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Abstract Aging is a complex and multifaceted process involving a variety of interrelated molecular mechanisms and cellular systems. Phenotypically, the biological aging process is accompanied by a gradual loss of cellular function and the systemic deterioration of multiple tissues, resulting in susceptibility to aging-related diseases. Emerging evidence suggests that aging is closely associated with telomere attrition, DNA damage, mitochondrial dysfunction, loss of nicotinamide adenine dinucleotide levels, impaired macro-autophagy, stem cell exhaustion, inflammation, loss of protein balance, deregulated nutrient sensing, altered intercellular communication, and dysbiosis. These age-related changes may be alleviated by intervention strategies, such as calorie restriction, improved sleep quality, enhanced physical activity, and targeted longevity genes. In this review, we summarise the key historical progress in the exploration of important causes of aging and anti-aging strategies in recent decades, which provides a basis for further understanding of the reversibility of aging phenotypes, the application prospect of synthetic biotechnology in anti-aging therapy is also prospected.

The interaction between endoplasmic reticulum (ER) and mitochondria has been shown to play a key role in hepatic steatosis during chronic obesity. β-nicotinamide mononucleotide (NMN) has been reported to regulate obesity, however, its molecular mechanism at the subcellular level remains unclear. Here, NMN improved liver steatosis and insulin resistance in chronic high-fat diet (HFD) mice. RNA-seq showed that compared with the liver of HFD mice, NMN intervention enhanced fat digestion and absorption and stimulated the cholesterol metabolism signaling pathways, while impaired insulin resistance and the fatty acid biosynthesis signaling pathways. Mechanistically, NMN ameliorated mitochondrial dysfunction and ER oxidative stress in the liver of HFD mice by increasing hepatic nicotinamide adenine dinucleotide (NAD+) (P < 0.01) levels. This effect increased the contact sites (mitochondria-associated membranes [MAMs]) between ER and mitochondria, thereby promoting intracellular ATP (P < 0.05) production and mitigating lipid metabolic disturbances in the liver of HFD mice. Taken together, this study provided a theoretical basis for restoring metabolic dynamic equilibrium in the liver of HFD mice by increasing MAMs via the nutritional strategy of NMN supplementation.

ObjectiveNurses constitute the largest group of healthcare workers worldwide, and job burnout is very common among them. This study aims to explore abnormal future thinking in nurses with burnout. Additionally, the study investigates whether these manifestations worsen as burnout progresses.MethodsThe study was conducted in inpatient ward nurses at a tertiary hospital in Hangzhou, China. In the first phase, two group of nurses were recruited: nurses with burnout (N = 70) and nurses without burnout (N = 70). In the second phase, three groups were recruited according to the burnout levels: mild burnout (N = 43), moderate burnout (N = 42) and severe burnout (N = 43). Data on job burnout were obtained using the Chinese Maslach Burnout Inventory. The Sentence Completion for Events in the Future Test (SCEFT) was employed to measure the content of future thinking, which was evaluated by two raters in terms of the specificity, emotional valence, and concrete content of the imagined future events. The proportions of specific types of events among all the produced events were calculated.ResultsThe results revealed that nurses with burnout, compared to nurses without burnout, imagined fewer specific future events, positive events, and events related to relationships and achievement. They also had more omissions. As the level of burnout increased, their impairment in future thinking worsened. Furthermore, the results also revealed that the scores of emotional exhaustion, depersonalization, and personal accomplishment had significant correlations with the proportions of positive events and events related to relationships and achievement/mastery in nurses’ future thinking content.ConclusionThe future thinking ability of nurses with burnout was impaired, and this impairment worsened as the symptoms of burnout progressed. The findings of the present study have important implications for nurse caring and advocate effective interventions targeting positive future thinking to mitigate nurses’ burnout.

