Search

Adipose tissue serves as an essential endocrine regulator in glucose homeostasis and is involved in the progression of obesity and type 2 diabetes mellitus (T2DM), at least in part, through the induction of a chronic inflammatory state. Adipose tissue insulin resistance has been associated with dysregulated insulin signaling, impaired glucose uptake, and lipid homeostasis [1, 2]. Advanced glycation end products (AGEs) interact with the receptor for advanced glycation end products (RAGE), (expressed in multiple cell types including adipocytes, macrophages, and endothelial cells) to trigger cell activation and inflammatory responses [3, 4]. RAGE appears to be involved in the progression of obesity, correlating with adipose tissue inflammation, adipocyte hypertrophy, and insulin sensitivity [5, 6]. Supporting a role for ligand activation of RAGE in these metabolic disturbances, a soluble form of RAGE (sRAGE) has been found to competitively bind to AGEs, thus blocking the initiation of the proinflammatory RAGE signaling cascade [7]. Moreover, high-fat feeding elevates the levels of RAGE ligands, HMGB1 and carboxymethyl lysine (CML)-AGE, in the liver and adipose tissue [6]. Studies have suggested that the accumulation of adipose tissue macrophages (ATMs) contributes to local and systemic insulin resistance. The physiology and pathophysiology of ATMs in obesity is, however, a complex process that involves the recruitment of circulating monocytes to white adipose tissue (WAT), a phenotypic switch leading to macrophage polarization [8], and the proliferation of resident macrophages in WAT [9]. It has been reported that RAGE ligands can induce macrophage activation and upregulation of inflammatory factors [10, 11]. In addition, inflammatory responses in adipose tissues are characterized by increased levels of free fatty acids, lipid peroxidation, and oxidative stress, facilitating insulin resistance [12, 13]. Nevertheless, the precise role of RAGE in adipose tissue is currently under appreciated. Although RAGE mRNA is highly expressed in adipocytes, ATMs, and other adipose tissue cell types the role(s) of RAGE in obesity-associated inflammation and insulin resistance is unclear. Methylglyoxal (MGO) is one of the most potent glycating agents and a major precursor of AGEs [12, 14]. In relation to this, a previous study has demonstrated the MGO-dependent inhibition of insulin receptor-mediated pathways in adipose tissue [15]. Similarly, MGO treatment of 3T3-L1 adipocytes impairs insulin signaling [16]. From a mechanistic standpoint, MGO-derived AGEs may interact with RAGE thereby contributing to the inflammatory microenvironment [17, 18]. In addition, the accumulation of MGO in adipose tissue is associated with increased tissue glycation, further contributing to the development of diabetic complications [16]. Here, we aimed to examine the relative roles of RAGE in the regulation of adipose tissue insulin resistance and ATM phenotype. We found that RAGE deficiency potently reduces the recruitment of circulating monocytes to AT, suppresses M1 macrophage polarization, and improves tolerance to both glucose and insulin. These data demonstrate that the RAGE has the potential to impact physiological and pathophysiological metabolic responses in adipose tissues.

Aluminium nitride high-temperature co-fired ceramic (AlN HTCC) substrate is a preferred electronic packaging material. It displays a low thermal expansion coefficient, low dielectric constant, low dielectric loss, and high thermal conductivity at a high frequency. It can also prefabricate the circuit inside. Considering the need to increase the specific surface area of AlN HTCC substrates and thereby enhance the heat dissipation performance, a rapid fabrication method involving chemically assisted laser ablation is proposed to machine microstructures on AlN HTCC substrates. The influence of power, atmosphere, and other factors on the ablation quality of AlN HTCC substrates was explored on this basis. The main component of the ablation products was Al in an Ar atmosphere. However, the modification layers in N2 and O2 atmospheres were composed of multiple components including Al, AlN, and Al2O3. The accuracy of the top and bottom widths of the microgrooves in the Ar atmosphere was higher than those for the N2 and O2 atmospheres. However, the variation of atmosphere had a negligible effect on the ablation depth. When the laser-energy density was 100 J/mm2 and the scanning distance was 10 μm, the ablation depth increased linearly from 150 μm to 350 μm as the laser power increased from 8 W to 20 W. The deviation in laser-energy density was established to predict the surface roughness and optimise the laser parameters. It was observed that the surface roughness increased with an increase in the deviation in laser-energy density. The surface roughness could be reduced by two–three times from that obtained by laser ablation with optimisation.

Mitsugumin 53 (MG53), which is expressed predominantly in striated muscle, has been demonstrated to be a myokine/cardiokine secreted from striated muscle under specific conditions. The important roles of MG53 in non‐striated muscle tissues have also been examined in multiple disease models. However, no previous study has implicated MG53 in the control of endothelial cell function. In order to explore the effects of MG53 on endothelial cells, human umbilical vein endothelial cells (HUVECs) were stimulated with recombinant human MG53 (rhMG53). Then, rhMG53 uptake, focal adhesion kinase (FAK)/Src/Akt/ERK1/2 signalling pathway activation, cell migration and tube formation were determined in vitro. The efficacy of rhMG53 in regulating angiogenesis was also detected in postnatal mouse retinas. The results demonstrated that rhMG53 directly entered into endothelial cells in a cholesterol‐dependent manner. The uptake of rhMG53 directly bound to FAK in endothelial cells, which resulted in a significant decrease in FAK phosphorylation at Y397. Accompanied by the dephosphorylation of FAK, rhMG53 uncoupled FAK‐Src interaction and reduced the phosphorylation of Src at Y416. Consequently, the activation of FAK/Src downstream signalling pathways, such as Akt and ERK1/2, was also significantly inhibited by rhMG53. Furthermore, rhMG53 remarkably decreased HUVEC migration and tube formation in vitro and postnatal mouse retinal angiogenesis in vivo. Taken together, these data indicate that rhMG53 inhibits angiogenesis through regulating FAK/Src/Akt/ERK1/2 signalling pathways. This may provide a novel molecular mechanism for the impaired angiogenesis in ischaemic diseases.

