Modulation of alveolar macrophage and mitochondrial fitness by medicinal plant-derived nanovesicles to mitigate acute lung injury and viral pneumonia.

Acute lung injury (ALI) is generally caused by severe respiratory infection and characterized by overexuberant inflammatory responses and inefficient pathogens-containing, the two major processes wherein alveolar macrophages (AMs) play a central role. Dysfunctional mitochondria have been linked with distorted macrophages and hence lung disorders, but few treatments are currently available to correct these defects. Plant-derive nanovesicles have gained significant attention because of their therapeutic potential, but the targeting cells and the underlying mechanism remain elusive. We herein prepared the nanovesicles from Artemisia annua, a well-known medicinal plant with multiple attributes involving anti-inflammatory, anti-infection, and metabolism-regulating properties. By applying three mice models of acute lung injury caused by bacterial endotoxin, influenza A virus (IAV) and SARS-CoV-2 pseudovirus respectively, we showed that Artemisia-derived nanovesicles (ADNVs) substantially alleviated lung immunopathology and raised the survival rate of challenged mice. Macrophage depletion and adoptive transfer studies confirmed the requirement of AMs for ADNVs effects. We identified that gamma-aminobutyric acid (GABA) enclosed in the vesicles is a major molecular effector mediating the regulatory roles of ADNVs. Specifically, GABA acts on macrophages through GABA receptors, promoting mitochondrial gene programming and bioenergy generation, reducing oxidative stress and inflammatory signals, thereby enhancing the adaptability of AMs to inflammation resolution. Collectively, this study identifies a promising nanotherapeutics for alleviating lung pathology, and elucidates a mechanism whereby the canonical neurotransmitter modifies AMs and mitochondria to resume tissue homeostasis, which may have broader implications for treating critical pulmonary diseases such as COVID-19.

The effect of exemestane administration on the lipid profile in women: Meta-analysis of randomized controlled trials.

OBJECTIVE: Postmenopausal women are prone to develop cardiovascular disorders. In addition, cardiovascular risk in women can be influenced by the long-term prescription of drugs that lead to estrogen deprivation, e.g., aromatase inhibitors, and that can cause dyslipidemia. Little is known about the impact of exemestane, an aromatase inhibitor, on serum lipids' concentration in women. Hence, we conducted a meta-analysis of randomized controlled trials (RCTs) to assess the influence of this pharmacological agent on the lipid profile in women. METHODS: The Scopus, Web of Science, PubMed/Medline and EMBASE databases were searched by two surveyors for manuscripts published from the inception of these databases until April 3rd, 2023. No language restrictions were applied to the search. The random effects model was used to generate the combined results as weighted mean difference (WMD) and 95% confidence interval (CI). RESULTS: In total, 8 eligible RCTs were included in the meta-analysis. Overall results from the random effects model indicate that exemestane administration increases LDL-C (WMD: 4.42 mg/dL, 95 % CI: 0.44, 8.41, P = 0.02) and decreases HDL-C (WMD: -6.03 mg/dL, 95 % CI: -7.77, -4.29, P < 0.001) and TC (WMD: -5.40 mg/dL, 95 % CI: -9.95, -0.86, P = 0.02) levels, respectively. Moreover, exemestane prescription only lowered TG concentrations when it was administered for < 12 months (WMD: -14.60 mg/dL, 95 % CI: -23.57 to -5.62, P = 0.001). CONCLUSION: Currently available evidence suggests that the administration of exemestane in females increases LDL-C values and reduces HDL-C, TC, and, when prescribed for less than 12 months, TG concentrations.

N-Acetylcysteine overcomes epalrestat-mediated increase of toxic 4-hydroxy-2-nonenal and potentiates the anti-arthritic effect of epalrestat in AIA model.

