Effects of Medium Additives on the Mycelial Growth and Polysaccharide Biosynthesis in Submerged Culture of Bjerkandera fumosa.

Medium additives have been shown to affect the synthesis of active products in fungi. This study investigated the effects of corn stalk, poplar sawdust, Tween-80, and oleic acid on mycelial biomass and physicochemical properties, as well as the bioactivity of polysaccharides, including exopolysaccharides (EPS) and intracellular polysaccharides (IPS), in the submerged culture of Bjerkandera fumosa. Results showed that the addition of corn stalk or poplar sawdust increased the production of EPS but decreased the production of IPS; Tween-80 had less effect on the production of EPS and IPS; and oleic acid stimulated polysaccharide production significantly. Polysaccharide property analysis showed that the addition of corn stalk or poplar sawdust promoted the production of high-molecular-weight components in polysaccharides and changed the monosaccharide composition of polysaccharides, as well as increased the mannose, glucuronic acid, and xylose contents of IPS. Tween-80 and oleic acid also changed the molecular weight distribution of polysaccharides but only slightly affected the composition of monosaccharides. The bioactivity assay indicated that the polysaccharides obtained by adding corn stalk possessed high hydroxyl radical scavenging and antitumor activities. The effect of poplar sawdust was slightly weaker than that of corn stalk. EPS and IPS obtained from a culture with Tween-80 and oleic acid possessed low antioxidant activity. Moreover, their antitumor activity was improved and lost, respectively. The results obtained in this work are useful for improving the understanding of the optimization and regulation of bioactive polysaccharide production in the submerged culture of B. fumosa.

Homozygous variants in CDC23 cause female infertility characterized by oocyte maturation defects.

Oocyte maturation defects are major phenotypes resulting in female infertility. Although many genetic factors have been found to be responsible for these phenotypes, the underlying pathogenic genes and variants remain to be identified. The anaphase promoting complex or cyclosome (APC/C) is known to be essential in the metaphase-to-anaphase transition. In this study, we identified two homozygous missense variants (c.986A > G, p.Y329C and c.988C > T, p.R330C) in CDC23 that are responsible for female infertility characterized by oocyte maturation defects in three infertile individuals. CDC23 (cell division cycle 23) is one of the core subunits of the APC/C. In vitro experiments showed that the variant c.986A > G (p.Y329C) led to a decrease in CDC23 protein level and the variant c.988C > T (p.R330C) changed the localization of CDC23 in HeLa cells and mouse oocytes. In vivo studies showed that Cdc23Y329C/Y329C mice successfully mimicked the patients' phenotype by causing low expression of CDC23 and APC4 and the accumulation of securin and cyclin B1 in oocytes. AZ3146 treatment was able to rescue the phenotype. Taken together, our findings reveal the important roles of CDC23 in human oocyte maturation and provide a new genetic marker for female infertility.

A novel homozygous variant in ZFP36L2 cause female infertility due to oocyte maturation defect.

Normal oocyte maturation is an important requirement for the success of human reproduction, and defects in this process will lead to female infertility and repeated IVF/ICSI failures. In order to identify genetic factors that are responsible for oocyte maturation defect, we used whole exome sequencing in the affected individual with oocyte maturation defect from a consanguineous family and identified a homozygous variant c.853_861del (p.285_287del) in ZFP36L2. ZFP36L2 is a RNA-binding protein, which regulates maternal mRNA decay and oocyte maturation. In vitro studies showed that the variant caused decreased protein levels of ZFP36L2 in oocytes due to mRNA instability and might lead to the loss of its function to degrade maternal mRNAs. Previous study showed that the pathogenic variants in ZFP36L2 were associated with early embryonic arrest. In contrast, we identified a novel ZFP36L2 variant in the affected individual with oocyte maturation defect, which further broadened the mutational and phenotypic spectrum of ZFP36L2, suggesting that ZFP36L2 might be a genetic diagnostic marker for the affected individuals with oocyte maturation defect.

Heterozygous loss-of-function variants in LHX8 cause female infertility characterized by oocyte maturation arrest.

