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The gut microbiota plays an important role in regulating the pharmacokinetics and pharmacodynamics of many drugs. FLZ, a novel squamosamide derivative, has been shown to have neuroprotective effects on experimental Parkinson's disease (PD) models. FLZ is under phase Ⅰ clinical trial now, while the underlying mechanisms contributing to the absorption of FLZ are still not fully elucidated. Due to the main metabolite of FLZ was abundant in feces but rare in urine and bile of mice, we focused on the gut microbiota to address how FLZ was metabolized and absorbed. In vitro studies revealed that FLZ could be exclusively metabolized to its major metabolite M1 by the lanosterol 14 alpha-demethylase (CYP51) in the gut microbiota, but was almost not metabolized by any other metabolism-related organs, such as liver, kidney, and small intestine. M1 was quickly absorbed into the blood and then remethylated to FLZ by catechol O-methyltransferase (COMT). Notably, dysbacteriosis reduced the therapeutic efficacy of FLZ on the PD mouse model by inhibiting its absorption. The results show that the gut microbiota mediate the absorption of FLZ through a FLZ–M1–FLZ circulation. Our research elucidates the vital role of the gut microbiota in the absorption of FLZ and provides a theoretical basis for clinical pharmacokinetic studies and clinical application of FLZ in the treatment of PD., Graphical abstract This study elucidates the role of gut microbiota in absorption of FLZ, a novel neuroprotective squamosamide derivative, providing theoretical basis for its clinical application in the treatment of Parkinson's disease.Image 1

C17H12F2O1, monoclinic, P 1 ‾ $P\overline{1}$ (no. 2), a = 7.3832(8) Å, b = 8.6467(9) Å, c = 11.3278(11) Å, α = 87.633(8)°, β = 88.022(8)°, γ = 65.364(10)°, V = 654.88(13) Å3, Z = 2, R gt (F) = 0.0369, wR ref (F 2) = 0.0987, T = 293(2) K.

Discrete and polymeric coordination complexes, namely [Cu2L4(ClO4)4]·2CH2Cl2·CH3OH (1), [Cu2L2(NO3)4(CH3OH)2] (2) and {[Cu2L4(NO3)4]}n (3), were obtained using bridged pyridine ligand 4-methyl-2,6-bis(pyridinyl-3-ethynyl)aniline (L) and Cu(II) salts in CH2Cl2/MeOH. The structure of the Cu2L4 cage or Cu2L2 macrocycle was generated depending on the selection of the anion (ClO4−/NO3−). The heterogeneous Fenton reaction experiments using H2O2 showed that discrete coordination complexes are good photocatalysts in which the Cu–N bond plays a major role in the photocatalytic degradation. The degradation mechanism could be described as a synergistic process of the Fenton reaction and high-valence copper ions using t-butanol as the hydroxyl radical scavenger. The photocatalytic degradation of methylene blue (MB) experiments showed that the photodegradation efficiency of the coordination complexes is higher than that of the polymeric Cu-MOFs.

7-Hydroxycoumarin is a privileged structure for anti-inflammatory drug development. In this study, several new 3-acetyl-7-hydroxycoumarin derivatives were designed, synthesized and tested as anti-inflammatory agents. Interestingly, Mannich bases and Betti bases were separately obtained under acidic or neutral conditions. The regioselectivity of aminomethylation was studied based on the atomic electron density distribution by analysing the Voronoi deformation density (VDD) atomic charges, which reasonably explained the experimental outcome. Detection of nitric oxide (NO) and tumour necrosis factor alpha (TNF-α) release revealed that Mannich bases displayed stronger anti-inflammatory activity than the corresponding Betti bases.