Epalrestat, an aldose reductase inhibitor (ARI), has been clinically adopted in treating diabetic neuropathy in China and Japan. Apart from the involvement in diabetic complications, AR has been implicated in inflammation. Here, we seek to investigate the feasibility of clinically approved ARI, epalrestat, for the treatment of rheumatoid arthritis (RA). The mRNA level of AR was markedly upregulated in the peripheral blood mononuclear cells (PBMCs) of RA patients when compared to those of healthy donors. Besides, the disease activity of RA patients is positively correlated with AR expression. Epalrestat significantly suppressed lipopolysaccharide (LPS) induced TNF-α, IL-1ß, and IL-6 in the human RA fibroblast-like synoviocytes (RAFLSs). Unexpectedly, epalrestat treatment alone markedly exaggerated the disease severity in adjuvant induced arthritic (AIA) rats with elevated Th17 cell proportion and increased inflammatory markers, probably resulting from the increased levels of 4-hydroxy-2-nonenal (4-HNE) and malondialdehyde (MDA). Interestingly, the combined treatment of epalrestat with N-Acetylcysteine (NAC), an anti-oxidant, to AIA rats dramatically suppressed the production of 4-HNE, MDA and inflammatory cytokines, and significantly improved the arthritic condition. Taken together, the anti-arthritic effect of epalrestat was diminished or even overridden by the excessive accumulation of toxic 4-HNE or other reactive aldehydes in AIA rats due to AR inhibition. Co-treatment with NAC significantly reversed epalrestat-induced upregulation of 4-HNE level and potentiated the anti-arthritic effect of epalrestat, suggesting that the combined therapy of epalrestat with NAC may sever as a potential approach in treating RA. Importantly, it could be regarded as a safe intervention for RA patients who need epalrestat for the treatment of diabetic complications.

Influence of thermal air oxidation on the chemical composition and uranium binding property of intrinsic dissolved organic matter from biochar.

In this work, uranium (U(VI)) binding characteristics of the intrinsic dissolved organic matters (DOM) from the biochars prepared under thermal air oxidation (TAO) and non-TAO conditions were studied using synchronous fluorescence spectra (SFS) and Fourier transform infrared (FTIR) in conjunction with the general two-dimensional correlation spectroscopy (2D-COS), heterospectral 2D-COS and moving-window (MW) 2D-COS. The chemical compositions of the intrinsic DOMs from biochars with/without TAO were investigated by Fourier transform-ion cyclotron resonance mass spectrometry (FT-ICR MS). Results showed that the preferential binding of U(VI) to functional groups followed the order: 937 (carboxyl γC-OH), 981 (carboxyl γC-OH), 1511 (aromatic vC = C), 1108 (esters or ethers vC-O), 1282 (esters or carboxyl vC-O), 1698 (saturated carboxylic acid or ketone vC = O) cm-1 for biochar DOM after TAO (OB600), and 937 (carboxyl γC-OH), 1484 (lipids δC-H or phenolic vC-O), 1201 (esters or carboxyl vC-O), 1112 (esters or ethers vC-O), 1706 (saturated aldehyde, carboxylic acid or ketone vC = O), 1060 (phenolic, esters or ethers vC-O), 1014 (phenolic, esters or ethers vC-O) cm-1 for the pristine biochar (B600). Fulvic-like substances at 375 nm in the biochar DOM showed a preferential binding with U(VI) after TAO, while humic-like substances played a more critical role in the U(VI) complexation with biochar DOM obtained from non-TAO condition. The results also indicated that TAO increased the content of fluorescent DOM and the chemical stability of DOM-U(VI) complexes. The FT-ICR MS results showed an increase in the relative abundance of protein-like, carbohydrates-like, tannins-like, unsaturated hydrocarbons, and condensed aromatic structure and a decrease in the relative abundance of lipid-like and lignin-like after TAO. Consequently, although biochar after TAO had a much poorer content of intrinsic DOM, its intrinsic DOM showed a much higher capacity in U(VI) precipitation. Therefore, the TAO substantially changed the chemical composition, binding property and environmental behavior of intrinsic DOM from biochar.