PURPOSE: The genetic causes of oocyte maturation arrest leading to female infertility are largely unknown, and no population-based genetic analysis has been applied in cohorts of patients with infertility. We aimed to identify novel pathogenic genes causing oocyte maturation arrest by using a gene-based burden test. METHODS: Through comparison of exome sequencing data from 716 females with infertility characterized by oocyte maturation arrest and 3539 controls, we performed a gene-based burden test and identified a novel pathogenic gene LHX8. Splicing event was evaluated using a minigene assay, expression of LHX8 protein was assessed in HeLa cells, and nuclear subcellular localization was determined in both HeLa cells and mouse oocytes. RESULTS: A total of 5 heterozygous loss-of-function LHX8 variants were identified from 6 independent families (c.389+1G>T, c.412C>T [p.Arg138∗], c.282C>A [p.Cys94∗]; c.257dup [p.Tyr86∗]; and c.180del, [p.Ser61Profs∗30]). All the identified variants in LHX8 produced truncated LHX8 protein and resulted in loss of LHX8 nuclear localization in both HeLa cells and mouse oocytes. CONCLUSION: By combining genetic evidence and functional evaluations, we identified a novel pathogenic gene LHX8 and established the causative relationship between LHX8 haploinsufficiency and female infertility characterized by oocyte maturation arrest.

Diagnostic value of FeNO and MMEF for predicting cough variant asthma in chronic cough patients with or without allergic rhinitis.

OBJECTIVE: To evaluate the diagnostic value of fractional exhaled nitric oxide (FeNO) and maximum mid-expiratory flow (MMEF) for differentiating cough variant asthma (CVA) from chronic cough in patients with or without allergic rhinitis. METHODS: In total, 328 patients with chronic cough who underwent spirometry and FeNO testing were consecutively included in the retrospective analysis. Patients were divided into the CVA (n = 125) or NCVA (n = 203) groups according to the diagnostic criteria of CVA. Receiver operating characteristic (ROC) curves were established to assess the diagnostic efficiency and optimal cutoff points of FeNO and MMEF for the prediction of CVA. RESULTS: The optimal cutoff values of FeNO and MMEF to discriminate CVA from chronic cough were 24.5 ppb (AUC, 0.765; sensitivity, 69.60%; specificity 72.91%; PPV, 61.27%; NPV, 79.57%) and 66.2% (AUC, 0.771; sensitivity, 67.20%; specificity 78.33%; PPV, 65.63%; NPV, 79.50%). The optimal cutoff values of combining FeNO with MMEF to discriminate CVA from chronic cough were >22 ppb for FeNO and <62.6% for MMEF (AUC, 0.877). In patients with and without allergic rhinitis, the optimal cutoff point of FeNO to discriminate CVA from chronic cough was 24.5 ppb (AUC, 0.820) and 33.5 ppb (AUC, 0.707), respectively. CONCLUSIONS: FeNO and MMEF might have greater value as negative parameters for differentiating CVA from chronic cough. Combining FeNO and MMEF provided a significantly better prediction than either alone. The diagnostic accuracy of FeNO for predicting CVA in chronic cough patients with allergic rhinitis was higher than in chronic cough patients without allergic rhinitis.

Associations of urinary polycyclic aromatic hydrocarbons with albuminuria in U.S. adults, NHANES 2003-2014.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) exposure has been shown to be a risk factor for many diseases. However, studies on the association between PAHs exposure and kidney disease are limited. The aim of this study was to explore the association between urinary PAHs and albuminuria based on a national representative sample from the general U.S. METHOD: The data utilized were extracted from the 2003-2014 National Health and Nutrition Examination Survey (NHANES). Eight urinary PAHs were detected as PAH metabolites (OH-PAHs). Multivariable logistic regression analyses were applied to examine the association between urinary OH-PAHs and urinary albumin-creatinine ratio (ACR). All models were adjusted for confounding demographic, anthropometric and lifestyle factors. RESULT: A total of 8149 NHANES (2003-2014) participants with complete data were eligible. Compared with the lowest quartile, an increased prevalence of high ACR level (>3 mg/mmol) was observed in the participants with the highest quartile of 2-hydroxynaphthalene [OR (95% CI), 1.56 (1.28-1.90), P < 0.001], 3-hydroxyfluorene [OR (95% CI), 1.29 (1.06-1.58), P = 0.011] and 2-hydroxyfluorene [OR (95% CI), 1.47 (1.20-1.80), P < 0.001] levels after adjusting for confounding factors. In subgroup analysis, significantly high OH-PAHs leveland a strong relationship between OH-PAHs and ACR were observed in current smokers in the adjusted model. CONCLUSION: High levels of urinary OH-PAHs were positively associated with high levels of ACR in the U.S. POPULATION: Our finding provided evidence that PAHs exposure might potentially be related to albuminuria and therefore might have implications for environmental governance and prevention/treatment of this condition.