Traditional white light-emitting diodes (LEDs) (blue chip + YAG:Ce3+ yellow phosphor) have the limitation of red deficiency, which limits their application in the illumination field. The single cation/anion substitution or co-doping of activators can increase the red component; however, the large energy loss is attributed to the ultra-long Stokes shift and energy transfer. This work attempts to utilize the short-distance Stokes shift and a small amount of energy transfer to increase the red component in two steps. First, based on a large number of previous research results, the Mg2Y2Al2Si2O12:Ce3+ phosphor is selected. Second, additional enhancement of the red component in the emission spectrum was achieved by ion co-doping Mn2+ into Mg2Y2Al2Si2O12:Ce3+. The emission peaks for samples Mg2Y2Al2Si2O12:Ce3+,Mn2+ shift from 600 to 635 nm with increase in the concentration of Mn2+, and the emission spectra intensity of Mg1.97Y1.93Al2Si2O12:0.07 Ce3+,0.03 Mn2+ anomalously increased by ∼37%, which was attributed to the increase in the distance between Ce3+ ions because of the doping of Mn2+ ions, and reduction in the concentration of defects in the crystal, resulting in the energy loss decreases of Ce3+. The emission peak of Mg1.97Y1.93Al2Si2O12:0.07 Ce3+,0.03 Mn2+ shifts to 618 nm and the quantum efficiency was as high as 83.07%. Furthermore, this sample has high thermal stability and the emission intensity was still 80.14% at 120 °C. As such, it has great potential in the application of white LEDs.

The Polar Silk Road (PSR) will open up China’s maritime trade route through the Arctic to Northwest Europe and affect the freight function structure of China’s coastal ports. This study evaluates p...

Detection of lead(II) (Pb2+) ions in water is important for the protection of human health and environment. The growing demand for onsite detection still faces challenges for sensitive and easy-to-use methods. In this work, a novel surface plasmon resonance (SPR) biosensor based on GR-5 DNAzyme and gold nanoparticles (AuNPs) was developed. Thiolated DNAzyme was immobilized on the gold surface of the sensor chip followed by anchoring the substrate-functionalized AuNPs through the DNAzyme-substrate hybridization. The coupling between the localized surface plasmon (LSP) of AuNPs and the surface plasmon polaritons (SPP) on the gold sensor surface was used to improve the sensitivity. The substrate cleavage in the presence of Pb2+ ions was catalyzed by DNAzyme, leading to the removal of AuNPs and the diminished LSP-SPP coupling. The optimal detection limit was 80 pM for the sensor fabricated with 1 μM DNAzyme, corresponding to two or three orders of magnitude lower than the toxicity levels of Pb2+ in drinking water defined by WHO and USEPA. By tuning the surface coverage of DNAzyme, the sensitivity and dynamic range could be controlled. This sensor also featured high selectivity to Pb2+ ions and simple detection procedure. Successful detection of Pb2+ ions in groundwater indicates that this method has the prospect in the onsite detection of Pb2+ ions in water. Given the variety of AuNPs and metal-specific DNAzymes, this detection strategy would lead to the development of more sensitive and versatile heavy metal sensors.

Self-healing materials arouse much attention because of their recoverable morphologies during (dis)charge. Herein, we report an effective and practical synthesis strategy that can adequately utiliz...

Traditional powder metallurgy was employed to prepare alumina–zirconia (Al2O3–ZrO2) and alumina–zirconia–aluminium (Al2O3–ZrO2–Al) ceramics. It was found that as the sintering temperature increases, the flexural strength of both ceramics increases first and then decreases. The maximum flexural strength of Al2O3–ZrO2 appears to be 430.7 MPa when sintered at 1650°C, and Al2O3–ZrO2–Al appears to be 448.8 MPa when sintered at 1600°C. As the sintering temperature increases, the grain size of each phase grows up, the porosity increases, the content of intragranular phase and monoclinic ZrO2 (m-ZrO2) increases. The addition of Al powder improves the dispersion of ZrO2, reduces the porosity of zirconia toughened alumina ceramics, and improves the bending strength. Al powder increases the content of the intragranular ZrO2, restrains the t–m phase transformation, results in the decreases of the relative amount of m-ZrO2 in ZrO2 (Xm ). Adding Al powder during ball milling is a simple method to increase the content of intragranular ZrO2 in Al2O3–ZrO2 ceramics.

Graphene quantum dots (GQDs) have wide prospective applications for optoelectronic fields owing to their unique characteristics, such as tunable bandgaps, high chemical and optical stability, as we...