Highlights I. Zearalenone directly and/or indirectly disturbs immune defense in the reproductive-immune axis; II. Zearalenone-induced toxicity on the reproductive-immune axis is accompanied by systemic inflammation caused by altered gut microbial metabolites (e.g., decreased butyrate, and increased lipopolysaccharides); III. Targeting these gut microbial metabolites counteracts Zearalenone-induced toxicity on the gut-reproductive-immune axis. Video Abstract

Summary: Chemerin, an adipocyte-secreted protein, has been recently suggested to be linked to metabolic syndrome and cardiac function in obese and diabetes mellitus. This study aimed to investigate the potential roles of adipokine chemerin on high fat-induced cardiac dysfunction. Chemerin (Rarres2) knockout mice, which were fed with either a normal diet or a high-fat diet for 20 weeks, were employed to observe whether adipokine chemerin affected lipid metabolism, inflammation, and cardiac function. Firstly, we found normal metabolic substrate inflexibility and cardiac function in Rarres2−/− mice with a normal diet. Notably, in a high-fat diet, Rarres2−/− mice showed lipotoxicity, insulin resistance, and inflammation, thus causing metabolic substrate inflexibility and cardiac dysfunction. Furthermore, by using in vitro model of lipid-overload cardiomyocytes, we found chemerin supplementation reversed the lipid-induced abnormalities above. Herein, in the presence of obesity, adipocyte-derived chemerin might function as an endogenous cardioprotective factor against obese-related cardiomyopathy.

Abstract Biomolecule-functionalized fluorescent gold nanocluster (AuNCs) have attracted a lot of attention due to good biocompatibility, stable physicochemical properties and considerable cost advantages. Inappropriate concentration of Cu2+ may cause a variety of diseases. In this study, AuNCs were synthesized in alkaline aqueous solution using bovine serum albumin (BSA) as a template. And then, the peptide CCYWDAHRDY was coupled to AuNCs. Furthermore, the fluorescence of synthesized CCYWDAHRDY-AuNCs response to Cu2+ was evaluated. As the results shown that the CCYWDAHRDY-AuNCs can sensitively detect Cu2+. After adding Cu2+ to the probe system, the fluorescence of the CCYWDAHRDY-AuNCs was quenched. The detection conditions were at pH 6 and 30 °C for 10 min, the linear relationship between Cu2+ concentration and fluorescence intensity were good in the range of 0.1 ~ 4.2 μmol/L. The regression equation was y = − 105.9x + 693.68, the linear correlation coefficient is 0.997, and the minimum detection limit was 52 nmol/L.

Flower bud formation in the apple tree life cycle is associated with multiple biological processes. To explore the physiological and molecular mechanisms underlying the protein and metabolite changes in buds with different flowering capabilities, axillary buds with no flowering (Ab), long-shoot buds with a low flowering rate (Lb), and spur buds with a higher flowering rate than the Lb (Sb) were analyzed using a Tandem Mass Tag™ proteomic technique in combination with nLC–MS/MS analyses. We identified 471 (88 up- and 383 down-regulated), 459 (176 up- and 283 down-regulated), and 548 (387 up- and 161 down-regulated) differentially expressed proteins in Sb vs. Lb, Sb vs. Ab, and Lb vs. Ab, respectively, that were involved in carbohydrate, amino acid and lipid transport, and metabolism. Additionally, 110 (91 increased and 19 decreased), 89 (71 increased and 18 decreased), and 99 (37 increased and 62 decreased) metabolites having significantly different levels were identified in Sb vs. Lb, Sb vs. Ab, and Lb vs. Ab, respectively. The identified metabolites were related to amino acids and their isoforms, sugars and polyols, and organic acids, and occurred at significantly greater levels in the Sbs than the other buds. Thus, flower bud formation is a complex process that involves various biochemical materials and signals, such as carbohydrates, amino acids and their isoforms, and organic acids.