Separation of charge carriers and generation of reactive oxygen species by TiO2 nanoparticles mixed with differently-coated gold nanorods under light irradiation.

Combinations of semiconductor nanoparticles (NPs) with noble metal NPs enable an increase in the photoactivity of semiconductor NPs into the visible and near-infrared regions. The design rationale of the semiconductor-metal hybrid nanostructures for the optimization of charge carrier separation and reactive oxygen species (ROS) generation remains unclear. In this study, the interactions of Au nanorods (AuNRs) with TiO2 NPs were modulated by controlling their surface charges. Positively charged AuNRs formed aggregates with the negatively charged TiO2 NPs (AuNR@CTAB/TiO2) upon mixing, suggesting that Schottky junctions may exist between Au and TiO2. In contrast, negatively charged AuNRs (AuNR@PSS) remained spatially separated from the TiO2 NPs in the mixed suspension (AuNR@PSS/TiO2), owing to electrostatic repulsion. We used electron spin resonance (ESR) spectroscopy to detect the separation of charged carriers and ROS generation in these two mixtures under simulated sunlight irradiation. We also explored the role of dissolved oxygen in charge carrier separation and ROS generation by continuously introducing oxygen into the AuNR@CTAB/TiO2 suspension under simulated sunlight irradiation. Moreover, the generation of ROS by the AuNR@CTAB/TiO2 and AuNR@PSS/TiO2 mixtures were also examined under 808 nm laser irradiation. Our results show that the photogenerated electrons of excited semiconductor NPs are readily transferred to noble metal NPs simply by collisions, but the transfer of photogenerated hot electrons from excited AuNRs to TiO2 NPs is more stringent and requires the formation of Schottky junctions. In addition, the introduction of oxygen is an efficient way to enhance the photocatalytic activity of semiconductor NPs/noble metal NPs system combinations.

Curcumin protects neurons against oxygen-glucose deprivation/reoxygenation-induced injury through activation of peroxisome proliferator-activated receptor-γ function.

The turmeric derivative curcumin protects against cerebral ischemic injury. We previously demonstrated that curcumin activates peroxisome proliferator-activated receptor-γ (PPARγ), a ligand-activated transcription factor involved in both neuroprotective and anti-inflammatory signaling pathways. This study tested whether the neuroprotective effects of curcumin against oxygen-glucose deprivation/reoxygenation (OGD/R)-induced injury of rat cortical neurons are mediated (at least in part) by PPARγ. Curcumin (10 µM) potently enhanced PPARγ expression and transcriptional activity following OGD/R. In addition, curcumin markedly increased neuronal viability, as evidenced by decreased lactate dehydrogenase release and reduced nitric oxide production, caspase-3 activity, and apoptosis. These protective effects were suppressed by coadministration of the PPARγ antagonist 2-chloro-5-nitrobenzanilide (GW9662) and by prior transfection of a small-interfering RNA (siRNA) targeting PPARγ, treatments that had no toxic effects on healthy neurons. Curcumin reduced OGD/R-induced accumulation of reactive oxygen species and inhibited the mitochondrial apoptosis pathway, as indicated by reduced release of cytochrome c and apoptosis-inducing factor and maintenance of both the mitochondrial membrane potential and the Bax/Bcl-2 ratio. Again, GW9662 or PPARγ siRNA transfection mitigated the protective effects of curcumin on mitochondrial function. Curcumin suppressed IκB kinase phosphorylation and IκB degradation, thereby inhibiting nuclear factor-κ B (NF-κB) nuclear translocation, effects also blocked by GW9662 or PPARγ siRNA. Immunoprecipitation experiments revealed that PPARγ interacted with NF-κB p65 and inhibited NF-κB activation. The present study provides strong evidence that at least some of the neuroprotective effects of curcumin against OGD/R are mediated by PPARγ activation.