Diabetes mellitus is a chronic endocrine disease result from absolute or relative insulin secretion deficiency, insulin resistance, or both, and has become a major and growing public healthy menace worldwide. Currently, clinical antidiabetic drugs still have some limitations in efficacy and safety such as gastrointestinal side effects, hypoglycemia, or weight gain. Rosmarinus officinalis is an aromatic evergreen shrub used as a food additive and medicine, which has been extensively used to treat hyperglycemia, atherosclerosis, hypertension, and diabetic wounds. A great deal of pharmacological research showed that rosemary extract and its phenolic constituents, especially carnosic acid, rosmarinic acid, and carnosol, could significantly improve diabetes mellitus by regulating glucose metabolism, lipid metabolism, anti-inflammation, and anti-oxidation, exhibiting extremely high research value. Therefore, this review summarizes the pharmacological effects and underlying mechanisms of rosemary extract and its primary phenolic constituents on diabetes and relative complications both in vitro and in vivo studies from 2000 to 2020, to provide some scientific evidence and research ideas for its clinical application.

Fibrotic disease can disrupt the normally transparent ocular tissues resulting in irreversible loss of vision. A common feature in fibrotic eye disease is the transdifferentiation of cells into myofibroblasts that can occur through a process known as epithelial-mesenchymal transition. Transforming growth factor β has a central role in fibrogenesis by modulating the fibroblast function, inducing myofibroblast transdifferentiation and promoting extracellular matrix accumulation. It has been implicated in numerous fibrotic eye diseases. This article aims to introduce the new progression on TGFβ and fibrotic ocular diseases and its clinical significance for providing the reference in clinical practices.

Glial cell line-derived neurotrophic factor (GDNF) has neurotrophic activity for the survival of dopaminergic neurons, which is under active investigation for Parkinson's disease (PD) therapy. FLZ is a potential new drug for PD treatment. However, it is unclear whether neurotrophic activity contributes to the neuroprotective effects of FLZ. Here we found that FLZ markedly improved the function of dopaminergic neurons in primary mesencephalic neuron/glia cultures. Further investigation demonstrated that astroglia were required for FLZ to function as a neurotrophic regulator, as FLZ failed to show neurotrophic effects in the absence of astroglia. We clarified that GDNF was responsible for the neurotrophic effects of FLZ since FLZ selectively stimulated GDNF production, which was confirmed by the finding that the neurotrophic effect of FLZ was attenuated by GDNF-neutralizing antibody. Mechanistic study demonstrated that GDNF induction by FLZ was CREB-dependent and that PI3K/Akt was the main pathway regulating CREB activity, which was confirmed by in vivo studies. We also validated that the induction of GDNF by FLZ contributed to PD treatment in vivo. In conclusion, the present data provided evidence that FLZ had robust neurotrophic effects on dopaminergic neurons through sustained induction of GDNF in astroglia by activating the PI3K/Akt/CREB pathway.

Accumulated evidence shows that sperm-associated antigen 6 (SPAG6) gene has multiple biological functions. It maintains the normal function of a variety of cells including ciliary/flagellar biogenesis and polarization, neurogenesis, and neuronal migration. Moreover, SPAG6 is found to be critically involved in auditory transduction and the fibroblast life cycle. Furthermore, SPAG6 plays an essential role in immuno-regulation. Notably, SPAG6 has been demonstrated to participate in the occurrence and progression of a variety of human cancers. New evidence shows that SPAG6 gene regulates tumor cell proliferation, apoptosis, invasion, and metastasis. Therefore, in this review, we describe the physiological function and mechanism of SPAG6 in human normal cells and cancer cells. We also highlight that SPAG6 gene may be an effective biomarker for the diagnosis of human cancer. Taken together, targeting SPAG6 could be a novel strategy for the treatment of human diseases including cancer. Keywords: SPAG6, microtubule, apoptosis, cancer, proliferation

Combinatorial problems are a fundamental research subject of theoretical computer science, and for a general graph many combinatorial problems are NP-hard and even #P-complete. Thus, it is interesting to seek or design special graphs for which these difficult combinatorial problems can be exactly solved. In this paper, we study some combinatorial problems for the Farey graphs, which are translated from Farey sequences and have received considerable attention from the scientific community. We determine exactly the domination number, the independence number, and the matching number. Moreover, we derive exact or recursive solutions to the number of minimum dominating sets, the number of dominating sets, the number of maximum independent sets, the number of independent sets, the number of maximum matchings, as well as the number of matchings. Finally, we obtain explicit expressions for the number of acyclic orientations and the number of root-connected acyclic orientations. Since the considered combinatorial problems have found wide applications in diverse fields, such as network science and graph data miming, this work is helpful for deepening our understanding of the applications for these combinatorial problems.