Metastasis is the most prevalent cause of cancer-related deaths and treatment failure in patients with hepatocellular carcinoma (HCC). Kaempferol is a natural flavonol belonging to the subgroup of flavonoids and exhibits potent anticancer activities. This study provides molecular evidence on the anti-invasive and anti-migratory effects of kaempferol on human HCC cells. The anti-invasive effect was investigated by applying kaempferol on two human HCC cell lines (Huh-7 and SK-Hep-1). Kaempferol reduced the invasion and migration of Huh-7 and SK-Hep-1 cells by Boyden chamber invasion assay and wound healing assay, respectively. A protease array analysis showed that Matrix Metalloproteinase-9 (MMP-9) was dramatically downregulated in HCC cells after kaempferol treatment. Gelatin zymography and Western blot assay showed that kaempferol reduced the activities and protein expression of MMP-9, respectively. Kaempferol also sufficiently suppressed the phosphorylation of the Akt expression. Overall, kaempferol inhibited the invasive properties of human HCC cells by targeting MMP-9 and Akt pathways. Hence, kaempferol could be used as an adjuvant therapeutic agent for the treatment of human HCC cells.

Aim: To explore the relationship between the neutrophil-to-lymphocyte ratio (NLR) and renal damage in patients with H-type hypertension. Materials & methods: A total of 618 patients between 2017 and 2019 were analyzed retrospectively. Results: NLR was significantly correlated with renal damage in hypertension patients. Appropriate cut-off value for NLR (2.247) was determined by receiver operating characteristic curve; linear regression analysis showed that NLR and estimated glomerular filtration rate, blood urea nitrogen/creatinine has a significant negative correlation in H-type hypertension group (p

Background 3β-HSD deficiency is a rare type of congenital adrenal hyperplasia (CAH), which is caused by HSD3B2 gene mutations. Objectives In order to improve the understanding and diagnosis of the disease, we analyzed and summarized the clinical characteristics, genetic variants and treatment for 3 children with 3β-HSD deficiency in this study. Material and methods A summary of the clinical data, hormone levels (17-hydroxyprogesterone, adrenocorticotropic hormone, cortisol, testosterone, dehydroepiandrosterone, androstenedione, renin, and aldosterone), therapeutic drugs, and gene sequencing results from 3 3β-HSD deficiency patients was created. Results The 3 patients developed external genital abnormalities and adrenal insufficiency in infancy. Steroid hormone levels were consistent with 3β-hydroxysteroid dehydrogenase deficiency. Gene sequencing for the 3 patients detected complex heterozygous mutations in the HSD3B2 gene, which confirmed the diagnosis of 3β-HSD deficiency type II. Among the mutation types, c.154_162delinsTCCTGTT and c.674T>A have not been reported in the literature. The 3 children were treated with glucocorticoid and mineralocorticoid replacement, which controlled the adrenal insufficiency satisfactorily. In 2 male patients, external genital dysplasia manifested as hypospadias and small penis. After long-acting testosterone intramuscular injection to increase the penis size, the hypospadias were repaired. Mild masculinization in the female patient resulted in skin pigmentation and clitoral hypertrophy; however, no surgical intervention was required. Conclusions The main clinical manifestations of 3β-HSD deficiency were adrenal insufficiency and sex hormone synthesis dysfunction. There was a strong phenotype correlation between the observed clinical manifestations in conjunction with steroid hormone levels and HSD3B2 mutations. The novel mutations c.154_162delinsTCCTGTT and c.674T>A were classified as pathogenic variants. Adrenal cortical function control was satisfactory after hormone replacement therapy, and hypospadias and small penis were attenuated using testosterone replacement therapy during mini-puberty for optimal surgical outcome.

Abstract Euphopepluanones F − K (1 − 4), four new jatrophane type diterpenoids were isolated from the seeds of Euphorbia peplus, along with eight known diterpenoids (5 − 12). Their structures were established on the basis of extensive spectroscopic analysis and X-ray crystallographic experiments. The new compounds 1 − 4 were assessed for their activities to induce lysosomal biogenesis through LysoTracker Red staining. Compound 2 significantly induced lysosomal biogenesis. In addition, compound 2 could increase the number of LC3 dots, indicating that it could activate the lysosomal-autophagy pathway. Graphic Abstract

The present study aimed to analyze the chemical composition and fumigant toxicity of essential oils (EOs) isolated by hydrodistillation from Piper hancei Maxim. EOs extracted from the dry stems and...

An efficient highly regioselective C5-H direct iodination of indoles is reported herein for the first time. Due to the versatility of aryl iodides, the method offers a general and practical access to the C5 functionalization of indoles. The approach features mild reaction conditions, good tolerance of functional groups, and more crucially, no metal involved in the reaction, thereby benefitting the late-stage decoration of medicinal molecules. A mechanistic study showed that the current iodination reaction proceeded via a radical pathway.