Transforming growth factor-ß1 rs1800470 polymorphism is associated with lung cancer risk: a meta-analysis.

BACKGROUND: Transforming growth factor-ß1 is a member of a large class of polypeptides that regulate the proliferation, differentiation, and carcinogenesis of epithelial cells. The rs1800470 polymorphism influences transforming growth factor-ß1 expression and has been associated with lung cancer susceptibility. However, the association between the rs1800470 polymorphism and lung cancer risk remains controversial. Thus, a meta-analysis was conducted. MATERIAL/METHODS: We comprehensively searched PubMed and EMBASE databases. Summary odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using random-effects models or fixed-effects models. RESULTS: Overall, there was a significant association between rs1800470 polymorphism and lung cancer susceptibility (OR=1.23; 95%CI, 1.03-1.47; P=0.02). In the stratified analysis by ethnicity, we found that this polymorphism was significantly associated with lung cancer in Asians (OR=1.26; 95%CI, 1.01-1.57; P=0.04). However, we did not find any significant association between this polymorphism and lung cancer risk in Caucasians (OR=1.04; 95%CI, 0.60-1.82; P=0.88). In the NSCLC subgroup, we found that rs1800470 polymorphism could increase NSCLC risk (OR=1.36; 95%CI, 1.06-1.74; P=0.02). CONCLUSIONS: This meta-analysis suggested that rs1800470 polymorphism was a risk factor of lung cancer.

Exploring the Specificity of Nanozymes.

Nanozymes, nanomaterials exhibiting enzyme-like activities, have emerged as a prominent interdisciplinary field over the past decade. To date, over 1200 different nanomaterials have been identified as nanozymes, covering four catalytic categories: oxidoreductases, hydrolases, isomerases, and lyases. Catalytic activity and specificity are two pivotal benchmarks for evaluating enzymatic performance. Despite substantial progress being made in quantifying and optimizing the catalytic activity of nanozymes, there is still a lack of in-depth research on the catalytic specificity of nanozymes, preventing the formation of consensual knowledge and impeding a more refined and systematic classification of nanozymes. Recently, debates have emerged regarding whether nanozymes could possess catalytic specificity similar to that of enzymes. This Perspective discusses the specificity of nanozymes by referring to the catalytic specificity of enzymes, highlights the specificity gap between nanozymes and enzymes, and concludes by offering our perspective on future research on the specificity of nanozymes.

Surface Ligand Engineering Ruthenium Nanozyme Superior to Horseradish Peroxidase for Enhanced Immunoassay.

Nanozymes have great potential to be used as an alternative to natural enzymes in a variety of fields. However, low catalytic activity compared with natural enzymes limits their practical use. It is still challenging to design nanozymes comparable to their natural counterparts in terms of the specific activity. In this study, a surface engineering strategy is employed to improve the specific activity of Ru nanozymes using charge-transferrable ligands such as polystyrene sulfonate (PSS). PSS-modified Ru nanozyme exhibits a peroxidase-like specific activity of up to 2820 U mg-1 , which is twice that of horseradish peroxidase (1305 U mg-1 ). Mechanism studies suggest that PSS readily accepts negative charge from Ru, thus reducing the affinity between Ru and ·OH. Importantly, the modified Ru-peroxidase nanozyme is successfully used to develop an immunoassay for human alpha-fetoprotein and achieves a 140-fold increase in detection sensitivity compared with traditional horseradish-peroxidase-based enzyme-linked immunosorbent assay. Therefore, this work provides a feasible route to design nanozymes with high specific activity that meets the practical use as an alternative to natural enzymes.

Herbal Products-Powered Thermosensitive Hydrogel with Phototherapy and Microenvironment Reconstruction for Accelerating Multidrug-Resistant Bacteria-Infected Wound Healing.