The role of hepatitis C virus (HCV) infection statuses in the development of type 2 diabetes mellitus (T2DM) has not been completely understood. To evaluate the prevalence of T2DM in patients with different HCV infection statuses. We conducted a systematic study on T2DM risk in five types of individuals with different HCV infection statuses: non-HCV controls, HCV-cleared patients, chronic HCV patients without cirrhosis, patients with HCV cirrhosis and patients with decompensated HCV cirrhosis. Studies published from 2010 to 2019 were selected. Both pairwise and network meta-analyses were employed to compare the T2DM risk among patients with different HCV infection statuses. The pairwise meta-analysis showed that non-HCV (OR = 0.60, 95% CI [0.47–0.78]) had a lower risk of T2DM compared with CHC, while cirrhosis had a significant higher risk (OR = 1.90, 95% CI [1.60–2.26]). Network meta-analysis further demonstrated patients with HCV infection were at a significantly higher risk of T2DM than those without HCV infection or with HCV clearance, while decompensated cirrhosis had a significant higher T2DM risk than non-HCV (OR = 3.84, 95% CI [2.01–7.34]), patients with HCV clearance (OR = 3.17, 95% CI [1.49–6.73]), and CHC patients (OR = 2.21, 95% CI [1.24–3.94]). HCV infection is a significant risk factor for developing T2DM. CHC, cirrhosis, and decompensated cirrhosis contribute to an increasingly greater risk of T2DM, but HCV clearance spontaneously or through clinical treatment may immediately reduce the risk of the onset and development of T2DM.

Membrane fouling, which limits the application of membrane bioreactors, has received considerable research attention in recent years. In this work, filtration modeling was performed in combination with surface plasmon resonance (SPR) analysis to investigate the membrane fouling mechanism. Sodium alginate (SA) and bovine serum albumin (BSA) were used to perform dead-end filtration on hydrophilic and hydrophobic poly (vinylidene fluoride) (PVDF) membranes. The initial foulant deposition and layer formation on membranes as well as the interaction between the BSA and SA were comprehensively analyzed. Results indicated that during SA filtration, initial fouling on hydrophilic membranes were primarily attributed to the particle-membrane interactions, while the fouling on the hydrophobic membrane were dominantly caused by the interactions among SA particles. The interaction between BSA and SA led to more severe membrane fouling and hydrophobic membrane was more sensitive to it, especially in the initial filtration process. The SPR results helped clarify the in-situ deposition behavior of BSA and SA particles on the PVDF surface. Compared to SA, BSA adsorbed faster on the PVDF membrane, and specific interactions played an essential role in BSA adsorption, whereas the deposition of SA on PVDF could be easily removed by shear force. Interactions between BSA and SA could alleviate the bonding between BSA and the PVDF membrane.

The effects of intestinal inflammation on the brain and behavior have received a lot of attention. Melanin (MSI) from Sepiapharaonis ink as an emerging functional food, it exhibited a significant protective effect on dextran sulfate sodium (DSS) induced colitis in previous study. In present study, C57BL/6J mice were free to drink 2.5% DSS solution to establish the colitis model. During the DSS treatment, mice were orally administrated with MSI once per day (75, 150, and 300 mg/kg, respectively). The results showed that MSI treatment ameliorated the depression and anxiety symptoms of colitis mice. Further mechanism studies indicated that MSI alleviated inflammatory response by adjusting cytokines TNF-α, IL-1β, IFN-γ, and IL-10, and proteins NLRP3/ASC/caspase-1 inflammasome), inhibited the activation of microglia, restored brain synaptic density, reduced oxidative stress (SOD, MDA) and regulated apoptosis (tunel staining, caspase-3). MSI could modulate depression-anxiety states by targeting inflammation, nerve tissue, oxidative stress and apoptosis. MSI administration could serve as an emerging blue food and nutrition strategy for the prevention of digestive tract inflammation and behavioral disorders.