Three novel jatrophane diterpenes, cyclojatrophanes A-C (1-3), were isolated from the seeds of Euphorbia peplus. Compounds 1-3 featured an unprecedented 5/5/5/11 tetracyclic ring system incorporating ditetrahydropyran rings. Their structures including their absolute configurations were established by extensive spectroscopic analysis, X-ray crystallographic experiments and chemical transformations. In addition, these compounds could significantly activate the lysosomal-autophagy pathway.

Harpertrioate A (1), an A,B,D-seco-limonoid with a rearranged ring B incorporating exocyclic C-30, was isolated from the EtOAc extract of Harrisonia perforata twigs. Its structure, including absolute configurations, was determined on the basis of spectroscopic data and X-ray crystallography. This compound exhibited biological activities against Alzheimer's disease by reducing Aβ42 and Aβ40 production and shifting APP processing toward nonamyloidogenic pathway. The effect of 1 on the Aβ production was comparable to that of gemfibrozil.

A Cu(II) coordination polymer, [Cu2(pztrz)2(μ-CH3COO)(CH3COO)]·3H2O (1), derived from mono-substituted 1,2,4-triazole derivative 3-(pyrazinyl)-1,2,4-triazole (Hpztrz) is isolated and structurally characterized. X-ray structural analysis shows that Hpztrz ligands and acetate anions demonstrate different coordination modes in complex 1. The two Cu(II) ions are bridged by the 1,2,4-triazole ring of Hpztrz to form a dinuclear unit, which is further linked by two bridging acetate anions to form a tetranuclear Cu4 unit. Interestingly, each Cu4 unit is connected to another four Cu4 units through the outer pyrazinyl of Hpztrz, resulting in a two-dimensional (2D) layer structure. Consecutive layers are further packed into three-dimensional (3D) structures through interlayer hydrogen-bonding interactions. Furthermore, variable-temperature magnetic susceptibility studies reveal that the antiferromagnetic interactions are mediated through 1,2,4-triazole-N1,N2 bridges and acetate bridges with coupling constants of J1 = − 69.98 cm−1 and J2 = − 2.15 cm−1. Synergistic co-coordination of 1,2,4-triazole and acetate ions with Cu(II) ions led to a dinuclear unit, then to a Cu4 unit and finally to a 2D layer. Consecutive layers are further packed into a 3D framework through interlayer hydrogen-bonding interactions. Furthermore, variable-temperature magnetic susceptibility studies indicated the existence of antiferromagnetic coupling between the Cu(II) ions.

L-Carnosine (β-alanyl-L-histidine) is a naturally occurring dipeptide, which has shown broad-spectrum anticancer activity. But the anticancer mechanisms and regulators remain unknown. In this study, we investigated the effects of carnosine on human glioma U87 and U251 cell lines under normoxia (21% O(2)) and hypoxia (1% O(2)). We showed that carnosine (25−75 mM) dose-dependently inhibited the proliferation of the glioma cells; carnosine (50 mM) inhibited their colony formation, migration, and invasion capacity. But there was no significant difference in the inhibitory effects of carnosine under normoxia and hypoxia. Treatment with carnosine (50 mM) significantly decreased the expression of glutamine synthetase (GS) at the translation level rather than the transcription level in U87 and U251 cells, both under normoxia and hypoxia. Furthermore, the silencing of GS gene with shRNA and glutamine (Gln) deprivation significantly suppressed the growth, migratory, and invasive potential of the glioma cells. The inhibitory effect of carnosine on U87 and U251 cells was partly achieved by inhibiting the Gln metabolism pathway. Carnosine reduced the expression of GS in U87 and U251 cells by promoting the degradation of GS through the proteasome pathway, shortening the protein half-life, and reducing its stability. Given that targeting tumor metabolism is a proven efficient therapeutic tactic, our results may present new treatment strategies and drugs for improving the prognosis of gliomas.

Glycation of extracellular matrix proteins has been demonstrated to contribute to the pathogenesis of vascular complications. However, no previous report has shown the role of glycated fibronectin (FN) in vascular endothelial growth factor (VEGF)‐induced angiogenesis. Thus, this study aimed to investigate the effects of glycated FN on VEGF signalling and to clarify the molecular mechanisms involved. FN was incubated with methylglyoxal (MGO) in vitro to synthesize glycated FN, and human umbilical vein endothelial cells (HUVECs) were seeded onto unmodified and MGO‐glycated FN. Then, VEGF‐induced angiogenesis and VEGF‐induced VEGF receptor‐2 (VEGFR‐2) signalling activation were measured. The results demonstrated that normal FN‐positive bands (260 kD) vanished and advanced glycation end products (AGEs) appeared in MGO‐glycated FN and glycated FN clearly changed to a higher molecular mass. The glycation of FN inhibited VEGF‐induced VEGF receptor‐2 (VEGFR‐2), Akt and ERK1/2 activation and VEGF‐induced cell migration, proliferation and tube formation. The glycation of FN also inhibited the recruitment of c‐Src to VEGFR‐2 by sequestering c‐Src through receptor for AGEs (RAGE) and the anti‐RAGE antibody restored VEGF‐induced VEGFR‐2, Akt and ERK1/2 phosphorylation, endothelial cell migration, proliferation and tube formation. Furthermore, the glycation of FN significantly inhibited VEGF‐induced neovascularization in the Matrigel plugs implanted into subcutaneous tissue of mice. Taken together, these data suggest that the glycation of FN may inhibit VEGF signalling and VEGF‐induced angiogenesis by uncoupling VEGFR‐2‐c‐Src interaction. This may provide a novel mechanism for the impaired angiogenesis in diabetic ischaemic diseases.