Berberine hydrochloride inhibits migration ability via increasing inducible NO synthase and peroxynitrite in HTR-8/SVneo cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Inadequate trophoblasts migration and invasion is considered as an initial event resulting in preeclampsia, which is closely related to oxidative stress. Berberine hydrochloride (BBR), extracted from the traditional medicinal plant Coptis chinensis Franch., exerts a diversity of pharmacological effects, and the crude drug has been widely taken by most Chinese women to treat nausea and vomit during pregnancy. But there is no research regarding its effects on trophoblast cell function. AIM OF THE STUDY: This study aimed to investigate the effect of BBR on human-trophoblast-derived cell line (HTR-8/SVneo) migration ability and its mechanism. MATERIALS AND METHODS: Cell viability was detected by CCK-8 assay. The effect of BBR on cells migration function was examined by scratch wound healing assay and transwell migration assay. Intracellular nitric oxide (NO), superoxide (O2-) and peroxynitrite (ONOO-) levels were measured by flow cytometry. The expression levels of inducible NO synthase (iNOS), eNOS, p-eNOS, MnSOD, CuZnSOD, Rac1, NOX1, TLR4, nuclear factor-κB (NF-κB), p-NFκB, pro-inflammatory cytokines (TNF-α, IL-1ß and IL-6) in cells were analyzed by Western blotting. Uric acid sodium salt (UA), the scavenger of ONOO-, PEG-SOD (a specific superoxide scavenger), L-NAME (a NOS inhibitor) and antioxidants (Vit E and DFO) were further used to characterize the pathway of BBR action. RESULTS: 5 µM BBR decreased both the migration distance and the number of migrated cells without affecting cells viability in HTR-8/SVneo cells after 24 h treatment. BBR could increase the level of NO in HTR-8/SVneo cells, and the over-production of NO might be attributable to iNOS, but not eNOS. BBR could increase intracellular O2- levels, and the over-production of O2- is closely related with Rac1 in HTR-8/SVneo cells. The excessive production of NO and O2- further react to form ONOO-, and the increased ONOO- level induced by BBR was blunted by UA. Moreover, UA improved the impaired migration function caused by BBR in HTR-8/SVneo cells. The depressed migration function stimulated by BBR in HTR-8/SVneo cells was diminished by PEG-SOD and L-NAME. Furthermore, BBR increased the expression of IL-6 in HTR-8/SVneo cells, and antioxidants (Vit E and DFO) could decrease the expression of IL-6 and iNOS induced by BBR. CONCLUSIONS: BBR inhibits the cell migration ability through increasing inducible NO synthase and peroxynitrite in HTR-8/SVneo cells, indicating that BBR and traditional Chinese medicines containing a high proportion of BBR should be used with caution in pregnant women.

Association of selenium and cadmium with heart failure and mortality based on the National Health and Nutrition Examination Survey.

BACKGROUND: The association of selenium and cadmium with heart failure and mortality has not been thoroughly explored. METHODS: We analysed data from the National Health and Nutrition Examination Survey (NHANES) database over 12 years (1999-2000, 2003-2004 and 2011-2018), which includes blood selenium and cadmium. Multivariable logistic regression and Cox proportional hazards regression were used. RESULTS: In total, 15,689 participants were enrolled. The multivariate analysis showed that low blood selenium (odds ratio [OR] = 0.952, p < 0.001) and high blood cadmium (OR = 1.345, p < 0.001) were independent risk factors of heart failure. During 96802 person-year follow-up, 1697 deaths occurred. The multivariable adjusted hazard ratio (HR) for all-cause mortality was 0.82 (95% confidence interval [CI] = 0.71-0.95) for middle selenium levels and 0.76 (95% CI = 0.65-0.88) for high selenium levels compared to low selenium levels. Taking the low cadmium levels as reference, the multivariable adjusted HR for all-cause mortality among high cadmium levels was 1.68 (95% CI = 1.44-1.96). Furthermore, the association between selenium, cadmium and cardiovascular mortality was similar to that of all-cause mortality. A subgroup analysis of the study population showed that in individuals with heart failure, although selenium levels were not associated with risk of all-cause mortality, high selenium levels were associated with a lower risk of cardiovascular mortality (HR = 0.33, p = 0.0032). CONCLUSIONS: Low blood selenium and high blood cadmium were independent risk factors of heart failure. Blood selenium was inversely associated with all-cause mortality and cardiovascular mortality, whereas blood cadmium was positively associated with them. Furthermore, blood selenium was associated with a lower risk of cardiovascular mortality in individuals with heart failure.

