Inhibition of integrin alpha v/beta 5 mitigates the protective effect induced by irisin in hemorrhage.

INTRODUCTION: Irisin plays an important role in regulating tissue stress, cardiac function, and inflammation. Integrin αvß5 was recently identified as a receptor for irisin to elicit its physiologic function. It remains unknown whether integrin αvß5 is required for irisin's function in modulating the physiologic response to hemorrhage. The objective of this study is to examine if integrin αvß5 contributes to the effects of irisin during the hemorrhagic response. METHODS: Hemorrhage was induced in mice by achieving a mean arterial blood pressure of 35-45 mmHg for one hour, followed by two hours of resuscitation. Irisin (0.5  µg/kg) was administrated to assess its pharmacologic effects in hemorrhage. Cilengitide, a cyclic Arg-Gly-Asp peptide (cRGDyK) which is an inhibitor of integrin αvß5, or control RGDS (1 mg/kg) was administered with irisin. In another cohort of mice, the irisin-induced protective effect was examined after knocking down integrin ß5 with nanoparticle delivery of integrin ß5 sgRNA using CRSIPR/Cas-9 gene editing. Cardiac function and hemodynamics were measured using echocardiography and femoral artery catheterization, respectively. Systemic cytokine releases were measured using Enzyme-linked immunosorbent assay (ELISA). Histological analyses were used to determine tissue damage in myocardium, skeletal muscles, and lung tissues. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was carried out to assess apoptosis in tissues. RESULTS: Hemorrhage induced reduction of integrin αvß5 in skeletal muscles and repressed recovery of cardiac performance and hemodynamics. Irisin treatment led to significantly improved cardiac function, which was abrogated by treatment with Cilengitide or knockdown of integrin ß5. Furthermore, irisin resulted in a marked suppression of tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1), muscle edema, and inflammatory cells infiltration in myocardium and skeletal muscles, which was attenuated by Cilengitide or knockdown of integrin ß5. Irisin-induced reduction of apoptosis in the myocardium, skeletal muscles, and lung, which were attenuated by either the inhibition of integrin αvß5, or knockdown of integrin ß5. CONCLUSION: Integrin αvß5 plays an important role for irisin in modulating the protective effect during hemorrhage.

Joint effect of maternal pre-pregnancy body mass index and folic acid supplements on gestational diabetes mellitus risk: a prospective cohort study.

BACKGROUND: The joint effect of folic acid (FA) supplements and maternal pre-pregnancy body mass index (BMI) on gestational diabetes mellitus (GDM) has not been fully addressed. This study aimed to examine the joint effect of FA supplements and pre-pregnancy BMI on GDM. METHODS: Pregnant women at 4 to 14 weeks of gestation (n = 3186) were recruited during their first prenatal visit in Qingdao from May 1, 2019, to June 27, 2021. The main outcome was GDM at 24-28 weeks' gestation. Screening was based on 75 g 2-hour oral glucose tolerance (OGTT), a fasting glucose ≥ 5.1 mmol/L, or a 1-hour result ≥ 10.0 mmol/L, or a 2-hour result ≥ 8.5 mmol/L. The interactive effect of FA supplements and pre-pregnancy BMI on GDM was examined using logistic regression analysis and ratio of odds ratios (ROR) was used to compare subgroup differences. RESULTS: Overall, 2,095 pregnant women were included in the analysis, and GDM incidence was 17.76%. Compared with women with pre-pregnancy BMI lower than 25.0 kg/m2 and FA-Sufficient supplements ≥ 400 µg/day (FA-S) population, the adjusted odds ratios (aORs) of FA-S and FA-Deficiency supplements < 400 µg/d (FA-D) were 3.57 (95% confidence interval [CI]: 2.02-6.34) and 10.82 (95% CI: 1.69-69.45) for the obese women (BMI ≥ 30.0 kg/m2), and the aORs of FA-S and FA-D were 2.17 (95% CI: 1.60-2.95) and 3.27 (95% CI: 1.55-6.92) for overweight women (25.0 kg/m2 ≤ BMI < 30.0 kg/m2). However, the risk of GDM did not differ significantly between the FA-D and the FA-S group in pre-pregnancy obese women (ROR = 2.70, 95%CI: 0.47-2.30), or overweight women (ROR = 0.66, 95%CI: 0.30-1.49). After further stratification of FA supplementation time, F-D and FA-S in obese women showed an interaction when FA supplement intake time < 3 months. However, there was no significant difference between subgroups (ROR = 1.63, 95% CI: 0.37-7.04). CONCLUSION: Maternal pre-pregnancy BMI was associated with the incidence of GDM, the dose of FA supplementation from pre-pregnancy to early pregnancy was not found to be related to the incidence of GDM. The dosage of FA supplement was not associated with GDM irrespective of maternal pre-pregnancy BMI.