Non-small cell lung cancer (NSCLC) is often complicated by pulmonary infection, which affects treatment and prognosis. Bacterial lipopolysaccharide (LPS) is an effective stimulator of inflammatory cytokine production, and previous studies have reported that LPS promotes tumor invasion and metastasis. Mangiferin is a plant-derived C-glucosylxanthone with many biological activities, such as antioxidation and anti-inflammation. This research mainly explored the mechanism of its antitumor activities on LPS-induced A549, NCI-H460, and NCI-H520 NSCLC cells. We determined that mangiferin exhibits growth inhibiting activity against LPS-induced NSCLC cells through the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. In addition, mangiferin reversed the LPS-induced downregulation of E-cadherin (epithelial marker); conversely, it significantly inhibited the expression of raised vimentin (mesenchymal markers). Moreover, the ability of NSCLC cells to migrate, as evidenced by the wound healing and transwell migration assays, and the expression of CXCR4 increased by LPS were significantly repressed by mangiferin. In addition, mangiferin markedly mediated protein levels of PER1 and NLRP3 in LPS-induced NSCLC cells and reduced the secretion of IL-1β. These results indicate that mangiferin is not only a remarkable anti-inflammatory compound but also an antitumor agent; thus, it has the potential for being developed into anti-inflammatory and antitumor drugs in the future.

Cantharidic acid (CA) is the hydrolysis product of the acid anhydride cantharidin, which is a natural toxin secreted by several species of blister beetles. Several studies have indicated that as an inhibitor of protein phosphatase 2 (PP2A), CA induces apoptosis in various human cancer cells. However, the effect of CA on human nasopharyngeal carcinoma (NPC) cells and the underlying pathways have not been addressed. In our current study, we tested the hypothesis that CA treatment reduces the viability of human NPC cells (HONE-1, NPC-39, and NPC-BM) by inducing apoptosis. Results indicated that CA markedly reduced cell viability, which was revealed by the upregulation of caspase activation in extrinsic and intrinsic apoptosis pathways as well as the upregulation of extracellular-signal-regulated kinase 1/2 (ERK1/2), p38, and c-Jun N-terminal kinase 1/2 (JNK1/2) pathways. Coadministration of a p38 inhibitor (SB203580) with CA abolished the activation of caspase proteins. These findings indicated that CA treatment leads to apoptosis in human NPC cells through the upregulation of caspase activation, mediated particularly by the p38 pathway. Hence, CA is a promising therapeutic agent for human NPC.

Three new diterpenoids (1–3) (two abietane type diterpenoids and a paralianone type diterpenoid), together with four known compounds (4–7) were isolated from the whole plants of Euphorbia peplus. T...

In this study, the water-soluble products formed during the hydrothermal carbonization of glucose were analyzed by liquid chromatography (LC)–mass spectrometry (MS) and LC–MS2 to determine the form...

Amphetamine (AMPH), an appetite suppressant, alters expression levels of neuropeptide Y (NPY) and cocaine- and amphetamine-regulated transcript (CART) in the hypothalamus. This study explored the potential role of cJun-N-terminal kinases (JNK) in appetite control, mediated by reactive oxygen species (ROS) and activator protein-1 (AP-1) in AMPH-treated rats. Rats were given AMPH daily for 4 days. Changes in feeding behavior and expression levels of hypothalamic NPY, CART, cFos, cJun, phosphorylated JNK (pJNK), as well as those of anti-oxidative enzymes, including superoxide dismutase (SOD), glutathione peroxidase (GP) and glutathione S-transferase (GST), were examined and compared. Following AMPH treatment, food intake and NPY expression decreased, whereas the other proteins expression and AP-1/DNA binding activity increased. Both cerebral cJun inhibition and ROS inhibition attenuated AMPH anorexia and modified detected protein, revealing a crucial role for AP-1 and ROS in regulating AMPH-induced appetite control. Moreover, both pJNK/CART and SOD/CART activities detected by double immunofluorescent staining increased in hypothalamic arcuate nucleus in AMPH-treated rats. The results suggested that pJNK/AP-1 signaling and endogenous anti-oxidants participated in regulating NPY/CART-mediated appetite control in rats treated with AMPH. These findings advance understanding of the molecular mechanism underlying the role of pJNK/AP-1 and oxidative stress in NPY/CART-mediated appetite suppression in AMPH-treated rats.

Shikonin mitigated tumor cell proliferation by elevating reactive oxygen species (ROS) levels. Herein, we investigated the effects of shikonin on renal cancer cell (RCC) cell proliferation. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay indicated that shikonin dose-dependently reduced the proliferation of Caki-1 and ACHN cells. Shikonin remarkably triggered necrosis and apoptosis in Caki-1 and ACHN cells in proportion to its concentration. Moreover, necrostatin-1 recovered cell viability in the presence of shikonin. Elevated ROS levels and mitochondrial dysfunction were also found in shikonin treatment groups. Pretreatment with N-acetyl cysteine remarkably mitigated shikonin-induced cell death and ROS generation. Western blot analysis revealed that shikonin reduced pro-PARP, pro-caspase-3, and Bcl-2 expression and increased cleavage PARP expression. Enhanced autophagy was also found in the shikonin-treated group as evidenced by acridine orange staining. Moreover, light chain 3B (LC3B)-II accumulation and enhanced p62 expression indicated that autophagy occurred in the shikonin-treated group. LC3B knockdown considerably recovered cell viability in the presence of shikonin. Shikonin treatment elevated p38 activity in a dose-dependent manner. In conclusion, our results revealed that shikonin triggered programmed cell death via the elevation of ROS level and p38 activity in different types of RCC cells. These findings suggested that shikonin may be a potential anti-RCC agent.