ICG-loaded and 125I-labeled theranostic nanosystem for multimodality imaging-navigated phototherapy of breast cancer.

Multimodality imaging-navigated precise phototherapy has been well-established as a promising strategy for enhancing the diagnostic and therapeutic efficiency of cancer in preclinical trials. However, proper theranostic agents with adequate biosafety and biological efficacy as well as simple components and preparations are still in great demand to promote the clinical translation of this regimen. Here, we developed a multifunctional nanosystem based on the self-assembly of FDA-approved indocyanine green (ICG) and 125I-labeled glycopeptides, which were composed of FDA-approved natural polysaccharide sodium alginate and endogenous tyrosine, for fluorescence imaging/single photon emission computed tomography (FLI/SPECT)-guided synergistic photothermal/photodynamic therapy (PTT/PDT) of breast cancer. The as-prepared ICG@ADY(125I) NPs possessed a stable nanostructure and radiolabel, an ICG-equivalent ROS and hyperthermia generation property, and a preferable photo/photothermal stability and biocompatibility, favoring its tumor homing, multimodality imaging, and phototherapy with high biosafety. Consequently, ICG@ADY(125I) NPs smoothly accumulated in tumors by virtue of their long blood circulation (t1/2 = 15.76 ± 1.34 h) and the EPR effect, thereby presenting highly sensitive FLI/SPECT images to realize cancer diagnosis. Guided by multimodality imaging, accurate PTT/PDT was performed using NIR laser irradiation, achieving a high tumor inhibition rate (81.8%) against 4T1 breast cancer models without appreciable side effects. Altogether, this theranostic nanosystem may have huge potential for the clinical diagnosis and treatment of breast cancer.

Indole-3-Carboxylic Acid From the Endophytic Fungus Lasiodiplodia pseudotheobromae LPS-1 as a Synergist Enhancing the Antagonism of Jasmonic Acid Against Blumeria graminis on Wheat.

The discovery of natural bioactive compounds from endophytes or medicinal plants against plant diseases is an attractive option for reducing the use of chemical fungicides. In this study, three compounds, indole-3-carbaldehyde, indole-3-carboxylic acid (3-ICA), and jasmonic acid (JA), were isolated from the EtOAc extract of the culture filtrate of the endophytic fungus Lasiodiplodia pseudotheobromae LPS-1, which was previously isolated from the medicinal plant, Ilex cornuta. Some experiments were conducted to further determine the antifungal activity of these compounds on wheat powdery mildew. The results showed that JA was much more bioactive than indole-3-carbaldehyde and 3-ICA against Blumeria graminis, and the disease severity caused by B. graminis decreased significantly with the concentration increase of JA treatment. The assay of the interaction of 3-ICA and JA indicated that there was a significant synergistic effect between the two compounds on B. graminis in each of the ratios of 3-ICA to JA (3-ICA:JA) ranging from 1:9 to 9:1. When the compound ratio of 3-ICA to JA was 2:8, the synergistic coefficient was the highest as 22.95. Meanwhile, a histological investigation indicated that, under the treatment of JA at 500 µg/ml or 3-ICA:JA (2:8) at 40 µg/ml, the appressorium development and haustorium formation of B. graminis were significantly inhibited. Taken together, we concluded that JA plays an important role in the infection process of B. graminis and that 3-ICA as a synergist of JA enhances the antagonism against wheat powdery mildew.

Challenges and Improvements of Novel Therapies for Ischemic Stroke.

Stroke is the third most common disease all over the world, which is regarded as a hotspot in medical research because of its high mortality and morbidity. Stroke, especially ischemic stroke, causes severe neural cell death, and no effective therapy is currently available for neuroregeneration after stroke. Although many therapies have been shown to be effective in preclinical studies of ischemic stroke, almost none of them passed clinical trials, and the reasons for most failures have not been well identified. In this review, we focus on several novel methods, such as traditional Chinese medicine, stem cell therapy, and exosomes that have not been used for ischemic stroke till recent decades. We summarize the proposed basic mechanisms underlying these therapies and related clinical results, discussing advantages and current limitations for each therapy emphatically. Based on the limitations such as side effects, narrow therapeutic window, and less accumulation at the injury region, structure transformation and drug combination are subsequently applied, providing a deep understanding to develop effective treatment strategies for ischemic stroke in the near future.