A randomized, controlled comparison of a stannous-containing dentifrice for reducing gingival bleeding and balancing the oral microbiome relative to a positive control.

PURPOSE: To evaluate the effect of a stannous-containing fluoride dentifrice on gingival health and on the composition of the oral microbiome versus a positive control dentifrice over 2 weeks, in a population of healthy adults with self-reported sub-optimal oral health at baseline. METHODS: This was a randomized, controlled, double-blind clinical study. 87 subjects with self-reported sub-optimal oral health at enrollment were randomized to brush twice daily with either an experimental dentifrice (n= 43) or a marketed positive control dentifrice (n= 43), both containing stannous chloride and 0.321% sodium fluoride. All subjects used a soft, manual toothbrush that was provided. The Mazza modification of gingival papillary bleeding Index (Mazza GI) was used to assess gingivitis at baseline and at Week 2. Supragingival plaque was collected for microbiome composition analyses at baseline, Week 1, and Week 2. RESULTS: 83 subjects completed the study. Baseline means were balanced between the treatment groups (P> 0.34). At Week 2, the positive control dentifrice demonstrated a 63.8% statistically significant (P< 0.0001) reduction relative to baseline for Mazza number of gingival bleeding sites. The experimental stannous containing dentifrice provided a comparable 63.5% gingival bleeding reduction versus baseline. There was no significant (P= 0.96) difference between the two dentifrices for either Mazza GI score or number of bleeding sites measured. The microbiome composition analysis at Week 1 found that 28 gingivitis-associated bacterial genera, including Porphyromonas, Tannerella, and Fusobacterium, were significantly inhibited in both dentifrice groups when compared to baseline, while the relative abundance of genera associated with oral health, such as Rothia, Streptococcus, Haemophilus, and Lautropia, was significantly elevated after treatment. These improvements in the oral ecosystem were sustained at Week 2. CLINICAL SIGNIFICANCE: An experimental stannous-containing sodium fluoride dentifrice significantly reduced gingival bleeding comparable to a positive control, and both dentifrices promoted a shift in the oral microbiome towards those genera associated with oral health in a subject population with self-reported sub-optimal oral health at baseline.

Qishen Yiqi Dropping Pills Ameliorates Doxorubicin-induced Cardiotoxicity in Mice via Enhancement of Cardiac Angiogenesis.

BACKGROUND Qishen Yiqi Dropping Pills (QYDP) is a Chinese traditional medicine that has been applied to treat coronary heart disease and ischemic heart failure in China. However, few studies have explored whether QYDP exerted an effect on doxorubicin (Doxo)-induced cardiotoxicity. Hence, in this study we investigated the effect of QYDP on cardiotoxicity induced by doxorubicin (Doxo) and its potential mechanism. MATERIAL AND METHODS Male C57BL/6 mice (20-25 g, 8-10 weeks old) were randomly assigned to 4 groups: Control group, QYDP group, Doxo group, and QYDP+Doxo group. The mice were intraperitoneal injected with Doxo weekly for 4 weeks to mimic the chronic toxicity. Four weeks after Doxo injection, echocardiography was applied to evaluate the left ventricular (LV) function, and the structure of the cardiac muscle fibers was analyzed with anti-actinin-2 antibody staining by immunofluorescence. Moreover, TUNEL staining and western blot analysis of Bax protein, Bcl-2 protein, and cleaved caspase-3 protein expression levels were conducted to explore whether QYDP exerted effect on cardiac apoptosis. In addition, Masson trichrome staining and western blot analysis of alpha-SMA protein expression levels were used to evaluate whether QYDP exerted an effect on cardiac fibrosis. Western blots and quantitative real-time polymerase chain reaction were applied to detect the vascular endothelial growth factor (VEGF) protein and mRNA levels in the myocardial tissue, and anti-CD31 antibody staining by immunohistochemistry was employed to explore whether QYDP exerted an effect on cardiac angiogenesis. RESULTS QYDP effectively attenuated cardiac dysfunction and cardiac muscle fibers disruption in Doxo treated mice. Moreover, QYDP reduced myocardial apoptosis and myocardial fibrosis in Doxo treated mice, accompanied with elevated protein levels of VEGF and enhancement of myocardial microvessel density. CONCLUSIONS QYDP could protect against Doxo-induced cardiotoxicity, which may be closely associated with enhanced cardiac angiogenesis. Hence, QYDP could be a promising alternative for the treatment of Doxo-induced cardiotoxicity.