Caenorhabditis elegans benefits from a large set of tools for genome manipulation. Yet, the precise single-copy insertion of very large DNA constructs (>10 kb) and the generation of inversions are still challenging. Here, we adapted the phiC31 integrase system for C. elegans. We generated an integrated phiC31 integrase expressing strain flanked by attP sites that serves as a landing pad for integration of transgenes by recombination-mediated cassette exchange (RCME). This strain is unc-119(−) so RMCE integrants can be produced simply by injection of a plasmid carrying attB sites flanking unc-119(+) and the gene(s) of interest. Additionally, phiC31 integrase is removed concomitantly with integration, eliminating the need to outcross away the integrase. Integrations were obtained for insert sizes up to ∼33.4 kb. Taking advantage of this integration method we establish a dual-color fluorescent operon reporter system able to study post-transcriptional regulation of mRNA. Last, we show that large chromosomal segments can be inverted using phiC31 integrase. Thus, the phiC31 integrase system should be a useful addition to the C. elegans toolkit.

Posttraumatic epilepsy (PTE) is a prevalent complication of brain trauma. Current anti-epileptic drugs available do not have satisfactory response to PTE. It is of desperate need to explore novel therapeutic approaches for curing PTE. Our prior work revealed that ferroptosis, a recently discovered mode of cell death, occurs in rodent model of PTE. In the present study, we aimed to further investigate the effect of ferrostatin-1 (Fer-1), a specific ferroptosis inhibitor, on seizure behavior and cognitive deficit in a mouse model of PTE. The preparation of PTE was performed by stereotaxical injection in the somatosensory cortex region of 50 mM FeCl 3 . Seizure activity was assessed via Racine scoring and electroencephalogram analysis. PTE-related cognitive function was evaluated by novel object recognition and Morris water maze tests. Ferroptosis-related indices including glutathione peroxidase (GPx) activity and protein expressions of 4-hydroxynonenal (4-HNE) were detected using a commercial kit and immunofluorescence, respectively. It was found that treatment with Fer-1 significantly exerted protective effects against acute seizure and memory decline, although no evident effect on epileptic progression. Fer-1 also exhibited good tolerability and safety as we observed that it hardly influenced the body weight. Furthermore, it was noted that administration of Fer-1 suppressed ferroptosis-related indices including GPx activity and protein expressions of 4-HNE in hippocampus. These data altogether indicate that Fer-1 has potent therapeutic effects against seizures and cognitive impairment following PTE-induced brain insult. Fer-1 may act as a promising drug for curing PTE patients.

Stromal cell-derived factor 1 (SDF-1, also known as CXCL12) and its receptor CXCR4 have shown to play a role in the homing and engraftment of hematopoietic stem and progenitor cells. SDF-1 is highly expressed in platelets and involved in thrombosis formation. However, the exact roles of platelet-derived SDF-1 and CXCR4 in platelet activation and mitochondrial function have not been revealed yet. Deletion of Sdf-1 and Cxcr4 specifically in platelets decreased agonist-induced platelet aggregation and dramatically impaired thrombin-induced glucose uptake. In SDF-1-deficient and CXCR4-deficient platelets, intracellular ATP secretions were reduced when activated by the addition of thrombin. SDF-1 deficiency in platelets can impair the routine respiration during resting state and maximal capacity of the electron transfer system (ETS) during activated state. Mitochondrial respiration measurements in permeabilized platelets indicated an impaired function of the oxidative phosphorylation system in -SDF-1 or CXCR4-deficient platelets. These results suggested a novel role of the SDF-1/CXCR4 axis in modulating platelet energy metabolism and activation by regulating mitochondrial respiration, glucose uptake, and ATP production.

Metabolites can mediate species interactions and the assembly of microbial communities. However, how these chemicals relate to the assembly processes and co-occurrence patterns of diazotrophic assemblages in root-associated soils remains largely unknown. Here, we examined the diversity and assembly of diazotrophic communities and further deciphered their links with metabolites on Tibetan Plateau. We found that the distribution of sugars and organic acids in the root-associated soils was significantly correlated with the richness of diazotrophs. The presence of these two soil metabolites explains the variability in diazotrophic community compositions. The differential concentrations of these metabolites were significantly linked with the distinctive abundances of diazotrophic taxa in same land types dominated by different plants or dissimilar soils by same plants. The assembly of diazotrophic communities is subject to deterministic ecological processes, which are widely modulated by the variety and amount of sugars and organic acids. Organic acids, for instance, 3-(4-hydroxyphenyl)propionic acid and citric acid, were effective predictors of the characteristics of diazotrophic assemblages across desert habitats. Diazotrophic co-occurrence networks tended to be more complex and connected within different land types covered by the same plant species. The concentrations of multiple sugars and organic acids were coupled significantly with the distribution of keystone species, such as Azotobacter, Azospirillum, Bradyrhizobium, and Mesorhizobium, in the co-occurrence network. These findings provide new insights into the assembly mechanisms of root-associated diazotrophic communities across the desert ecosystems of the Tibetan Plateau.Key points• Soil metabolites were significantly linked to the diversity of diazotrophic community.• Soil metabolites determined the assembly of diazotrophic community.• Sugars and organic acids were coupled mainly with keystone species in networks.