NIR-activated self-sensitized polymeric micelles for enhanced cancer chemo-photothermal therapy.

NIR-activated therapies based on light-responsive drug delivery systems are emerging as a remote-controlled method for cancer precise therapy. In this work, fluorescent dye indocyanine green (ICG)-conjugated and bioactive compound gambogic acid (GA)-loaded polymeric micelles (GA@PEG-TK-ICG PMs) were smoothly fabricated via the self-assembly of the reactive oxygen species (ROS)-responsive thioketal (TK)-linked amphiphilic polymer poly(ethyleneglycol)-thioketal-(indocyanine green) (PEG-TK-ICG). The resultant micelles demonstrated increased resistance to photobleaching, enhanced photothermal conversion efficiency, NIR-controlled drug release behavior, preferable biocompatibility, and excellent tumor accumulation performance. Moreover, upon an 808 nm laser irradiation, the micellar photoactive chromophore ICG converted the absorbed optical energy to both hyperthermia for photothermal therapy (PTT) and ROS as the feedback trigger to the micelles for the tumor-specific release of GA, which could serve as not only a chemotherapeutic drug to directly kill tumor cells but also a heat shock protein 90 (HSP90) inhibitor to realize the photothermal sensitization. As a result, an extremely high tumor inhibition rate (97.9%) of mouse 4 T1 breast cancer models was achieved with negligible side effects after the chemo-photothermal synergistic therapy. This NIR-activated nanosystem with photothermal self-sensitization function may provide a feasible option for the effective treatment of aggressive breast cancers.

Multifunctional Hybrid Hydrogel Enhanced Antitumor Therapy through Multiple Destroying DNA Functions by a Triple-Combination Synergistic Therapy.

Brachytherapy, as an effective setting for precise cancer therapy in clinic, can lead to serious DNA damage. However, its therapeutic efficacy is always limited by the DNA self-repair property, tumor hypoxia-associated radiation resistance as well as inhomogeneous distribution of the radioactive material. Herein, a multifunctional hybrid hydrogel (131 I-hydrogel/DOX/GNPs aggregates) is developed by loading gold nanoparticle aggregates (GNPs aggregates) and DOX into a radionuclide iodine-131 (131 I) labelled polymeric hydrogels (131 I-PEG-P(Tyr)8 ) for tumor destruction by completely damaging DNA self-repair functions. This hybrid hydrogel exhibits excellent photothermal/radiolabel stability, biocompatibility, and fluorescence/photothermal /SPECT imaging properties. After local injection, the sustained releasing DOX within tumor greatly inhibits the DNA replication. Meanwhile, GNPs aggregates as a radiosensitizer and photosensitizer show a significant improvement of brachytherapeutic efficacy and cause serious DNA damage. Simultaneously, GNPs aggregates induce mild photothermal therapy under 808 nm laser irradiation, which not only inhibits self-repair of the damaged DNA but also effectively relieves tumor hypoxic condition to enhance the therapeutic effects of brachytherapy, leading to a triple-synergistic destruction of DNA functions. Therefore, this study provides a highly efficient tumor synergistic therapy platform and insight into the synergistic antitumor mechanism in DNA level.

Identification of natural compounds as SARS-CoV-2 entry inhibitors by molecular docking-based virtual screening with bio-layer interferometry.