Doublecortin-Like Kinase 1 (DCLK1) Regulates B Cell-Specific Moloney Murine Leukemia Virus Insertion Site 1 (Bmi-1) and is Associated with Metastasis and Prognosis in Pancreatic Cancer.

BACKGROUND/AIMS: Cancer stem cells (CSCs) are largely responsible for tumor relapse and metastatic behavior. Doublecortin-like kinase 1 (DCLK1) was recently reported to be a biomarker for gastrointestinal CSCs and involved in the epithelial-mesenchymal transition (EMT) and tumor progression. B cell-specific Moloney murine leukemia virus insertion site 1 (Bmi-1) is a crucial regulator of CSC self-renewal, malignant transformation and EMT, and a previous study from our group showed that Bmi-1 is upregulated in pancreatic cancer progression and participates in EMT. However, it remains unclear whether DCLK1 is involved in pancreatic cancer or whether DCLK1 is associated with the altered level of Bmi-1 expression. METHODS: The correlation of DCLK1 expression and clinical features of pancreatic cancer was analyzed in 210 paraffin-embedded archived pancreatic cancer specimens by immunohistochemical analysis. The biological effects of DCLK1 siRNA on cells were investigated by examining cell proliferation using a cell counting kit and cell colony assays, cell migration by wound healing assay and cell invasion by Transwell invasion assay. We further investigated the effect of therapeutic siRNA targeting DCLK1 on pancreatic cancer cell growth in vivo. Moreover, the molecular mechanism by which DCLK1 upregulates Bmi-1 expression was explored using real-time PCR, western blotting and Co-immunoprecipitation assay. RESULTS: DCLK1 is overexpressed in pancreatic cancer and is related to metastasis and prognosis. Knockdown of DCLK1 markedly suppressed cell growth in vitro and in vivo and also inhibited the migration and invasion of pancreatic cancer cells. Furthermore, we found that DCLK1 silencing could inhibit EMT in cancer cells via downregulation of Bmi-1 and the mesenchymal markers Snail and Vimentin and upregulation of the epithelial marker E-cadherin. Moreover, high DCLK1 expression in human pancreatic cancer samples was associated with a mesenchymal phenotype and increased cell proliferation. Further co-immunoprecipitation indicated that DCLK1 did not interact with Bmi-1 directly. CONCLUSION: Our data suggest that upregulation of DCLK1 may contribute to pancreatic cancer metastasis and poor prognosis by increasing Bmi-1 expression indirectly. The findings indicate that inhibiting DCLK1 expression might be a novel strategy for pancreatic cancer therapy.

Genome sequencing and heterologous expression of antiporters reveal alkaline response mechanisms of Halomonas alkalicola.