Objective The aim of the study was to construct and validate a robust prognostic model based on liquid‐liquid phase separation (LLPS)–related genes in lung squamous cell carcinoma (LUSC). Methods The Cancer Genome Atlas dataset was used as the discovery set to identify the LLPS‐related differentially expressed genes (DEGs) between LUSC and normal tissue. These DEGs were screened by the LASSO Cox regression analysis to identify the genes with nonzero coefficient, which were next included in the multivariate Cox regression analysis to construct the prediction model. The dataset GSE41271 was adopted as the validation set to verify the efficacy of the model. Enrichment analysis and the CIBERSORT were performed to illustrate potential immune mechanisms underlying the prediction model. Results A total of 48 LLPS‐related genes were aberrantly expressed in LUSC. Among them, 7 genes were selected by the LASSO Cox regression analysis to construct the prediction model. Risk index (RI) was calculated according to the model for each patient. The prognosis was significantly different between the patients with high and low RI in the discovery set and the validation set (p, A prognostic model based on the LLPS‐related genes using LASSO regression and multivariate Cox regression analyses was constructed and validated for LUSC. The risk index (RI) calculated for each patient according to the model was significantly related to patients’ prognosis and caner‐related immune activities.

The systematic collation and mining of ethnic medicine literature is the key to the screening and textual research of classic prescriptions. This study focused on the textual research of such key issues as the source of prescriptions, the translation of minority languages into Chinese characters and their corresponding medical terms, the original plants of drugs, and the standard dosage. It is believed that the methods and experience of textual research of classic prescriptions in traditional Chinese medicine(TCM) can be utilized by the ethnic medicine. At the same time, the prominent problems unique to ethnic medicine cannot be neglected.(1)Attention should be paid to extraterritorial traditional medical literature in the textual research of the source of prescriptions. For instance, Indian medical literature is the source of many classic prescriptions in Tibetan medicine, Ibn Sina's Canon of Medicine the source of those in Uygur and Hui medicine, and ancient Indian Buddhist classics the source of those in Dai medicine.(2)The translation and comparison of medical terms in different language systems requires the cooperation of linguists, historians, and medical experts, the combination of historical research, historical linguistics and clinical research methods, and the use of cross-language comparison. In recent years, the related research achievements like multiple translated and annotated versions of classical literature in ethnic medicine and their respective terminology standards have been constantly emerging.(3)In textual research of the original plants of drugs, the following two points deserve attention: one is that the same drug is used in different ethnic medical systems, but there are differences in the understanding of drug properties and active parts; the other is that the original plants of the same drug vary in different ethnic medical systems.(4)The derivation of some classic prescriptions in ethnic medicine from foreign classics results in the difference among measurement systems. In addition, the detailed dosage fails to be covered in some ethnic literature, so the dosage standard should be determined depending on clinical practice and expert consensus.

Tianzhu white yak is a rare local yak breed with a pure white coat in China. In recent years, breeders have discovered long-haired individuals characterized by long hair on the forehead in the Tianzhu white yak, and the length and density of the hair on these two parts of the body are higher than that of the normal Tianzhu white yak. To elucidate the genetic mechanism of hair length in Tianzhu white yak, we re-sequence the whole genome of long-haired Tianzhu White yak (LTWY) (n = 10) and normal Tianzhu White yak (NTWY) (n = 10). Then, fixation index (FST), θπ ratio, cross-population composite likelihood ratio (XP-CLR), integrated haplotype score (iHS), cross-population extended haplotype homozygosity (XP-EHH), and one composite method, the de-correlated composite of multiple signals (DCMS) were performed to discover the loci and genes related to long-haired traits. Based on five single methods, we found two hotspots of 0.2 and 1.1 MB in length on chromosome 6, annotating two (FGF5, CFAP299) and four genes (ATP8A1, SLC30A9, SHISA3, TMEM33), respectively. Function enrichment analysis of genes in two hotspots revealed Ras signaling pathway, MAPK signaling pathway, PI3K-Akt signaling pathway, and Rap1 signaling pathway were involved in the process of hair length differences. Besides, the DCMS method further found that four genes (ACOXL, PDPK1, MAGEL2, CDH1) were associated with hair follicle development. Henceforth, our work provides novel genetic insights into the mechanisms of hair growth in the LTWY.