Wound healing and infection remain significant challenges due to the ineffectiveness against multidrug-resistant (MDR) bacteria and the complex oxidative wound microenvironments. To address these issues, thymoquinone-reinforced injectable and thermosensitive TQ@PEG-PAF-Cur hydrogels with dual functions of microenvironment reshaping and photodynamic therapy are developed. The hydrogel comprises natural compound thymoquinone (TQ) and poly (ethylene glycol)-block-poly (alanine-co-phenyl alanine) copolymers (PEG-PAF) conjugated with natural photosensitizer curcumin (Cur). The incorporation of TQ and Cur reduces the sol-to-gel transition temperature of TQ@PEG-PAF-Cur to 30°C, compared to PEG-PAF hydrogel (37°C), due to the formation of strong hydrogen bonding, matching the wound microenvironment temperature. Under blue light excitation, TQ@PEG-PAF-Cur generates significant amounts of reactive oxygen species such as H2O2, 1O2, and ·OH, exhibiting rapid and efficient bactericidal capacities against methicillin-resistant Staphylococcus aureus and broad spectrum ß-lactamases Escherichia coli via photodynamic therapy (PDT). Additionally, Cur effectively inhibits the expressions of proinflammatory cytokines in skin tissue-forming cells. As a result, the composite hydrogel can rapidly transform into a gel to cover the wound, reshape the wound microenvironment, and accelerate wound healing in vivo. This collaborative antibacterial strategy provides valuable insights to guide the development of multifunctional materials for efficient wound healing.

Ultrasmall metal alloy nanozymes mimicking neutrophil enzymatic cascades for tumor catalytic therapy.

Developing strategies that emulate the killing mechanism of neutrophils, which involves the enzymatic cascade of superoxide dismutase (SOD) and myeloperoxidase (MPO), shows potential as a viable approach for cancer therapy. Nonetheless, utilizing natural enzymes as therapeutics is hindered by various challenges. While nanozymes have emerged for cancer treatment, developing SOD-MPO cascade in one nanozyme remains a challenge. Here, we develop nanozymes possessing both SOD- and MPO-like activities through alloying Au and Pd, which exhibits the highest cascade activity when the ratio of Au and Pd is 1:3, attributing to the high d-band center and adsorption energy for superoxide anions, as determined through theoretical calculations. The Au1Pd3 alloy nanozymes exhibit excellent tumor therapeutic performance and safety in female tumor-bearing mice, with safety attributed to their tumor-specific killing ability and renal clearance ability caused by ultrasmall size. Together, this work develops ultrasmall AuPd alloy nanozymes that mimic neutrophil enzymatic cascades for catalytic treatment of tumors.

Somatic KMT2D loss-of-function mutations in lung squamous cell carcinoma: a single-center cohort study.

Background: The significant progress has been made in targeted therapy for lung adenocarcinoma (LUAD) in the past decade. Only few targeted therapeutics have yet been approved for the treatment of lung squamous cell carcinoma (LUSC). Several higher frequency of gene alterations are identified as potentially actionable in LUSC. Our work aimed to explore the complex interplay of multiple genetic alterations and pathways contributing to the pathogenesis of LUSC, with a very low frequency of a single driver molecular alterations to develop more effective therapeutic strategies in the future. Methods: We retrospectively analyzed the targeted next-generation sequencing (NGS) data (approximately 600 genes) of 335 patients initially diagnosed with non-small cell lung cancer (NSCLC) at our institution between January 2019 and March 2023 and explored the somatic genome alteration difference between LUSC and LUAD. Results: We analyzed that the presence of loss-of-function (LoF) mutations (nonsense, frameshift, and splice-site variants) in histone-lysine N-methyltransferase 2D (KMT2D) was much more prevalent in LUSC (11/53, 20.8%) than in LUAD (6/282, 2.1%). Moreover, our data indicated TP53 co-mutated with KMT2D LoF in 90.9% (10/11) LUSC and 33.3% (2/6) LUAD. Notably, the mutation allele fraction (MAF) of KMT2D was very similar to that of TP53 in the co-mutated cases. Genomic profiling of driver gene mutations of NSCLC showed that 81.8% (9/11) of the patients with LUSC with KMT2D LoF mutations had PIK3CA amplification and/or FGFR1 amplification. Conclusions: Our results prompted that somatic LoF mutations of KMT2D occur frequently in LUSC, but are less frequent in LUAD and therefore may potentially contribute to the pathogenesis of LUSC. Concurrent TP53 mutations, FGFR1 amplification, and PIK3CA amplification are very common in LUSC cases with KMT2D LoF mutations. It needs more deeper investigation on the interplay of the genes and pathways and uses larger cohorts in the future.