Coronavirus Disease 2019 (COVID-19) is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which enter the host cells through the interaction between its receptor binding domain (RBD) of spike glycoprotein with angiotensin-converting enzyme 2 (ACE2) receptor on the plasma membrane of host cell. Neutralizing antibodies and peptide binders of RBD can block viral infection, however, the concern of accessibility and affordability of viral infection inhibitors has been raised. Here, we report the identification of natural compounds as potential SARS-CoV-2 entry inhibitors using the molecular docking-based virtual screening coupled with bilayer interferometry (BLI). From a library of 1871 natural compounds, epigallocatechin gallate (EGCG), 20(R)-ginsenoside Rg3 (RRg3), 20(S)-ginsenoside Rg3 (SRg3), isobavachalcone (Ibvc), isochlorogenic A (IscA) and bakuchiol (Bkc) effectively inhibited pseudovirus entry at concentrations up to 100 µM. Among these compounds, four compounds, EGCG, Ibvc, salvianolic acid A (SalA), and isoliensinine (Isl), were effective in inhibiting SARS-CoV-2-induced cytopathic effect and plaque formation in Vero E6 cells. The EGCG was further validated with no observable animal toxicity and certain antiviral effect against SARS-CoV-2 pseudovirus mutants (D614G, N501Y, N439K & Y453F). Interestingly, EGCG, Bkc and Ibvc bind to ACE2 receptor in BLI assay, suggesting a dual binding to RBD and ACE2. Current findings shed some insight into identifications and validations of SARS-CoV-2 entry inhibitors from natural compounds.

The efficacy of intravenous vitamin C in critically ill patients: A meta-analysis of randomized controlled trials.

BACKGROUND & AIMS: A large number of clinical studies have shown that intravenous vitamin C supplementation is beneficial for critically ill patients, but current research conclusions are controversial. This meta-analysis included high-quality randomized controlled trials (RCTs) to evaluate the efficacy of intravenous vitamin C in critically ill patients. METHODS: We searched PubMed, EMBASE and the Cochrane Library from inception to August 15, 2020 to identify published reports of RCTs evaluating the role of intravenous vitamin C in critically ill patients. Risk ratios values (RRs) and 95% confidence intervals (CIs) were calculated by random-effects meta-analysis. Trial sequential analysis (TSA), meta-regression, subgroup analyses and sensitivity analyses were also performed. RESULTS: Our meta-analysis included 18 RCTs involving 2001 patients (1005 with vitamin C treatment and 996 control treatment). Intravenous vitamin C administration reduced the intensive care unit (ICU) length of stay (LOS) (MD = -0.36, 95% CI: -0.60 to -0.11, P = 0.004) and hospital LOS (MD = -1.50, 95% CI: -2.64 to -0.35, P = 0.01) but had no significant effect on the longest follow-up mortality, hospital or ICU mortality and change in Sequential Organ Failure Assessment (SOFA) score. TSAs for mortality, ICU and hospital LOS were inconclusive. CONCLUSIONS: Intravenous vitamin C administration may shorten ICU LOS and hospital LOS. It had no effect on mortality and organ failure. All TSAs were inconclusive, and the value of vitamin C for critically ill patients needs to be demonstrated in more high-quality RCTs.

Immunonutrition for traumatic brain injury in children and adolescents: protocol for a systematic review and meta-analysis.

INTRODUCTION: Traumatic brain injury (TBI) is the leading cause of paediatric trauma death and disability worldwide. The 'Guidelines for the Management of Severe Traumatic Brain Injury (Fourth Edition)' recommend that nutritional goals should be achieved within 5-7 days of injury. Immune-enhancing nutrition or immunonutrition, referring to the addition of specialised nutrients, including glutamine, alanine, omega-3 fatty acids and nucleotides, to standard nutrition formulas, may improve surgical outcomes in the perioperative period. However, the role of immune-enhancing nutritional supplements for patients with paediatric TBI remains unclear. We will conduct a systematic review to determine the efficacy and safety of immunonutrition for patients with paediatric TBI and provide evidence for clinical decision-making. METHODS AND ANALYSIS: Studies reporting immune-enhancing nutrition treatments for patients with paediatric TBI will be included. Outcomes of interest include the length of hospital stay, wound infections, all-cause mortality, non-wound infection, including pneumonia, urinary tract infection and bacteraemia, and the reports adverse events. Duration of follow-up has no restriction. Primary studies consisting of randomised controlled trials (RCTs) and non-RCTs will be eligible for this review, and only studies published in English will be included. We will search the Medline, Embase and Cochrane Library databases from their inception dates to January 2020. We will also search clinicaltrials.gov and the WHO International Clinical Trials Registry Platform for additional information. Two reviewers will independently select studies and extract data. Risk-of-bias will be assessed with tools based on the Cochrane risk-of-bias criteria and Newcastle-Ottawa Quality Assessment Scale. A meta-analysis will be used to pool data when there are sufficient studies with homogeneity. Heterogeneity of the estimates across studies will be assessed; if necessary, a subgroup analysis will be performed to explore the source of heterogeneity. The Grades of Recommendation, Assessment, Development and Evaluation method will be applied to assess the level of evidence obtained from this systematic review. ETHICS AND DISSEMINATION: The proposed systematic review and meta-analysis will be based on published data, and thus ethical approval is not required. The results of this review will be published. PROSPERO REGISTRATION NUMBER: CRD42020154814.