Maintaining normal functions of ovarian granulosa cells (GCs) is essential for oocyte development and maturation. The dysfunction of GCs impairs nutrition supply and estrogen secretion by follicles, thus negatively affecting the breeding capacity of farm animals. Impaired GCs is generally associated with declines in Nicotinamide adenine dinucleotide (NAD+) levels, which triggers un-controlled oxidative stress, and the oxidative stress, thus, attack the subcellular structures and cause cell damage. β-nicotinamide mononucleotide (NMN), a NAD+ precursor, has demonstrated well-known antioxidant properties in several studies. In this study, using two types of ovarian GCs (mouse GCs (mGCs) and human granulosa cell line (KGN)) as cell models, we aimed to investigate the potential effects of NMN on gene expression patterns and antioxidant capacity of both mGCs and KGN that were exposed to hydrogen peroxide (H2O2). As shown in results of the study, mGCs that were exposed to H2O2 significantly altered the gene expression patterns, with 428 differentially expressed genes (DEGs) when compared with those of the control group. Furthermore, adding NMN to H2O2-cultured mGCs displayed 621 DEGs. The functional enrichment analysis revealed that DEGs were mainly enriched in key pathways like cell cycle, senescence, and cell death. Using RT-qPCR, CCK8, and β-galactosidase staining, we found that H2O2 exposure on mGCs obviously reduced cell activity/mRNA expressions of antioxidant genes, inhibited cell proliferation, and induced cellular senescence. Notably, NMN supplementation partially prevented these H2O2-induced abnormalities. Moreover, these similar beneficial effects of NMN on antioxidant capacity were confirmed in the KGN cell models that were exposed to H2O2. Taken together, the present results demonstrate that NMN supplementation protects against H2O2-induced impairments in gene expression pattern, cell cycle arrest, and cell death in ovarian GCs through boosting NAD+ levels and provide potential strategies to ameliorate uncontrolled oxidative stress in ovarian GCs.

Diabetes associated injury healing and other tissue irregularities are viewed as a significant concern. The purpose of the study is to design the wound regeneration activity of Ficus carica extract (FFE) loaded amphiphilic polymeric scaffold of poly(xylitol-g-adipate-co-glutamide) (PXAG)–polyhydroxybutyrate (PHB) for potential diabetic affected wound regeneration. The PXAG copolymer was prepared by the condensation method, and the polymeric scaffolds of PXAG-PHB, PXAG-PHB/FFE were developed through the ultra-sonication process and magnetic stirrer processes. The chemical structure, crystalline nature, thermal stability, size, surface charge and surface morphology of PXAG-PHB and PXAG-PHB/FFE polymeric scaffolds were investigated. The PXAG-PHB/FFE exhibits 99.0% free radical scavenging activity which was determined by the DPPH method. The inhibition zones by the PXAG-PHB/FFE indicate it had a higher antibacterial activity with the Escherichia coli (gram-negative) and Staphylococcus aureus (gram-positive) pathogens. The PXAG, PXAG-PHB and PXAG-PHB/FFE polymeric scaffolds exhibited good viability against diabetic induced wound cells (WS1) in 100 μg/mL concentrations up to 72 h incubation. Since the synthesized PXAG-PHB/FFE polymeric scaffolds possess excellent thermal stability, bioactivity, biocompatibility and antioxidant activity along with potent antimicrobial activity, they play a potential role in diabetic wound tissue regenerations.