Halomonas alkalicola CICC 11012s is an alkaliphilic and halotolerant bacterium isolated from a soap-making tank (pH > 10) from a household-product plant. This strain can propagate at pH 12.5, which is fatal to most bacteria. Genomic analysis revealed that the genome size was 3,511,738 bp and contained 3295 protein-coding genes, including a complete cell wall and plasma membrane lipid biosynthesis pathway. Furthermore, four putative Na+/H+ and K+/H+ antiporter genes, or gene clusters, designated as HaNhaD, HaNhaP, HaMrp and HaPha, were identified within the genome. Heterologous expression of these genes in antiporter-deficient Escherichia coli indicated that HaNhaD, an Na+/H+ antiporter, played a dominant role in Na+ tolerance and pH homeostasis in acidic, neutral and alkaline environments. In addition, HaMrp exhibited Na+ tolerance; however, it functioned mainly in alkaline conditions. Both HaNhaP and HaPha were identified as K+/H+ antiporters that played an important role in high alkalinity and salinity. In summary, genome analysis and heterologous expression experiments demonstrated that a complete set of adaptive strategies have been developed by the double extremophilic strain CICC 11012s in response to alkalinity and salinity. Specifically, four antiporters exhibiting different physiological roles for different situations worked together to support the strain in harsh surroundings.

Novosphingobium clariflavum sp. nov., isolated from a household product plant.

A Gram-stain-negative, rod-shaped, bright-yellow-pigmented bacterium, designated 164T, was isolated from a used sponge for equipment cleaning at a household product plant in China. The 16S rRNA gene sequence comparisons indicated that strain 164T was most closely related to Novosphingobium panipatense DSM 22890T (98.28 % similarity) and shared sequence similarities of 97.73-98.27 % with other members of the genus Novosphingobium. In DNA-DNA hybridization studies the relatedness between strain 164T and its closest phylogenetic neighbours was <70 %, which indicated that strain 164T represented a novel species of the genus Novosphingobium. The DNA G+C content of strain 164T was 65.9 mol%. The major respiratory quinone was ubiquinone Q-10 (83.5 %) with minor amounts of Q-9 (16.5 %). The polar lipid profile included diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidyldimethylethanolamine, sphingoglycolipid, phosphatidylcholine, unidentified aminolipids and unidentified aminophospholipids. Spermidine was the major polyamine. The major fatty acids were summed feature 8 (consisting of C18 : 1ω7c and/or C18 : 1ω6c) and C14 : 0 2-OH. The results obtained from phylogenetic analysis, DNA-DNA hybridization, and chemotaxonomic and phenotypic analysis support the conclusion that strain 164T represents a novel species of the genus Novosphingobium, for which the name Novosphingobium clariflavum sp. nov. is proposed. The type strain is 164T (=CICC 11035sT=DSM 103351T).

Halomonas alkalicola sp. nov., isolated from a household product plant.

A Gram-stain-negative, alkaliphilic and moderately halophilic bacterium, designated 56-L4-10aEnT, was isolated from a household product plant in China. Cells of the novel isolate were rod-shaped, non-spore-forming and non-motile. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain 56-L4-10aEnT belongs to the genus Halomonas, with the six closest neighbours being Halomonas mongoliensis Z-7009T (97.59 % 16S rRNA gene sequence similarity), Halomonas ventosae Al12T (97.35 %), Halomonas campaniensis 5AGT (97.22 %), Halomonas alimentaria YKJ-16T (97.22 %), Halomonas shengliensis SL014B-85T (97.12 %) and Halomonas fontilapidosi 5CRT (97.09 %). The main polar lipids of strain 56-L4-10aEnT contained diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine. The predominant respiratory quinone was Q-9, with Q-8 as a minor component. The major fatty acids were C18 : 1ω7c/C18 : 1ω6c and C16 : 0. Strain 56-L4-10aEnT was clearly distinguished from the type strains mentioned above through phylogenetic analysis, DNA-DNA hybridization, fatty acid composition data and a range of physiological and biochemical characteristics comparisons. It is evident from the genotypic and phenotypic data that strain 56-L4-10aEnTcould be classified as a representative of a novel species of the genus Halomonas, for which the name Halomonas alkalicola sp. nov. is proposed. The type strain is 56-L4-10aEnT (=CICC 11012sT=DSM 103354T).

Rhizotomy targeting the intermediate nerve, the glossopharyngeal nerve and the upper 1st to 2nd rootlets of the vagus nerve for the treatment of laryngeal neuralgia combined with intermediate nerve neuralgia--a case report.