Rapid and Easy Enrichment Strategy for Naturally Acetylated N Termini Based on LysN Digestion and Amine-Reactive Resin Capture.

Protein N-terminal acetylation (Nα-acetylation) is one of the most common modifications in both eukaryotes and prokaryotes. Although studies have shown that Nα-acetylation plays important roles in protein assembly, stability, and location, the physiological role has not been fully elucidated. Therefore, a robust and large-scale analytical method is important for a better understanding of Nα-acetylation. Here, an enrichment strategy was presented based on LysN digestion and amine-reactive resin capture to study naturally acetylated protein N termini. Since LysN protease cleaves at the amino-terminus of the lysine residue, all resulting peptides except naturally acetylated N-terminal peptides contain free amino groups and can be removed by coupling with AminoLink Resin. Therefore, the naturally acetylated N-terminal peptides were left in solution and enriched for further liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. The method was very simple and fast, which contained no additional chemical derivatization except protein reduction and alkylation necessarily needed in bottom-up proteomics. It could be used to study acetylated N termini from complex biological samples without bias toward different peptides with various physicochemical properties. The enrichment specificity was above 99% when it was applied in HeLa cell lysates. Neo-N termini generated by endogenous degradation could be directly distinguished without the use of stable-isotope labeling because no chemical derivatization was introduced in this method. Furthermore, this method was highly complementary to the traditional analytical methods for protein N termini based on trypsin only with ArgC-like activity. Therefore, the described method was beneficial to naturally acetylated protein N termini profiling.

ICG-Conjugated and 125 I-Labeled Polymeric Micelles with High Biosafety for Multimodality Imaging-Guided Photothermal Therapy of Tumors.

Noninvasive multimodality imaging-guided precision photothermal therapy (PTT) is proven to be an effective strategy for tumor theranostics by integrating diagnostics and therapeutics in one nanoplatform. In this study, indocyanine green (ICG)-conjugated and radionuclide iodine-125 (125 I)-labeled polymeric micelles (PEG-PTyr(125 I)-ICG PMs) are strategically prepared by the self-assembly of the ICG-decorated amphiphilic diblock polymer poly(ethylene glycol)-poly(l-tyrosine-125 I)-(indocyanine green) (PEG-PTyr(125 I)-ICG). The as-prepared polymeric micelles exhibit favorable biocompatibility, excellent size/photo/radiolabel stability, a high-photothermal conversion efficiency, a passive tumor-targeting ability, and a fluorescence (FL)/photoacoustic (PA)/single photon emission computed tomography (SPECT) imaging property. After tail intravenous injection, the polymeric micelles can efficiently accumulate at the tumor site and present comprehensive FL/PA/SPECT images with a high sensitivity, excellent spatial resolution, and unlimited tissue penetration under near-infrared (NIR) irradiation. Upon 808 nm laser irradiation, the subsequent precision PTT of tumors can be achieved with minimal cumulative side effects. Thus, this capable multifunctional nanoplatform with simple components and preparation procedures for FL/PA/SPECT multimodality imaging-guided PTT can be a potential candidate for clinical tumor theranostics.

Two new compounds, Talaromycin A and B, isolated from an endophytic fungus, Talaromyces aurantiacus.

Two new compounds Talaromycin A (1) and Talaromycin B (2) were isolated from a liquid culture of Talaromyces aurantiacus. The structures of 1 and 2 were elucidated by IR, MS, 1D and 2D NMR spectra and comparison of the experimental and calculated electronic circular dichroism spectra. Additional known compounds (3-6) were also isolated. These compounds were tested for monoamine oxidase, acetylcholinesterase and PI3K inhibitory activity, but showed only weak activity.