Objective: The diabetic heart is characterized by extensive lipid accumulation which often leads to cardiac contractile dysfunction. The underlying mechanism involves a pivotal role for vacuolar-type H+-ATPase (v-ATPase, functioning as endosomal/lysosomal proton pump). Specifically, lipid oversupply to the heart causes disassembly of v-ATPase and endosomal deacidification. Endosomes are storage compartments for lipid transporter CD36. However, upon endosomal deacidification, CD36 is expelled to translocate to the sarcolemma, thereby inducing myocardial lipid accumulation, insulin resistance, and contractile dysfunction. Hence, the v-ATPase assembly may be a suitable target for ameliorating diabetic cardiomyopathy. Another function of v-ATPase involves the binding of anabolic master-regulator mTORC1 to endosomes, a prerequisite for the activation of mTORC1 by amino acids (AAs). We examined whether the relationship between v-ATPase and mTORC1 also operates reciprocally; specifically, whether AA induces v-ATPase reassembly in a mTORC1-dependent manner to prevent excess lipids from entering and damaging the heart. Methods: Lipid overexposed rodent/human cardiomyocytes and high-fat diet-fed rats were treated with a specific cocktail of AAs (lysine/leucine/arginine). Then, v-ATPase assembly status/activity, cell surface CD36 content, myocellular lipid uptake/accumulation, insulin sensitivity, and contractile function were measured. To elucidate underlying mechanisms, specific gene knockdown was employed, followed by subcellular fractionation, and coimmunoprecipitation. Results: In lipid-overexposed cardiomyocytes, lysine/leucine/arginine reinternalized CD36 to the endosomes, prevented/reversed lipid accumulation, preserved/restored insulin sensitivity, and contractile function. These beneficial AA actions required the mTORC1–v-ATPase axis, adaptor protein Ragulator, and endosomal/lysosomal AA transporter SLC38A9, indicating an endosome-centric inside-out AA sensing mechanism. In high-fat diet-fed rats, lysine/leucine/arginine had similar beneficial actions at the myocellular level as in vitro in lipid-overexposed cardiomyocytes and partially reversed cardiac hypertrophy. Conclusion: Specific AAs acting through v-ATPase reassembly reduce cardiac lipid uptake raising the possibility for treatment in situations of lipid overload and associated insulin resistance.

Aging is a natural process with concomitant changes in the gut microbiota and associate metabolomes. Beta-nicotinamide mononucleotide, an important NAD+ intermediate, has drawn increasing attention to retard the aging process. We probed the changes in the fecal microbiota and metabolomes of pre-aging male mice (C57BL/6, age: 16 months) following the oral short-term administration of nicotinamide mononucleotide (NMN). Considering the telomere length as a molecular gauge for aging, we measured this in the peripheral blood mononuclear cells (PBMC) of pre-aging mice and human volunteers (age: 45–60 years old). Notably, the NMN administration did not influence the body weight and feed intake significantly during the 40 days in pre-aging mice. Metabolomics suggested 266 upregulated and 58 downregulated serum metabolites. We identified 34 potential biomarkers linked with the nicotinamide, purine, and proline metabolism pathways. Nicotinamide mononucleotide significantly reduced the fecal bacterial diversity (p < 0.05) with the increased abundance of Helicobacter, Mucispirillum, and Faecalibacterium, and lowered Akkermansia abundance associated with nicotinamide metabolism. We propose that this reshaped microbiota considerably lowered the predicated functions of aging with improved immune and cofactors/vitamin metabolism. Most notably, the telomere length of PBMC was significantly elongated in the NMN-administered mice and humans. Taken together, these findings suggest that oral NMN supplementation in the pre-aging stage might be an effective strategy to retard aging. We recommend further studies to unravel the underlying molecular mechanisms and comprehensive clinical trials to validate the effects of NMN on aging.

The heart is metabolically flexible. Under physiological conditions, it mainly uses lipids and glucose as energy substrates. In uncontrolled diabetes, the heart switches towards predominant lipid utilization, which over time is detrimental to cardiac function. Additionally, diabetes is accompanied by high plasma ketone levels and increased utilization of energy provision. The administration of exogenous ketones is currently being investigated for the treatment of cardiovascular disease. Yet, it remains unclear whether increased cardiac ketone utilization is beneficial or detrimental to cardiac functioning. The mechanism of lipid-induced cardiac dysfunction includes disassembly of the endosomal proton pump (named vacuolar-type H+-ATPase; v-ATPase) as the main early onset event, followed by endosomal de-acidification/dysfunction. The de-acidified endosomes can no longer serve as a storage compartment for lipid transporter CD36, which then translocates to the sarcolemma to induce lipid accumulation, insulin resistance, and contractile dysfunction. Lipid-induced v-ATPase disassembly is counteracted by the supply of specific amino acids. Here, we tested the effect of ketone bodies on v-ATPase assembly status and regulation of lipid uptake in rodent/human cardiomyocytes. 3-β-hydroxybutyrate (3HB) exposure induced v-ATPase disassembly and the entire cascade of events leading to contractile dysfunction and insulin resistance, similar to conditions of lipid oversupply. Acetoacetate addition did not induce v-ATPase dysfunction. The negative effects of 3HB could be prevented by addition of specific amino acids. Hence, in sedentary/prediabetic subjects ketone bodies should be used with caution because of possible aggravation of cardiac insulin resistance and further loss of cardiac function. When these latter maladaptive conditions would occur, specific amino acids could potentially be a treatment option.