BACKGROUND: In neurosurgery, the most common type of facial and pharyngeal pain is trigeminal neuralgia. In contrast, glossopharyngeal neuralgia is relatively rare, and laryngeal neuralgia is the most rarely observed. CASE PRESENTATION: A case of laryngeal neuralgia combined with intermediate nerve neuralgia that was admitted to our hospital in May 2012 was reported here. The patient was a 58-year-old middle-aged female, who experienced 2 years of paroxysmal burning and stabbing pain near the thyroid perichodrium, in the skin covering the right front side of the neck, and deep in inner ear. CONCLUSION: The surgical treatment plan similar to that for glossopharyngeal neuralgia could be applied if laryngeal neuralgia is associated with glossopharyngeal neuralgia and intermediate neuralgia or if no obvious improvement is achieved with the above mentioned treatment approaches.

Organic Li4C8H2O6 nanosheets for lithium-ion batteries.

Organic tetralithium salts of 2,5-dihydroxyterephthalic acid (Li4C8H2O6) with the morphologies of bulk, nanoparticles, and nanosheets have been investigated as the active materials of either positive or negative electrode of rechargeable lithium-ion batteries. It is demonstrated that, in the electrolyte of LiPF6 dissolved in ethylene carbonate (EC) and dimethyl carbonate (DMC), reversible two-Li-ion electrochemical reactions are taking place with redox Li4C8H2O6/Li2C8H2O6 at ~2.6 V for a positive electrode and Li4C8H2O6/Li6C8H2O6 at ~0.8 V for a negative electrode, respectively. In the observed system, the electrochemical performance of high to low order is nanosheets > nanoparticles > bulk. Remarkably, Li4C8H2O6 nanosheets show the discharge capacities of 223 and 145 mAh g(-1) at 0.1 and 5 C rates, respectively. A capacity retention of 95% is sustained after 50 cycles at 0.1 C rate charge/discharge and room temperature. Moreover, charging the symmetrical cells with Li4C8H2O6 nanosheets as the initial active materials of both positive and negative electrodes produces all-organic LIBs with an average operation voltage of 1.8 V and an energy density of about 130 Wh kg(-1), enlightening the design and application of organic Li-reservoir compounds with nanostructures for all organic LIBs.

All organic sodium-ion batteries with Na4C8H2O6.

Developing organic compounds with multifunctional groups to be used as electrode materials for rechargeable sodium-ion batteries is very important. The organic tetrasodium salt of 2,5-dihydroxyterephthalic acid (Na4DHTPA; Na4C8H2O6), which was prepared through a green one-pot method, was investigated at potential windows of 1.6-2.8 V as the positive electrode or 0.1-1.8 V as the negative electrode (vs. Na(+)/Na), each delivering compatible and stable capacities of ca. 180 mAh g(-1) with excellent cycling. A combination of electrochemical, spectroscopic and computational studies revealed that reversible uptake/removal of two Na(+) ions is associated with the enolate groups at 1.6-2.8 V (Na2C8H2O6/Na4C8H2O6) and the carboxylate groups at 0.1-1.8 V (Na4C8H2O6/Na6C8H2O6). The use of Na4C8H2O6 as the initial active materials for both electrodes provided the first example of all-organic rocking-chair SIBs with an average operation voltage of 1.8 V and a practical energy density of about 65 Wh kg(-1).

Interactions and effects of a stannous-containing sodium fluoride dentifrice on oral pathogens and the oral microbiome.