A strategy by exogenous addition of quorum sensing molecule farnesol to improve the production, antioxidant activity and antitumor activity of extracellular polysaccharide (EPS) of Grifola frondosa by liquid fermentation was proposed in the study. The highest yield of EPS induced by farnesol was 1.25 g/L, which was 150% higher than that of the control. Four polysaccharides including EPS-C-0M, EPS-C-0.2M, EPS-F-0M and EPS-F-0.2M were extracted and purified under the conditions of control and farnesol respectively. The physicochemical properties, antioxidant activities and antitumor activities were studied. Their chemical composition differed in sugar, protein and uronic acid contents, and they were composed of six constituent monosaccharides with different ratios, with the average molecular weights of 1.12 × 103, 1.89 × 103, 1.41 × 103 and 2.02 × 103 kDa, respectively. They presented similar FT-IR spectra, but different surface morphology. Antioxidant experiments showed that they had strong scavenging activities on ABTS+, hydroxyl radical, O2− and DPPH radical. Antitumor experiments showed that they had strong inhibitory effects on human cervical cancer (HeLa) cells and human liver cancer cells (HepG2) cells. Among the four polysaccharides, EPS-F-0.2M showed the highest antioxidant and antitumor activities, indicating that farnesol could regulate the biological activity of EPS by affecting structure and properties. These results demonstrated that appropriate adjustment of culture conditions had potential application in the development of polysaccharides with high antioxidant and antitumor activity. It provided a new strategy to enhance the production and bioactivity of edible and medicinal fungal polysaccharides by using quorum sensing molecules.

BackgroundTo explore whether patients with distinct intraductal carcinoma of the prostate (IDC-P) subtypes respond differently to standard first-line therapy among patients with metastatic castration resistant prostate cancer (mCRPC).MethodsWe retrospectively analyzed data of 170 mCRPC patients receiving abiraterone (ABI) or docetaxel (DOC) as first-line therapy between 2014 and 2019. PSA response, PSA progression-free survival (PSA-PFS), radiographic progression-free survival (rPFS), and overall survival (OS) were analyzed and compared based on the presence of IDC-P and its sub-patterns.ResultsTotally, IDC-P was confirmed in 91/170 (53.5%) patients. Among them, 36/91 (39.6%) and 55/91 (60.4%) harbored IDC-P pattern 1 and pattern 2, respectively. The presence of IDC-P was confirmed to be associated with poor prognosis in the whole cohort. Patients with IDC-P pattern 1 shared similar clinical outcomes to those without IDC-P in both ABI and DOC treatment. However, compared to patients with IDC-P pattern 1 and without IDC-P, IDC-P pattern 2 had markedly poorer prognosis in either ABI (PSA-PFS: PPPPP=0.021; rPFS: P=0.027) or pattern 2 (PSA-PFS: P=0.003; rPFS: P=0.007) was significantly inferior to ABI.ConclusionCompared to DOC, ABI exhibited better efficacy in patients with IDC-P of either pattern. However, IDC-P pattern 2 still responded unsatisfactorily to either ABI or DOC therapy. Novel therapeutic strategies appropriate for IDC-P pattern 2 need to be further investigated in the future.

Proliferative vitreoretinopathy (PVR) involves retinal pigment epithelium (RPE) cell proliferation and migration and leads to tractional retinal detachment. Demethoxycurcumin (DMC), a curcuminoid, has anti-inflammatory and anti-tumour properties. However, whether DMC affects the migration of RPE cells and the molecular mechanism of human PVR remains unclear. The aim of the current study was to investigate the effects of DMC on the inhibition of migration and proteinase expression of human ARPE-19 cells. Herein, we provided molecular evidence associated with PVR prevention through DMC by inhibiting ARPE-19 cell migration. We performed gelatin zymography, Western blot and RT-PCR and respectively found that DMC is sufficient to reduce matrix metalloproteinase-2 (MMP-2) activity, protein level and mRNA expression. DMC suppressed the nuclear levels of transcriptional factors specificity protein 1 and c-Fos, which are involved in the modulation of the transcriptional activation of the MMP-2 gene. DMC also inhibited STAT-3 phosphorylation in ARPE-19 cells. Selective STAT-3 induction by a STAT-3 activator, colivelin, reverted MMP activity and protein expression and cell migration, which were reduced in response to DMC. The results proved the inhibitory effect of DMC on RPE cell migration and MMP-2 expression by the down-regulation of the STAT-3 signalling pathway.

Hydrochars are solid byproducts formed during the liquid-phase biorefinery process and could be used to generate functional carbonaceous materials, but the detailed molecular structure and the form...

Sanguisorba officinalis L., one kind of perennial plants, has been widely distributed in southern Europe, northern Africa and China. The objective of the present work was to evaluate the antibacterial captivities of polyphenolic extract (PE) of S. officinalis L. on five pathogenic bacteria, including Gram-negative bacteria (Escherichia coli and Salmonella typhimurium) and Gram-positive bacteria (Staphylococcus aureus, Listeria monocytogenes and Bacillus subtilis). The antibacterial activities were determined by the diameter of inhibition zone, minimum inhibitory concentration and minimum bactericidal concentration tests. The results showed that purified PE had significantly better performance in inhibiting bacteria than crude PE (P

Fluorination is a feasible method to modify the properties of graphene. However, the fluorination methods still meet different limitations such as inconvenient, low-yield, high-cost, etc. Here, a room-temperature method at ambient conditions was presented to synthesize fluorinated graphene oxide (FGO). The obtained FGO had the F content of ca. 28.6 at%. The mechanism of the reaction at ambient conditions was discussed by theoretical calculations, which showed that the oxygen groups facilitated to generate stable C F bonds by overcoming a low reaction barrier. This work provides an easy synthesis of FGO, broadening the applications of functionalized graphene, for example, increasing the magnetic inducing efficiency to ca. 1.03 × 10−2 μB/F.