BackgroundRecently, NUS1 and GP2 genes were reported to be associated with the risk of type 2 diabetes (T2D) in a Japanese population. Given the sharing of pathogenic contribution from genetic factors between T2D and gestational diabetes mellitus (GDM), we conducted the study to systematically examine the relationship of NUS1 and GP2 genes with the susceptibility to GDM in Chinese Han population.MethodsA total of 4,250 subjects comprised of 1,282 patients with GDM and 2,968 controls were recruited, and 20 tag single nucleotide polymorphisms (SNPs) (10 from NUS1 and 10 from GP2) were selected for genotyping. Association analyses were conducted for GDM and its related biomedical indexes including fasting glucose and HbA1c levels.ResultsTwo SNPs, rs80196932 from NUS1 (P=2.93×10-5) and rs117267808 from GP2 (P=5.68×10-5), were identified to be significantly associated with the risk of GDM. Additionally, SNP rs80196932 was significantly associated with HbA1c level in both patients with GDM (P=0.0009) and controls (P=0.0003), while SNP rs117267808 was significantly associated with fasting glucose level in both patients with GDM (P=0.0008) and controls (P=0.0007). Serum levels of protein NUS1 and GP2 were measured for the study subjects, and significant differences were identified among groups with different genotypes of SNP rs80196932 and rs117267808, respectively.ConclusionsOur findings indicate that NUS1 and GP2 genes contribute to the risk of GDM, which would help to offer the potential to improve our understanding of the etiology of GDM and, in turn, could facilitate the development of novel medicines and treatments for GDM.

Abstract Background To investigate any associations between blood glucose (BG) and lipid levels in patients with different glucose tolerance statuses, including type 2 diabetes (T2DM) and impaired glucose regulation (IGR) cases as well as normal glucose tolerance (NGT) individuals. Methods A total of 354 participants were recruited to this study including 174 in the T2DM group, 112 in the IGR group and 68 in the NGT group. We compared BG, insulin and C-peptide (CP), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) serum levels during a 3 h oral glucose tolerance test (OGTT) in the 3 groups. Results Basic overall HbA1c serum concentration percentages were 5.52, 6.33 and 9.76% for the NTG, IGR and T2DM cases. During the OGTT, insulin secretion in the IGR group was almost double that of the T2DM group. CP levels were highest in the IGR patients and OGTT related BG concentrations were highest in the T2DM group followed by IGR, but in the IGR group hyperglycemia was less pronounced than in T2DM patients (P

The heart is a metabolically flexible omnivore that can utilize a variety of substrates for energy provision. To fulfill cardiac energy requirements, the healthy adult heart mainly uses long-chain fatty acids and glucose in a balanced manner, but when exposed to physiological or pathological stimuli, it can switch its substrate preference to alternative substrates such as amino acids (AAs) and ketone bodies. Using the failing heart as an example, upon stress, the fatty acid/glucose substrate balance is upset, resulting in an over-reliance on either fatty acids or glucose. A chronic fuel shift towards a single type of substrate is linked with cardiac dysfunction. Re-balancing myocardial substrate preference is suggested as an effective strategy to rescue the failing heart. In the last decade, we revealed that vacuolar-type H+-ATPase (v-ATPase) functions as a key regulator of myocardial substrate preference and, therefore, as a novel potential treatment approach for the failing heart. Fatty acids, glucose, and AAs selectively influence the assembly state of v-ATPase resulting in modulation of its proton-pumping activity. In this review, we summarize these novel insights on v-ATPase as an integrator of nutritional information. We also describe its exploitation as a therapeutic target with focus on supplementation of AA as a nutraceutical approach to fight lipid-induced insulin resistance and contractile dysfunction of the heart.