Numerous studies have investigated the effects of stannous ions on specific microbes and their efficacy in reducing dental plaque. Nonetheless, our understanding of their impact on the oral microbiome is still a subject of ongoing exploration. Therefore, this study sought to evaluate the effects of a stannous-containing sodium fluoride dentifrice in comparison to a zinc-containing sodium fluoride dentifrice and a control group on intact, healthy oral biofilms. Utilizing the novel 2bRAD-M approach for species-resolved metagenomics, and FISH/CLSM with probes targeting periodontal and caries associated species alongside Sn2+ and Zn2+ ions, we collected and analyzed in situ biofilms from 15 generally healthy individuals with measurable dental plaque and treated the biofilms with dentifrices to elucidate variations in microbial distribution. Although significant shifts in the microbiome upon treatment were not observed, the use of a stannous-containing sodium fluoride dentifrice primarily led to an increase in health-associated commensal species and decrease in pathogenic species. Notably, FISH/CLSM analysis highlighted a marked reduction in representative species associated with periodontitis and caries following treatment with the use of a stannous-containing sodium fluoride dentifrice, as opposed to a zinc-containing sodium fluoride dentifrice and the control group. Additionally, Sn2+ specific intracellular imaging reflected the colocalization of Sn2+ ions with P. gingivalis but not with other species. In contrast, Zn2+ ions exhibited non-specific binding, thus suggesting that Sn2+ could exhibit selective binding toward pathogenic species. Altogether, our results demonstrate that stannous ions could help to maintain a healthy oral microbiome by preferentially targeting certain pathogenic bacteria to reverse dysbiosis and underscores the importance of the continual usage of such products as a preventive measure for oral diseases and the maintenance of health.

Carbon Nanotube-encapsulated Chestnut Inner Shell O,N-doped Graded Porous Carbon as Stable and High-Sulfur Loading Electrode for Lithium-Sulfur Batteries.

The shuttle effect of lithium-sulfur (Li-S) batteries and the poor conductivity of sulfur (S) and lithium polysulfide severely limit their practical applications. Currently, compounding carbon materials with S is one of the effective ways to solve this problem. Therefore, green, low-cost chestnut inner shell biochar (CISC) with graded porous structure was used as the S carrier in this experiment, and carbon nanotubes (CNTs) coating was employed as the S protective layer to improve the electrical conductivity and inhibit the shuttle effect. The results showed that the CISC prepared in this experiment had a relatively high specific surface area (1135.11 m2 g-1 ), and the S loading rate was as high as 65.72 %. The graded porous structure and high specific surface area of CISC can increase the loading rate of S and thus increase the battery capacity. Meanwhile, the naturally contained O and N elements can improve the chemisorption of S. The initial discharge capacity of the CISC@S/CNTs battery at 0.1 C is 967.3 mAh g-1 , and the capacity retention rate is 74.3 % after 500 cycles. The unique composite structure improves the battery's electrical conductivity, reduces the dissolution of polysulfides, and enhances the battery cycle stability.

Kinetics and mechanism effects of 2D carbon supports in hydrogen spillover composites.

Extensive research has been performed using two-dimensional (2D) carbon materials as catalyst supports to achieve high-performance hydrogen storage composites through the hydrogen spillover phenomenon. However, the kinetics and mechanism effects of different support materials still need to be investigated. This study employed high-energy ball milling to fabricate Co1-xS/C60 and C1-xS/rGO composites with stable structures and abundant hydrogen storage sites. We explored the mechanism of hydrogen adsorption behavior through electrode kinetic studies and density functional theory calculations, revealing the intrinsic relationship between material composition, structure, and hydrogen diffusion kinetics. The 2D flakes of C60 and rGO support and connect C1-xS nanoparticles, providing electron transport pathways for the composites. Theoretically, the spherical C60 support with less steric hindrance showed a more vital ability to increase the hydrogen adsorption capacity, while kinetically, thin film rGO offers fast channels for hydrogen diffusion. These findings contribute to our understanding of hydrogen spillover and present opportunities to investigate the synergistic effects in 2D carbon-based composites.

Critical Functions of Histone Deacetylases (HDACs) in Modulating Inflammation Associated with Cardiovascular Diseases.