Development of Rice-Seed-Based Oral Allergy Vaccines Containing Hypoallergenic Japanese Cedar Pollen Allergen Derivatives for Immunotherapy.

Allergen-specific immunotherapy is the only available curative treatment for IgE-mediated allergen diseases. A safe hypoallergenic allergen derivative with high efficiency is required as a tolerogen to induce immune tolerance to the causitive allergens. In this study, to generate a rice-based oral allergy vaccine for Japanese cedar (JC) pollinosis, the tertiary structures of major JC pollen allergens, Cry j 1 and Cry j 2, were more completely destructed by shuffling than the previous ones without losing immunogenicity and then were specifically expressed in the endosperm of transgenic rice seed. They accumulated at high levels and were deposited in endoplasmic reticulum (ER) and ER-derived protein bodies. The low allergenicity of these deconstructed Cry j 1 and Cry j 2 allergens was evaluated by examining their binding activities to the specific IgE antibody and by the basophil degranulation test.

The biflavonoids as protein tyrosine phosphatase 1B inhibitors from Selaginella uncinata and their antihyperglycemic action.

Nine biflavonoids (1-9) were isolated from ethanolic extract of Selaginella uncinata (Desv.) Spring. Their structures were determined by spectra analysis. Compounds 1-9 were classified into four types according to the connection styles of the two flavonoid parts. Among them, 1 was elucidated as a new compound, while 4 was one with a new configuration. All isolates exhibited inhibitory activities against protein tyrosine phosphatase 1B (PTP1B) in an enzyme assay with IC50 values ranging from 4.6 to 16.1 µM, and the relationship between the structures and activities was discussed. Docking simulations of these compounds demonstrated they had tight binding capacities towards the allosteric site of PTP1B. Additionally, the glucose uptake activities of 1-9 were evaluated in insulin-resistant HepG2 cells, while the effect of 1 on the activation of IRS-1/PI3K/Akt pathway was revealed by Western Blot analysis.

[Determination of zearalenone and α-zearalenol in vegetable oil and grain products by C_(18)-Al_2O_3 solid phase extraction column purification coupled with ultra-performance liquid chromatography tandem mass spectrometry].

OBJECTIVE: To develop a method for simultaneous determination of zearalenone( ZEN) and α-zearalenol( α-ZEL) in vegetable oil and grain products by solid phase extraction column purification coupled with ultra-performance liquid chromatography tandem mass spectrometry. METHODS: Firstly, ZEN and α-ZEL in grain products were extracted by hexane/ethyl acetate( 50 : 50, V/V), and then extracted as vegetable oil by acetonitrile-water solution( 90: 10, V/V), and purified by C_(18)-Al_2O_3 solid phase extraction column. ZEN and α-ZEL was separated by UPLC with acetonitrile-water gradient elution on C_(18) column( 2. 1 mm × 100 mm, 1. 6 µm), and qualified/quantified by mass spectrometry with ESI negative MRM mode with ~(13)C_(18)-zearalenone as internal standard. RESULTS: The linearity of ZEN and α-ZEL ranged from 1. 0-500 ng/mL. The limit of detection for ZEN and α-ZEL in vegetable oil and grain products was 0. 3 and 0. 2 µg/kg, respectively. The limit of quantification for ZEN and α-ZEL in vegetable oil and grain products was 1. 0 and 0. 5 µg/kg. The average recoveries of ZEN and α-ZEL for spiked samples of 1. 0-100 µg/kg were 93. 5%-108. 0% and 92. 0%-105. 0%. The relative standard deviations of ZEN and α-ZEL were 3. 2%-8. 5% and 4. 6%-7. 8%( n = 6). 55 samples sold in Hangzhou supermarkets were analyzed. ZEN was detected in all corn germ oil with median and maximum contents of 126. 2 and 453. 1 µg/kg. α-ZEL was detected in 50% corn germ oil with median and maximum contents of 2. 0 and 5. 0µg/kg. CONCLUSION: The method possesses several advantages including sensitivity, precision, good efficiency of purification, simplicity and economy, and it is applicable to the batch analysis of zearalenone and α-zearalenol in vegetable oil and grain products.