In the work, mucor miehei lipase (MML) was covalently immobilized on the 2,4,6-trichloro-1,3,5-triazine (TCT)-modified magnetite nanoparticles. Then, the immobilized MML was utilized in the synthesis of functionalized 4H-Chromenes via a multicomponent reaction firstly. Under the optimized reaction conditions, immobilized MML displayed high catalytic performance (Yield: 81–96%) and excellent reusability, indicating a high potential for practical operation.

ContextUpon palmitate oversupply, membrane fatty acid-transporter CD36 (SR-B2) permanently translocates from endosomal storage to the sarcolemma, inducing lipotoxicity. CD36 translocation results from endosomal alkalinisation elicited by palmitate-induced disattachment of the cytoplasmic V1-subcomplex from the membrane-integrated V0-subcomplex of vacuolar-type H+-ATPase.ObjectiveDevelop a CD36 fluorescent labeling technique as initial step towards live cell imaging.MethodsThree human CD36 (hCD36) mutants were constructed via insertion of a tetracysteine motif at different positions within the extracellular domain. Constructs were lentivirally transduced for subsequent CD36 labeling with fluorescein-arsenical hairpin-binder (FlAsH). Cell imaging was combined with V0/V1 immunostaining and Western blotting.ResultsTransduction of hCD36-wildtype and mutants yielded corresponding proteins in HL-1 cardiomyocytes. Tetracysteine mutant-2 (hCD36-TC2) showed similar fatty acid uptake to wildtype. FlAsH staining revealed a speckled pattern reminiscent of endosomes. We found decreased V1 co-localization with CD36 upon high-palmitate culturing. Conversely, V0 consistently co-localized with CD36.ConclusionhCD36-TC2 is a possible candidate for application of biarsenical dyes in live imaging studies pending further investigation. Our data is compatible with V0/V1 disassembly in high-palmitate-treated cells.

Microbe-derived butyrate plays an important role in the gut health of young mammals during the weaning stage. A greater understanding of how butyrate regulates intestinal development is necessary for overcoming post-weaning diarrheal diseases. We aimed to investigate whether jejunal microbial metabolite butyrate modulates the apoptosis/proliferation balance and immune response in piglets during the post-weaning period of the first 3 weeks of life. On the one hand, during the first week post-weaning, the relative abundances of the dominant bacterial families Erysipelotrichaceae (P < 0.01) and Lachnospiraceae (P < 0.01) were increased, which induced decreases in both butyrate production (P < 0.05) and its receptor (G-protein coupled receptor 43) expression (P < 0.01). The resulting intestinal inflammation (inferred from increased TNF-α and IFN-γ expression) contributed to the onset of cell apoptosis and the inhibition of cell-proliferation along the crypt-villus axis, which were followed by impaired jejunal morphology (i.e., increased crypt-depth) (P < 0.05) and intestinal dysfunction (i.e., decreased creatine kinase, and lactate dehydrogenase) (P < 0.05). On the other hand, during the second week post-weaning, the relative abundances of Lactobacillaceae (P < 0.01) and Ruminococcaceae (P < 0.05) were increased. The increases were accompanied by increased butyrate production (P < 0.05) and its receptor expression (P < 0.01), leading to the inhibition of cell apoptosis and the stimulation of cell proliferation via decreased pro-inflammatory cytokines and thereby the improvement of intestinal development and function. Herein, this study demonstrates that microbial-driven butyrate might be a key modulator in the maintenance of intestinal homeostasis after weaning. The findings suggest that strategies to promote butyrate production can maintain the apoptosis/proliferation balance via minimizing intestinal inflammation, and thereby improving post-weaning jejunal adaptation toward gut health.