Histone deacetylases (HDACs) are a superfamily of enzymes that catalyze the removal of acetyl functional groups from lysine residues of histone and non-histone proteins. There are 18 mammalian HDACs, which are classified into four classes based on the primary homology with yeast HDACs. Among these groups, Class I and II HDACs play a major role in lysine deacetylation of the N-terminal histone tails. In mammals, HDACs play a pivotal role in the regulation of gene transcription, cell growth, survival, and proliferation. HDACs regulate the expression of inflammatory genes, as evidenced by the potent anti-inflammatory activity of pan-HDAC inhibitors, which were implicated in several pathophysiologic states in the inflammation process. However, it is unclear how each of the 18 HDAC proteins specifically contributes to the inflammatory gene expression. It is firmly established that inflammation and its inability to converge are central mechanisms in the pathogenesis of several cardiovascular diseases (CVDs). Emerging evidence supports the hypothesis that several different pro-inflammatory cytokines regulated by HDACs are associated with various CVDs. Based on this hypothesis, the potential for the treatment of CVDs with HDAC inhibitors has recently begun to attract attention. In this review, we will briefly discuss (1) pathophysiology of inflammation in cardiovascular disease, (2) the function of HDACs in the regulation of atherosclerosis and cardiovascular diseases, and (3) the possible therapeutic implications of HDAC inhibitors in cardiovascular diseases. Recent studies reveal that histone deacetylase contributes critically to mediating the pathophysiology of inflammation in cardiovascular disease. HDACs are also recognized as one of the major mechanisms in the regulation of inflammation and cardiovascular function. HDACs show promise in developing potential therapeutic implications of HDAC inhibitors in cardiovascular and inflammatory diseases.

Irisin Preserves Cardiac Performance and Insulin Sensitivity in Response to Hemorrhage.

Irisin, a cleaved product of the fibronectin type III domain containing protein-5, is produced in the muscle tissue, which plays an important role in modulating insulin resistance. However, it remains unknown if irisin provides a protective effect against the detrimental outcomes of hemorrhage. Hemorrhages were simulated in male CD-1 mice to achieve a mean arterial blood pressure of 35-45 mmHg, followed by resuscitation. Irisin (50 ng/kg) and the vehicle (saline) were administrated at the start of resuscitation. Cardiac function was assessed by echocardiography, and hemodynamics were measured through femoral artery catheterization. A glucose tolerance test was used to evaluate insulin sensitivity. An enzyme-linked immunosorbent assay was performed to detect inflammatory factors in the muscles and blood serum. Western blot was carried out to assess the irisin production in skeletal muscles. Histological analyses were used to determine tissue damage and active-caspase 3 apoptotic signals. The hemorrhage suppressed cardiac performance, as indicated by a reduced ejection fraction and fractional shortening, which was accompanied by enhanced insulin resistance and hyperinsulinemia. Furthermore, the hemorrhage resulted in a marked decrease in irisin and an increase in the production of tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1). Additionally, the hemorrhage caused marked edema, inflammatory cell infiltration and active-caspase 3 positive signals in skeletal muscles and cardiac muscles. Irisin treatment led to a significant improvement in the cardiac function of animals exposed to a hemorrhage. In addition, irisin treatment improved insulin sensitivity, which is consistent with the suppressed inflammatory cytokine secretion elicited by hemorrhages. Furthermore, hemorrhage-induced tissue edema, inflammatory cell infiltration, and active-caspase 3 positive signaling were attenuated by irisin treatment. The results suggest that irisin protects against damage from a hemorrhage through the modulation of insulin sensitivity.

Cancer-associated fibroblasts secreted miR-103a-3p suppresses apoptosis and promotes cisplatin resistance in non-small cell lung cancer.

BACKGROUND: The cisplatin resistance of non-small cell lung cancer (NSCLC) patients results in low response rate and overall survival rate. Exosomes contribute to pathological processes of multiple cancers. OBJECTIVE: In this study, we explored the function and mechanisms of exosomal miR-103a-3p derived from cancer-associated fibroblast (CAF) in cisplatin resistance in NSCLC. RESULTS: MiR-103a-3p was highly expressed in CAFs and CAF exosomes, and exosomal miR-103a-3p derived from CAFs in NSCLC. CAFs exosomes co-cultured with NSCLC cells promoted miR-103a-3p expression both in NSCLC cells and its exosomes. Functional experiments showed that exo-miR-103a-3p derived from CAFs promoted cisplatin resistance and inhibited apoptosis in NSCLC cells. Pumilio2 (Pum2) bound with miR-103a-3p in cytoplasm and nucleus, and facilitated packaging into CAF-derived exosomes in NSCLC cells. Further analysis showed Bak1 was a direct target of miR-103a-3p, and miR-103a-3p accelerated cisplatin resistance in NSCLC cells via Bak1 downregulation. In vivo tumorigenesis assay showed CAF-derived exosomal miR-103a-3p enhanced cisplatin resistance and inhibited cell apoptosis in NSCLC. CONCLUSION: Our study revealed that CAFs-derived exosomal miR-103a-3p promoted cisplatin resistance by suppressing apoptosis via targeting Bak1, which provided a potential therapeutic target for cisplatin resistance in NSCLC.

