of a dog's tail-wagging behavior during interactions with humans, providing a useful paradigm for studying dogs' social behaviors and the underlying neural mechanisms.

The inhibitor of β-catenin and TCF (ICAT) blocks the binding of TCF to β-catenin and has been demonstrated as a suppressor of the Wnt/β-catenin signaling pathway. It has been reported to exert a different function around a wide variety of cancers. However, its function and underlying mechanisms in human cervical cancer remains unknown. In the present study, the expression of ICAT in 41 human cervical cancer tissues and 30 normal cervical tissues was evaluated by immunohistochemical analysis. ICAT was found highly expressed in cancer tissues. ICAT overexpression significantly promoted SiHa cell proliferation in vitro by causing G1 arrest, and enhanced cell migration and invasion whereas, ICAT knockdown induced opposite effects in Caski cells which have higher expression of ICAT. Downregulation or overexpression of ICAT resulted in an altered expression of the epithelial-mesenchymal transition (EMT). Furthermore, immunoprecipitation assays revealed that ICAT pormoted cervical cancer EMT by competing in E-cadhenin binding to β-caterin. Overexpression of ICAT in SiHa cells promoted tumor growth and EMT was also demonstrated by the xenograft mouse experiment. These results demonstrate that ICAT contributed to the progression of cervical cancer and may play a role in the regulation of EMT by distrupting the E-cadherin/β-catenin complex. It may be a novel potential therapeutic target for therapy in human cervical cancer.

Primary malignant melanoma of the esophagus (PMME) is a rare gastrointestinal melanoma with a high rate of recurrence and metastasis. The standard of care for PMME has not been established yet due to a lack of understanding of its clinical and molecular pathogenesis. Thus, we performed genomic profiling on a recurrent PMME case to seek novel opportunities for the management of this rare disease. Between 2013 and 2016, 6 tissue samples including 3 from the primary tumors, 2 from the relapsed tumors, and 1 from a normal control were collected from a patient diagnosed with PMME and were subjected to whole-exome sequencing to track the dynamic genetic changes. Additionally, we also analyzed a cohort of 398 samples obtained from the TCGA skin cutanesous melanoma (TCGA-SKCM) dataset to assess the frequency and determine the clinical implications of genomic events found in the presented study. ARHGAP35 (p.L1022M) was the only mutation shared across temporal PMME lesions. The PMME samples showed higher levels of genetic instability and intra-tumor heterogeneity. They also shared several concordant copy number variations (CNV). All lesions were concordant with the evolution trajectory, and shrinkage of the founding clone caused the subclonal population to become dominant in PT1c, which was likely the reason behind metastatic seeding. ARHGAP35 mutations were found in 6% of the TCGA-SKCM cohort samples. The presence of the mutations was associated with poor progression-free survival (PFS) by both univariate and multivariate Cox regression analyses. Our study showed that the primary tumor clone disseminates earlier in PMME. This highlights the need to understand the mechanism involved in the early PMME recurrence to optimize treatment.

Accumulating clinical evidence suggests that hyperuricemia is associated with an increased risk of type 2 diabetes. However, it is still unclear whether elevated levels of uric acid can cause direct injury of pancreatic β-cells. In this study, we examined the effects of uric acid on β-cell viability and function. Uric acid solution or normal saline was administered intraperitoneally to mice daily for 4 weeks. Uric acid-treated mice exhibited significantly impaired glucose tolerance and lower insulin levels in response to glucose challenge than did control mice. However, there were no significant differences in insulin sensitivity between the two groups. In comparison to the islets in control mice, the islets in the uric acid-treated mice were markedly smaller in size and contained less insulin. Treatment of β-cells in vitro with uric acid activated the NF-κB signaling pathway through IκBα phosphorylation, resulting in upregulated inducible nitric oxide synthase (iNOS) expression and excessive nitric oxide (NO) production. Uric acid treatment also increased apoptosis and downregulated Bcl-2 expression in Min6 cells. In addition, a reduction in insulin secretion under glucose challenge was observed in the uric acid-treated mouse islets. These deleterious effects of uric acid on pancreatic β-cells were attenuated by benzbromarone, an inhibitor of uric acid transporters, NOS inhibitor L-NMMA, and Bay 11-7082, an NF-κB inhibitor. Further investigation indicated that uric acid suppressed levels of MafA protein through enhancing its degradation. Collectively, our data suggested that an elevated level of uric acid causes β-cell injury via the NF-κB-iNOS-NO signaling axis.

Quantitative information on the response of global terrestrial net primary production (NPP) to climate change and increasing atmospheric CO2 is essential for climate change adaptation and mitigation in the 21st century. Using a process-based ecosystem model (the Dynamic Land Ecosystem Model, DLEM), we quantified the magnitude and spatiotemporal variations of contemporary (2000s) global NPP, and projected its potential responses to climate and CO2 changes in the 21st century under the Special Report on Emission Scenarios (SRES) A2 and B1 of Intergovernmental Panel on Climate Change (IPCC). We estimated a global terrestrial NPP of 54.6 (52.8-56.4) PgC yr(-1) as a result of multiple factors during 2000-2009. Climate change would either reduce global NPP (4.6%) under the A2 scenario or slightly enhance NPP (2.2%) under the B1 scenario during 2010-2099. In response to climate change, global NPP would first increase until surface air temperature increases by 1.5 °C (until the 2030s) and then level-off or decline after it increases by more than 1.5 °C (after the 2030s). This result supports the Copenhagen Accord Acknowledgement, which states that staying below 2 °C may not be sufficient and the need to potentially aim for staying below 1.5 °C. The CO2 fertilization effect would result in a 12%-13.9% increase in global NPP during the 21st century. The relative CO2 fertilization effect, i.e. change in NPP on per CO2 (ppm) bases, is projected to first increase quickly then level off in the 2070s and even decline by the end of the 2080s, possibly due to CO2 saturation and nutrient limitation. Terrestrial NPP responses to climate change and elevated atmospheric CO2 largely varied among biomes, with the largest increases in the tundra and boreal needleleaf deciduous forest. Compared to the low emission scenario (B1), the high emission scenario (A2) would lead to larger spatiotemporal variations in NPP, and more dramatic and counteracting impacts from climate and increasing atmospheric CO2.

Iron is involved in various physiological processes of the human body to maintain normal functions. Abnormal iron accumulation in brain has been reported as a pathogenesis of several neurodegenerative disorders and cognitive impairments. Hemojuvelin (HVJ) is a membrane-bound and soluble protein in mammals that is responsible for the iron overload condition known as juvenile hemochromatosis. Although iron accumulation in brain has been related to neurodegenerative diseases, it remains unknown the effect of mutation of HVJ gene on cognitive performance. In our studies, HJV(-/-) mice showed deficits in novel object recognition and Morris water maze tests. Furthermore, the expression ration of apoptotic marker Bax and anti-apoptotic marker Bcl-2 in the hippocampus and prefrontal cortex showed higher levels in HJV(-/-) mice. Our results suggested that deletion of HJV gene could increase apoptosis in brain which might contribute to learning and memory deficits in mutant mice. These results indicated that HJV(-/-) mice would be a useful model to study cognitive impairment induced by iron overload in brain.

LIM and SH3 protein 1 (LASP-1) is a specific focal adhesion protein that is known to be involved in numerous biological and pathological processes. LASP-1 overexpression has been described in several types of cancers, but its expression and role in clear cell renal cell cancer (ccRCC) remains unknown.