The diabetic heart is characterized by a shift in substrate utilization from glucose to lipids, which may ultimately lead to contractile dysfunction. This substrate shift is facilitated by increased translocation of lipid transporter CD36 (SR-B2) from endosomes to the sarcolemma resulting in increased lipid uptake. We previously showed that endosomal retention of CD36 is dependent on the proper functioning of vacuolar H+-ATPase (v-ATPase). Excess lipids trigger CD36 translocation through inhibition of v-ATPase function. Conversely, in yeast, glucose availability is known to enhance v-ATPase function, allowing us to hypothesize that glucose availability, via v-ATPase, may internalize CD36 and restore contractile function in lipid-overloaded cardiomyocytes. Increased glucose availability was achieved through (a) high glucose (25 mM) addition to the culture medium or (b) adenoviral overexpression of protein kinase-D1 (a kinase mediating GLUT4 translocation). In HL-1 cardiomyocytes, adult rat and human cardiomyocytes cultured under high-lipid conditions, each treatment stimulated v-ATPase re-assembly, endosomal acidification, endosomal CD36 retention and prevented myocellular lipid accumulation. Additionally, these treatments preserved insulin-stimulated GLUT4 translocation and glucose uptake as well as contractile force. The present findings reveal v-ATPase functions as a key regulator of cardiomyocyte substrate preference and as a novel potential treatment approach for the diabetic heart.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that has proved refractory to drug treatment. Given evidence of neuroprotection in animal models of ischemic stroke, we assessed the prenylflavonoid xanthohumol from the Common Hop (Humulus lupulus L.) for therapeutic potential in murine neuroblastoma N2a cells stably expressing human Swedish mutant amyloid precursor protein (N2a/APP), a well-characterized cellular model of AD. The ELISA and Western-blot analysis revealed that xanthohumol (Xn) inhibited Aβ accumulation and APP processing, and that Xn ameliorated tau hyperphosphorylation via PP2A, GSK3β pathways in N2a/APP cells. The amelioration of tau hyperphosphorylation by Xn was also validated on HEK293/Tau cells, another cell line with tau hyperphosphorylation. Proteomic analysis (2D-DIGE-coupled MS) revealed a total of 30 differentially expressed lysate proteins in N2a/APP vs. wild-type (WT) N2a cells (N2a/WT), and a total of 21 differentially expressed proteins in lysates of N2a/APP cells in the presence or absence of Xn. Generally, these 51 differential proteins could be classified into seven main categories according to their functions, including: endoplasmic reticulum (ER) stress-associated proteins; oxidative stress-associated proteins; proteasome-associated proteins; ATPase and metabolism-associated proteins; cytoskeleton-associated proteins; molecular chaperones-associated proteins, and others. We used Western-blot analysis to validate Xn-associated changes of some key proteins in several biological/pathogenic processes. Taken together, we show that Xn reduces AD-related changes in stably transfected N2a/APP cells. The underlying mechanisms involve modulation of multiple pathogenic pathways, including those involved in ER stress, oxidative stress, proteasome molecular systems, and the neuronal cytoskeleton. These results suggest Xn may have potential for the treatment of AD and/or neuropathologically related neurodegenerative diseases.