Over the last 40 years, the incidence and prevalence of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) have continued to increase. Compared to other epithelial neoplasms in the same organ, GEP-NENs exhibit indolent biological behavior, resulting in more chances to undergo surgery. However, the role of surgery in high-grade or advanced GEP-NENs is still controversial. Surgery is associated with survival improvement of well-differentiated high-grade GEP-NENs, whereas poorly differentiated GEP-NENs that may benefit from resection require careful selection based on Ki67 and other tissue biomarkers. Additionally, surgery also plays an important role in locally advanced and metastatic disease. For locally advanced GEP-NENs, isolated major vascular involvement is no longer an absolute contraindication. In the setting of metastatic GEP-NENs, radical intended surgery is recommended for patients with low-grade and resectable metastases. For unresectable metastatic disease, a variety of surgical approaches, including cytoreduction of liver metastasis, liver transplantation, and surgery after neoadjuvant treatment, show survival benefits. Primary tumor resection in GEP-NENs with unresectable metastatic disease is associated with symptom control, prolonged survival, and improved sensitivity toward systemic therapies. Although there is no established neoadjuvant or adjuvant strategy, increasing attention has been given to this emerging research area. Some studies have reported that neoadjuvant therapy effectively reduces tumor burden, improves the effectiveness of subsequent surgery, and decreases surgical complications.

Introduction: The role of intraoperative ventilation strategies in subjects undergoing surgery is still contested. This meta-analysis study was performed to assess the relationship between the low tidal volumes strategy and conventional mechanical ventilation in subjects undergoing surgery.Methods: A systematic literature search up to December 2020 was performed in OVID, Embase, Cochrane Library, PubMed, and Google scholar, and 28 studies including 11,846 subjects undergoing surgery at baseline and reporting a total of 2,638 receiving the low tidal volumes strategy and 3,632 receiving conventional mechanical ventilation, were found recording relationships between low tidal volumes strategy and conventional mechanical ventilation in subjects undergoing surgery. Odds ratio (OR) or mean difference (MD) with 95% confidence intervals (CIs) were calculated between the low tidal volumes strategy vs. conventional mechanical ventilation using dichotomous and continuous methods with a random or fixed-effect model.Results: The low tidal volumes strategy during surgery was significantly related to a lower rate of postoperative pulmonary complications (OR, 0.60; 95% CI, 0.44–0.83, p < 0.001), aspiration pneumonitis (OR, 0.63; 95% CI, 0.46–0.86, p < 0.001), and pleural effusion (OR, 0.72; 95% CI, 0.56–0.92, p < 0.001) compared to conventional mechanical ventilation. However, the low tidal volumes strategy during surgery was not significantly correlated with length of hospital stay (MD, −0.48; 95% CI, −0.99–0.02, p = 0.06), short-term mortality (OR, 0.88; 95% CI, 0.70–1.10, p = 0.25), atelectasis (OR, 0.76; 95% CI, 0.57–1.01, p = 0.06), acute respiratory distress (OR, 1.06; 95% CI, 0.67–1.66, p = 0.81), pneumothorax (OR, 1.37; 95% CI, 0.88–2.15, p = 0.17), pulmonary edema (OR, 0.70; 95% CI, 0.38–1.26, p = 0.23), and pulmonary embolism (OR, 0.65; 95% CI, 0.26–1.60, p = 0.35) compared to conventional mechanical ventilation.Conclusions: The low tidal volumes strategy during surgery may have an independent relationship with lower postoperative pulmonary complications, aspiration pneumonitis, and pleural effusion compared to conventional mechanical ventilation. This relationship encouraged us to recommend the low tidal volumes strategy during surgery to avoid any possible complications.

Neuroinflammation plays an important role in neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease. HACE1 (HECT domain and Ankyrin repeat Containing E3 ubiquitin-protein ligase 1) is a tumor suppressor. Recent evidence suggests that HACE1 may be involved in oxidative stress responses. Due to the critical role of ROS in neuroinflammation, we speculated that HACE1 might participate in neuroinflammation and related neurodegenerative diseases, such as PD. In this study, we investigated the role of HACE1 in neuroinflammation of PD models. We showed that HACE1 knockdown exacerbated LPS-induced neuroinflammation in BV2 microglial cells in vitro through suppressing ubiquitination and degradation of activated Rac1, an NADPH oxidase subunit. Furthermore, we showed that HACE1 exerted vital neuronal protection through increasing Rac1 activity and stability in LPS-treated SH-SY5Y cells, as HACE1 knockdown leading to lower tolerance to LPS challenge. In MPTP-induced acute PD mouse model, HACE1 knockdown exacerbated motor deficits by activating Rac1. Finally, mutant α-synuclein (A53T)-overexpressing mice, a chronic PD mouse model, exhibited age-dependent reduction of HACE1 levels in the midbrain and striatum, implicating that HACE1 participated in PD pathological progression. This study for the first time demonstrates that HACE1 is a negative regulator of neuroinflammation and involved in the PD pathogenesis by regulating Rac1 activity. The data support HACE1 as a potential target for PD and other neurodegenerative diseases.