The in vitro anticancer effects of FS48 from salivary glands of Xenopsylla cheopis on NCI-H460 cells via its blockage of voltage-gated K+ channels.

Voltage-gated K+ (Kv) channels play a role in the cellular processes of various cancer cells, including lung cancer cells. We previously identified and reported a salivary protein from the Xenopsylla cheopis, FS48, which exhibited inhibitory activity against Kv1.1-1.3 channels when assayed in HEK 293T cells. However, whether FS48 has an inhibitory effect on cancer cells expressing Kv channels is unclear. The present study aims to reveal the effects of FS48 on the Kv channels and the NCI-H460 human lung cancer cells through patch clamp, MTT, wound healing, transwell, gelatinase zymography, qRT-PCR and WB assays. The results demonstrated that FS48 can be effective in suppressing the Kv currents, migration, and invasion of NCI-H460 cells in a dose-dependent manner, despite the failure to inhibit the proliferation. Moreover, the expression of Kv1.1 and Kv1.3 mRNA and protein were found to be significantly reduced. Finally, FS48 decreases the mRNA level of MMP-9 while increasing TIMP-1 mRNA level. The present study highlights for the first time that blood-sucking arthropod saliva-derived protein can inhibit the physiological activities of tumour cells via the Kv channels. Furthermore, FS48 can be taken as a hit compound against the tumour cells expressing Kv channels.

Large-scale analysis of de novo mutations identifies risk genes for female infertility characterized by oocyte and early embryo defects.

BACKGROUND: Oocyte maturation arrest and early embryonic arrest are important reproductive phenotypes resulting in female infertility and cause the recurrent failure of assisted reproductive technology (ART). However, the genetic etiologies of these female infertility-related phenotypes are poorly understood. Previous studies have mainly focused on inherited mutations based on large pedigrees or consanguineous patients. However, the role of de novo mutations (DNMs) in these phenotypes remains to be elucidated. RESULTS: To decipher the role of DNMs in ART failure and female infertility with oocyte and embryo defects, we explore the landscape of DNMs in 473 infertile parent-child trios and identify a set of 481 confident DNMs distributed in 474 genes. Gene ontology analysis reveals that the identified genes with DNMs are enriched in signaling pathways associated with female reproductive processes such as meiosis, embryonic development, and reproductive structure development. We perform functional assays on the effects of DNMs in a representative gene Tubulin Alpha 4a (TUBA4A), which shows the most significant enrichment of DNMs in the infertile parent-child trios. DNMs in TUBA4A disrupt the normal assembly of the microtubule network in HeLa cells, and microinjection of DNM TUBA4A cRNAs causes abnormalities in mouse oocyte maturation or embryo development, suggesting the pathogenic role of these DNMs in TUBA4A. CONCLUSIONS: Our findings suggest novel genetic insights that DNMs contribute to female infertility with oocyte and embryo defects. This study also provides potential genetic markers and facilitates the genetic diagnosis of recurrent ART failure and female infertility.

[Effect and mechanism of lipopolysaccharides-induced myeloid-derived suppressor cells on airway inflammation in asthmatic mice].

OBJECTIVE: To explore the effect and mechanism of lipopolysaccharides (LPS)-induced CD11b⁺Gr-1⁺ myeloid-derived suppressor cells (MDSCs) on airway inflammation in asthmatic mice. METHODS: A total of 34 female BALB/c mice were selected. Among them, 4 mice received an intraperitoneal injection of LPS for inducing the accumulation of MDSCs. And the MDSCs were separated with CD11b immunomagnetic beads from spleen extract. Another 30 mice were randomly divided into normal control, asthmatic and cell treatment groups. The mice in the asthmatic and cell treatment groups were sensitized with ovalbumin by a combination of intraperitoneal injection and challenges to establish the murine asthmatic model. At Days 14 and 21 post-sensitization, the mice in cell treatment group received an intravenous injection of LPS-induced MDSCs. At 24 hours after the last allergen challenge, the number of inflammatory cells were counted and morphological identification of leucocytes in bronchoalveolar lavage fluid (BALF) was performed to analyze the degree of airway inflammation in conjunctions with pathological sections. The BALF and serum levels of interleukin-13 were measured by enzyme-linked immunosorbent assay (ELISA). The number of CD4⁺CD25⁺Foxp3⁺ regulatory T cells (Tregs) in peripheral blood was measured by flow cytometry. RESULTS: The total number of cells, the percentage of neutrophils and eosinophils of BALF in the cell treatment group [(17.0 ± 8.3)×104/ml, 11.1% ± 2.0%, 9.8% ± 2.9%] were significantly lower than those in the asthmatic group [(36.0 ± 15.9)×104/ml, 20.8% ± 4.0%, 14.1% ± 4.2%] (P = 0.000, 0.000, 0.011). Compared to the asthmatic group, the BALF and serum levels of IL-13 were significantly lower [(34.7 ± 7.1) vs (105.0 ± 9.0) ng/L, (34.0 ± 4.7) vs (48.1 ± 6.1) ng/L] (both P = 0.000) and the number of CD4⁺CD25⁺Foxp3⁺ regulatory T cells increased in peripheral blood (8.0% ± 1.3% vs 5.1% ± 2.1%, P = 0.002) and airway inflammation was significantly relieved in the cell treatment group. CONCLUSION: LPS-induced MDSCs may improve airway inflammation through up-regulating Tregs in peripheral blood and suppressing Th2 effector function in asthmatic mice.