The intestinal mucosal development of piglets (Sus scrofa) during the weaning stage is important to their disease susceptibility and later growth. Quantitative real-time PCR (RT-qPCR) is commonly used to screen for differentially expressed genes and, for accurate results, proper reference housekeeping genes are essential. Here we assessed the mRNA expression of 18 well-known candidate reference genes at different parts of the gastrointestinal tract (GIT) of piglets during the weaning process by RT-qPCR assay. GeNorm analysis revealed that B2M/HMBS/HPRT1 were the three most stable reference genes and GAPDH was the least stable gene in the duodenum, jejunum, ileum, colon, and whole GIT. BestKeeper analysis found that B2M/HMBS/PGK11, HMBS/B2M/HPRT1, B2M/HMBS/HSPCB, B2M/HPRT1/HMBS, and B2M/HMBS/HPRT1 were the most stable genes in the duodenum, jejunum, ileum, colon, and whole GIT, respectively, whereas GAPDH, B-actin, and 18S rRNA were the least stable genes at different parts of the GIT. To confirm the crucial role of appropriate housekeeping genes in obtaining reliable results, we analyzed the expression of ALP using each of the 18 reference genes to normalize the RT-qPCR data. We found that the expression levels of ALP normalized using the most stable reference genes (B2M/HMBS/HPRT1) differed greatly from the expression levels obtained when the data were normalized using the least stable genes (GAPDH, B-actin, and 18S). We concluded that B2M/HMBS/HPRT1 were the optimal reference genes for gene expression analysis by RT-qPCR in the intestinal mucosal development stages of piglets at weaning. Our findings provide a set of porcine housekeeping reference genes for studies of mRNA expression in different parts of the pig intestine.

The development of advanced electrocatalysts for oxygen reduction and evolution is of paramount significance to fuel cells, water splitting, and metal-air batteries. Heteroatom-doped carbon materials have exhibited great promise because of their excellent electrical conductivity, abundance, and superior durability. Rationally optimizing active sites of doped carbons can remarkably enhance their electrocatalytic performance. In this study, nitrogen and oxygen codoped carbon nanotubes were readily synthesized from the pyrolysis of polydopamine-carbon nanotube hybrids. Different electron microscopes, Raman spectra and X-ray photoelectron spectroscopy (XPS) were employed to survey the morphological and componential properties. The newly-obtained catalyst features high-quality nitrogen and oxygen species, favourable porous structures and excellent electric conductivity, and thus exhibits remarkably bifunctional oxygen electrode activity. This research further helps to advance the knowledge of polydopamine and its potential applications as efficient electrocatalysts to replace noble metals.

Two of our long term efforts are to discover compounds with synergistic antifungal activity from metabolites of marine derived microbes and to optimize the production of the interesting compounds produced by microorganisms. In this respect, new applications or mechanisms of already known compounds with a high production yield could be continually identified. Surfactin is a well-known lipopeptide biosurfactant with a broad spectrum of antimicrobial and antiviral activity; however, there is less knowledge on surfactin's antifungal activity. In this study, we investigated the synergistic antifungal activity of C(15)-surfactin and the optimization of its production by the response surface method.Using a synergistic antifungal screening model, we found that the combination of C(15)-surfactin and ketoconazole (KTC) showed synergistic antifungal effect on Candida albicans SC5314 when the concentrations of C(15)-surfactin and KTC were 6.25 µg/mL and 0.004 µg/mL, respectively. These concentrations were lower than their own efficient antifungal concentrations, which are >100 µg/mL and 0.016 µg/mL, respectively. The production of C(15)-surfactin from Bacillus amyloliquefaciens was optimized by the response surface methodology in shaker flask cultivation. The Plackett-Burman design found sucrose, ammonium nitrate and NaH(2)PO(4) x 2H(2)O to have significant effects on C(15)-surfactin production. The optimum values of the tested variables were 21.17 g/L sucrose, 2.50 g/L ammonium nitrate and 11.56 g/L NaH(2)PO(4)·2H(2)O. A production of 134.2 mg/L, which were in agreement with the prediction, was observed in a verification experiment. In comparison to the production of original level (88.6 mg/L), a 1.52-fold increase had been obtained.This work first found that C(15)-surfactin was an efficient synergistic antifungal agent, and demonstrated that response surface methodology was an effective method to improve the production of C(15)-surfactin.