A 27-year-old pregnant female underwent cesarean section due to preeclampsia. Two days after the delivery, she presented with acute onset of blurred vision in the left eye. Optical coherence tomography (OCT) revealed characteristic findings of acute macular neuroretinopathy (AMN) in both eyes. During the follow-up, her vision improved gradually, but outer nuclear layer thinning with disruption of ellipsoid zone was identified from OCT. OCT angiography was arranged and revealed both vascular defect in superficial and deep vascular plexus, which correlated with previous AMN lesions in both eyes. Subsequent microvascular change in AMN was found to involve both superficial and deep vascular plexus, which is different from the current consensus that AMN mainly involved deep vascular plexus. By using the OCT angiography, we can better visualize the detail retinal vascular structure and may identify the real mechanism in this rare retinal disorder.

The massive production and wide application of vanadium dioxide nanoparticles (VO2 NPs) has raised safety concerns of VO2 NPs exposure through various routes, especially via inhalation. To determine the pulmonary toxicity of VO2 NPs in vitro, we report here on short-term (1 day) and long-term (20 days) comparative toxicity studies of VO2 NPs (denoted as C-VO2, 20–30 nm) and VO2 microparticles (denoted as M-VO2, ∼1 μm) on the lung cell line A549. Different toxic effects were observed under different durations of exposures to VO2 particles. VO2 particles induced cell growth inhibition and death in a dose- and size-dependent style after short-term exposure. The cell viability dropped when the concentration of C-VO2 was 2.5 μg ml−1, C-VO2 causing much more severe cell viability loss than M-VO2 at the same concentration. For long-term exposure, the cell viability dropped to less than 50% after exposure to C-VO2 at a dose of 0.2 μg ml−1, while cells exposed to M-VO2 under the same conditions remained normal, confirming the higher toxicity of C-VO2 than that of M-VO2. Moreover, the long-term exposure to C-VO2 only inhibited the cell proliferation. We found that 0.05 μg ml−1 was the highest non-toxic dose of C-VO2 to A549 cells for long-term exposure. The dissolution of VO2 contributed to the cytotoxicity of VO2. In addition, reactive oxygen species (ROS) generation, mitochondrial damage, cell membrane leakage, apoptosis, and inflammation were observed in the cells after short-term exposure to VO2 particles in the concentration range tested, indicating that the possible toxicological mechanism might be ROS generation and cell cycle arrest in the G0/G1 phase. ROS generation, mitochondrial damage, and inflammation in cells were also observed during the long-term exposure to C-VO2 at concentrations of 0.1 μg ml−1 and 0.2 μg ml−1, but the cells recovered after a subsequent 5 day recovery period. Our results show that there are significant differences between the short-term and long-term cytotoxicities of VO2.

Purpose: To report the surgical results and technique of perfluorocarbon-assisted neurosensory retinal flap transplantation into macular hole for concomitant macular hole and complicated retinal detachment. Method: This is a retrospective, consecutive case series of 7 cases with concomitant macular hole and complicated retinal detachment with proliferative vitreoretinopathy. All eyes had previous vitrectomy and internal limiting membrane peeling, or very large (>1,000 μm) macular holes. Perfluorocarbon liquid-assisted free neurosensory retinal flap transplantation into the macular hole, and subretinal fluid drainage through iatrogenic retinectomy/retinotomy were performed, followed by air-fluid exchange with gas or silicone oil tamponade. Results: All eyes had retina reattached. Macular hole was closed in all eyes, with the graft visualized by optical coherence tomography. The best corrected visual acuity in logarithm of minimal angle of resolution improved from 2.80 ± 0.45 preoperatively to 1.40 ± 0.51 postoperatively (p < 0.01). Conclusions: Neurosensory retinal flap may be a good option in closing macular holes in eyes with concomitant macular hole and complicated retinal detachment. Because of its specific properties, the flap is easy to handle during the operation. Retinectomy or retinotomy serves to release traction, drain subretinal fluid, and provide retinal flap tissue.

Background Prostate cancer is highly prevalent with a high mortality among males worldwide. Naringenin has been demonstrated to exhibit multiple cellular functions. In this study, we examined the effects of naringenin on prostate cancer. Materials and methods Transwell and zymography assays were used to detect cell migration and urokinase plasminogen activator (uPA) activity, respectively. Alternation of protein expression was measured by western blot analysis. Results Transwell assay and zymography revealed that naringenin suppressed the migration and invasion of PC-3 cells and uPA activity in proportion to the concentration of naringenin. Western blot analysis indicated that naringenin up-regulated E-cadherin expression, but down-regulated the expression of vimentin, SNAIL family zinc finger 1 (SNAI1), SNAIL family zinc finger 2 (SNAI2), and TWIST family bHLH transcription factor 1 (TWIST1). Conclusion Naringenin inhibited the migration and invasion of PC-3 cells by reversing expression of proteins involved in epithelial-to-mesenchymal transition and down-regulation of uPA activity. Thus, naringenin may be a promising anti-metastasis agent for prostate cancer.