[Inhibition of lipopolysaccharide-induced myeloid-derived suppressor cells in the proliferation of spleen T lymphocytes].

OBJECTIVE: To explore the effects of lipopolysaccharide (LPS)-induced myeloid-derived suppressor cells (MDSCs) on the proliferation of spleen T lymphocytes. METHODS: BALB/c mice were randomly divided into two groups: LPS group and normal control group. They were injected intraperitoneally with LPS and normal saline solution respectively. MDSCs were separated with CD11b immunomagnetic beads from the spleen extract of mice. The morphological characteristics of MDCSs were observed by Wright-Giemsa staining and the characteristic molecules on cell surface identified by flow cytometry. And the effects of MDSCs on the in vitro proliferation of T cells were determined by methyl-thiazolyl-tetrazolium bromide (MTT). RESULTS: The proportion of MDSCs in the spleen of the LPS group was much more than that of the normal control group (27.4% ± 6.6% vs 5.1% ± 3.8%; t = 5.06, P = 0.007). CD11b(+)Gr-1(+)MDSCs could be separated by CD11b immunomagnetic beads from the spleen of mice injected with LPS at a high purity of 84.0% ± 4.2%. MTT method showed that the proliferation of T cells decreased significantly after a co-cultivation with CD11b(+)MDSCs versus the control group. And it was positively correlated with the number of MDSCs (F = 46.26, P = 0.000). CONCLUSIONS: A high purity of LPS-induced myeloid-derived suppressor cells may be separated with CD11b immunomagnetic beads. And it has dose-dependent inhibitory effects on the proliferation of the spleen T lymphocytes.

Inhibition of phosphodiesterase: A novel therapeutic target for the treatment of mild cognitive impairment and Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia and is ranked as the 6th leading cause of death in the US. The prevalence of AD and dementia is steadily increasing and expected cases in USA is 14.8 million by 2050. Neuroinflammation and gradual neurodegeneration occurs in Alzheimer's disease. However, existing medications has limitation to completely abolish, delay, or prevent disease progression. Phosphodiesterases (PDEs) are large family of enzymes to hydrolyze the 3'-phosphodiester links in cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in signal-transduction pathways for generation of 5'-cyclic nucleotides. It plays vital role to orchestrate several pharmacological activities for proper cell functioning and regulating the levels of cAMP and cGMP. Several evidence has suggested that abnormal cAMP signaling is linked to cognitive problems in neurodegenerative disorders like AD. Therefore, the PDE family has become a widely accepted and multipotential therapeutic target for neurodegenerative diseases. Notably, modulation of cAMP/cGMP by phytonutrients has a huge potential for the management of AD. Natural compounds have been known to inhibit phosphodiesterase by targeting key enzymes of cGMP synthesis pathway, however, the mechanism of action and their therapeutic efficacy has not been explored extensively. Currently, few PDE inhibitors such as Vinpocetine and Nicergoline have been used for treatment of central nervous system (CNS) disorders. Considering the role of flavonoids to inhibit PDE, this review discussed the therapeutic potential of natural compounds with PDE inhibitory activity for the treatment of AD and related dementia.