Longitudinal Multi-omics and Microbiome Meta-analysis Identify an Asymptomatic Gingival State That Links Gingivitis, Periodontitis, and Aging.

Most adults experience episodes of gingivitis, which can progress to the irreversible, chronic state of periodontitis, yet roles of plaque in gingivitis onset and progression to periodontitis remain elusive. Here, we longitudinally profiled the plaque metagenome, the plaque metabolome, and salivary cytokines in 40 adults who transited from naturally occurring gingivitis (NG) to healthy gingivae (baseline) and then to experimental gingivitis (EG). During EG, rapid and consistent alterations in plaque microbiota, metabolites, and salivary cytokines emerged as early as 24 to 72 h after oral-hygiene pause, defining an asymptomatic suboptimal health (SoH) stage of the gingivae. SoH features a swift, full activation of 11 salivary cytokines but a steep synergetic decrease of plaque-derived betaine and Rothia spp., suggesting an anti-gum inflammation mechanism by health-promoting symbionts. Global, cross-cohort meta-analysis revealed, at SoH, a greatly elevated microbiome-based periodontitis index driven by its convergence of both taxonomical and functional profiles toward the periodontitis microbiome. Finally, post-SoH gingivitis development accelerates oral microbiota aging by over 1 year within 28 days, with Rothia spp. depletion and Porphyromonas gingivalis elevation as hallmarks. Thus, the microbiome-defined, transient gum SoH stage is a crucial link among gingivitis, periodontitis, and aging.IMPORTANCE A significant portion of world population still fails to brush teeth daily. As a result, the majority of the global adult population is afflicted with chronic gingivitis, and if it is left untreated, some of them will eventually suffer from periodontitis. Here, we identified periodontitis-like microbiome dysbiosis in an asymptomatic SoH stage as early as 24 to 72 h after oral-hygiene pause. SoH features a swift, full activation of multiple salivary cytokines but a steep synergetic decrease of plaque-derived betaine and Rothia spp. The microbial ecology during early gingivitis is highly similar to that in periodontitis under both taxonomical and functional contexts. Unexpectedly, exposures to gingivitis can accelerate over 10-fold the normal rate of oral microbiota aging. Our findings underscore the importance of intervening at the SoH stage of gingivitis via proper oral-hygiene practices on a daily basis, so as to maintain a periodontitis-preventive plaque and ensure the healthy aging of the oral ecosystem.

[Fluorescence spectra and imaging of Platymonas subcordiformis via LSCM].

Primary investigation of Platymonas subcordiformis was performed with laser scanning microscopic technology. Both autofluorescence spectra and autofluorescence imaging of Platymonas subcordiformis were achieved by one photon excitation of 488 nm Ar+ laser. Autofluorescence images revealed cup-shaped object inside the Platymonas subcordiformis cell, and the corresponding fluorescence peak located at 682 nm was attributed to chloroplast. Moreover, in single channel mode, there existed a round-shaped object in chloroplast center, showing strong fluorescence by 800 nm femtosecond laser excitation. Also, the authors obtained both the individual cup-shaped chloroplast and round-shaped object image and the overlaid images by using dual-channel mode. Meanwhile, six main fluorescence peaks were found. Single photon excitation can be used to obtain autofluorescence image and autofluorescence spectra of Platymonas subcordiformis, while two photon excitation combined with multitrack mode and Lambda mode can be used not only to observe internal structure, but also for the analysis of existence of biological and chemical substances with higher sensitivity than single photon excitation. LSCM technique can be a promising tool for rapid, convenient, real-time and effective investigation in ocean algae.