PURPOSE This study aimed to investigate the therapeutic potential of tumor suppression and mechanism for different implantation modes of iodine-125 (I-125) seeds irradiation in a mice xenograft model, and its skeletal complications. MATERIALS AND METHODS A total of 24 mice carrying A549 lung tumor-derived xenografts were randomly assigned to four groups, including non-radioactive (sham) seeds implantation, I-125 seeds fractional implantation, I-125 seeds single implantation and I-125 seeds single implantation combined with anlotinib. Ki67 immunohistochemistry, TUNEL immunofluorescence and CD31 morphometric analysis were used to determine the proliferation index, rate of apoptotic cells and microvessel density, respectively. Additionally, the side effects on the skeletal system in mice treated with I-125 seeds implantation were evaluated by histomorphometric staining with tartrate-resistant acid phosphate (TRAP) and alkaline phosphatase (ALP) expression in femur, tartrate-resistant acid phosphatase 5b (TRACP-5b) and procollagen type I N-terminal propeptide (PINP) levels in serum were evaluated by enzyme-linked immunosorbent assay (ELISA). RESULTS The I-125 seeds single and fractionated implantation had similar therapeutic effects and complications when the total number of I-125 seeds was the same. A single implantation of I-125 seeds with or without anlotinib could analogously inhibit the tumor growth in xenografts mice, while the single implantation combined with anlotinib had more effective in tumor inhibition. The results of Ki67, TUNEL and CD31 staining confirmed an evident reduction in tumor cell proliferation and angiogenesis, as well as an increase in apoptosis. A relatively integrated bone metabolism was indicated after I-125 seeds single implantation with or without anlotinib, and the results were similar in I-125 seeds fractional implantation, including a reduction in the number of TRAP-positive cells and an increase in ALP expression level. Additionally, the serum TRACP-5b activity was decreased and the serum PINP concentration was increased following I-125 seeds implantation. CONCLUSIONS Single and fractionated implantation pattern of I-125 radioactive seeds had similar therapeutic efficacy against tumor growth, while brachytherapy with I-125 seeds implantation may be an effective and safe treatment strategy for its potential protection against cancer treatment-induced bone loss.

BackgroundJin Ning Fang (JNF) is widely used as an adjuvant therapy for lung cancer. However, its molecular mechanism against lung cancer is still unclear.MethodsThe chemical compounds JNF were screened from the TCMSP database and its target proteins were then predicted. The genes related to lung cancer were collected from the CTD and DisGeNET databases. Next, targets were integrated with disease-related genes to obtain candidate genes. Functional enrichment and protein-protein interaction (PPI) analysis were also performed, followed by construction of pharmacological network. Meanwhile, Autodock was used to assess the affinity between targets and compound. Finally, the anti-cancer effect of JNF on lung cancer cells was detected and some predicted key genes was validated by using real-time PCR.ResultsTwenty-five overlapping targets were obtained, and pathway analysis showed that JNF might exert its anti-cancer function by regulating some biological pathways, such as apoptosis pathway. PPI and pharmacological network revealed several core targets (such as AKT1, AR, and ESR1) and three compounds (quercetin, calcium carbonate, and beta-sitosterol). Then, beta-sitosterol had a high affinity with AKT1, AR, and ESR1. Further in vitro experiments confirmed that JNF could inhibit proliferation and promote apoptosis of A549 cells. The expression of FDPS, PIM1, VCAM1, SLC29A1, NQO1, and ESR1 were significantly decreased, while mRNA level of AR and ANPEP were markedly increased after JNF treatment.ConclusionJNF may exert anti-lung cancer effect through multiple targets and pathways, and identified genes may be used as potential biomarkers for diagnosis and treatment of lung cancer.