Glioblastoma (GBM) is the most mortality brain cancer in the world. Due to high invasion and drug resistance cause the poor prognosis of GBM. Naringenin, an ingredient of citrus, exhibits many cellular functions such as antioxidant, anti-inflammation, and anticancer. Naringenin inhibits the migration of bladder and lung cancer via modulation of MMP-2 and/or MMP-9 activities, Naringenin inhibits migration and trigger apoptosis in gastric cancer cells through downregulation of AKT pathway. However, the effects of naringenin in GBM still remain to be elucidated. In this study, we reveal the molecular mechanisms of naringenin in the inhibition of migration and invasion in GBM. No overt alternation of cell proliferation was found in of GBM 8901 cells treated with different concentration of naringenin. Slight decreased cell viability was found in GBM 8401 cell treated with 200 and 300 μM naringenin. Significant reduction of migration and invasion as assayed by Boyden chamber analysis was found in of GBM cells treated with 100, 200, and 300 μM naringenin. Zymography analysis also revealed that the activities of MMP-2 and MMP-9 of GBM cells were significantly inhibited in response to 100, 200, or 300 μM naringenin treatment. Proteins of MMP-2 and MMP-9 were downregulated in naringenin treated GBM cells. In addition, naringenin also attenuated the activities of ERK and p38. Naringenin decreased mesenchymal markers (snail and slug) expression as revealed by Western blot analysis. Taken together, our findings indicated that naringenin eliminated the migration and invasion of GBM cells through multiple mechanisms including inhibition of MMPs, ERK, and p38 activities and modulation of EMT markers. Our results also suggested that naringenin may be a potential agent to prevent metastasis of GBM.

Purpose. To evaluate logical surgical approaches to closing macular holes in eyes with proliferative diabetic retinopathy with retinal detachment. Methods. Retrospective, interventional case series. Results. 10 eyes in 10 patients were included in this study. The inverted internal limiting membrane (ILM) flap technique was used in 2 eyes, while inverted ILM insertion was used in 5 eyes, and free ILM flaps in 3 eyes. Closed macular holes and retinal reattachment were observed in all eyes. Best corrected visual acuity improved from 1.33 ± 0.39 preoperatively to 1.02 ± 0.36 postoperatively (p=0.03). Conclusion. Various surgical approaches utilized in managing macular holes may effectively close macular holes and reattach retinas. This trial is registered with NCT 03618498.

Epigallocatechin-3-gallate (EGCG) has been demonstrated to exhibit anticancer effects; however, the mechanisms behind these are not yet clear. The objective of the present study was to assess the effect of EGCG on smoking-induced, precancerous, bronchial epithelial cell lesions and determine a potential protective mechanism. Human bronchial epithelial (HBE) cells were treated with cigarette smoke extract (CSE). Benzopyrene-DNA adducts were detected by immunofluorescence cytochemistry. Changes to microRNA (miRNA) expression levels were detected via microarray. The effects of EGCG on smoke-induced benzopyrene-DNA adduct formation and the subsequent change in miRNA expression were analyzed. Subsequently, the protective effect of EGCG on smoke inhalation-induced precancerous lesions was investigated. The expression levels of miRNA target genes were also analyzed. After CSE treatment, benzopyrene-DNA adducts appeared in HBE cells, along with a resultant change in miRNA expression. EGCG inhibited the effects of CSE exposure; benzopyrene-DNA adduct formation was reduced and miRNA expression changes were suppressed. In vivo, EGCG significantly reduced benzopyrene-DNA adduct formation and the subsequent development of precancerous lesions in rat lungs induced by cigarette smoke inhalation. Moreover, EGCG downregulated CYP1A1 overexpression, a target gene of multiple smoking-induced miRNAs, in rat lungs. EGCG may reduce the risk of lung cancer by downregulating the expression of the key gene CYP1A1, preventing the formation of smoking-induced benzopyrene-DNA adducts and alleviating smoking-induced bronchial epithelial dysplasia and heterogeneity.

Aim: Fish soup is a traditional Chinese food usually offered as a healthy supplement to elders, pregnant women and persons who just had surgery. Silver perch (Santé premium silver perch essence, SPSPE) extract contains various quality proteins, collagen, minerals, trace elements, and branch chain amino acids (BCAA) that could help individuals recover from exhaustion and control body weight. However, there are very limited studies exploring the effects of fish extracts on exercise performance and fatigue, and relevant physiological mechanisms. Therefore, the purpose of this study was to investigate the effects of chronic SPSPE administration on exhaustive exercise performance.Method: Male Wistar rats weighing around 250 g were divided into 4 groups: Control, 1X SPSPE (6.2 ml/kg), 2X SPSPE (12.4 ml/kg) and 5X SPSPE (31.0 ml/kg). Rats were administrated SPSPE by oral gavage feeding every day for 33 days. Their body weight were measured every week. Before and after the exhaustive swimming test, the blood was collected for circulating lactate, glucose, ammonia, hormones, and myoglobin analysis. Rats were sacrificed after performing an exhaustive swimming exercise test. The liver tissues were collected for glycogen content and H&E staining.Results: After the administration of 1X and 5X SPSPE, swimming fatigue was significantly delayed (p = 0.024). There was no difference in the hormone plasma level between the control and SPSPE groups. The induction of plasma corticosterone and TBARS by exhaustive swimming exercise could be decreased by SPSPE administration. The increased plasma myoglobin concentration from exhaustive swimming exercise was weakened by SPSPE supplementation. The higher glycogen sparing contained in liver tissue was observed in SPSPE-treated groups (p < 0.05).Conclusion: SPSPE could efficiently delay swimming fatigue through sparing of liver glycogen and attenuation of plasma TBARS, myoglobin induction by exhaustive exercise. Our findings provide a scientific-based fundamental information and better understanding for developing a fish extract-based anti-fatigue supplement.