Upregulation of PGC-1α expression by pioglitazone mediates prevention of sepsis-induced acute lung injury.

The imbalance between pro-inflammatory M1 and anti-inflammatory M2 macrophages plays a critical role in the pathogenesis of sepsis-induced acute lung injury (ALI). Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) may modulate macrophage polarization toward the M2 phenotype by altering mitochondrial activity. This study aimed to investigate the role of the PGC-1α agonist pioglitazone (PGZ) in modulating sepsis-induced ALI. A mouse model of sepsis-induced ALI was established using cecal ligation and puncture (CLP). An in vitro model was created by stimulating MH-S cells with lipopolysaccharide (LPS). qRT-PCR was used to measure mRNA levels of M1 markers iNOS and MHC-II and M2 markers Arg1 and CD206 to evaluate macrophage polarization. Western blotting detected expression of peroxisome proliferator-activated receptor gamma (PPARγ) PGC-1α, and mitochondrial biogenesis proteins NRF1, NRF2, and mtTFA. To assess mitochondrial content and function, reactive oxygen species levels were detected by dihydroethidium staining, and mitochondrial DNA copy number was measured by qRT-PCR. In the CLP-induced ALI mouse model, lung tissues exhibited reduced PGC-1α expression. PGZ treatment rescued PGC-1α expression and alleviated lung injury, as evidenced by decreased lung wet-to-dry weight ratio, pro-inflammatory cytokine secretion (tumor necrosis factor-α, interleukin-1ß, interleukin-6), and enhanced M2 macrophage polarization. Mechanistic investigations revealed that PGZ activated the PPARγ/PGC-1α/mitochondrial protection pathway to prevent sepsis-induced ALI by inhibiting M1 macrophage polarization. These results may provide new insights and evidence for developing PGZ as a potential ALI therapy.

Upregulation of PGC-1α expression by pioglitazone mediates prevention of sepsis-induced acute lung injury

Abstract The imbalance between pro-inflammatory M1 and anti-inflammatory M2 macrophages plays a critical role in the pathogenesis of sepsis-induced acute lung injury (ALI). Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) may modulate macrophage polarization toward the M2 phenotype by altering mitochondrial activity. This study aimed to investigate the role of the PGC-1α agonist pioglitazone (PGZ) in modulating sepsis-induced ALI. A mouse model of sepsis-induced ALI was established using cecal ligation and puncture (CLP). An in vitro model was created by stimulating MH-S cells with lipopolysaccharide (LPS). qRT-PCR was used to measure mRNA levels of M1 markers iNOS and MHC-II and M2 markers Arg1 and CD206 to evaluate macrophage polarization. Western blotting detected expression of peroxisome proliferator-activated receptor gamma (PPARγ) PGC-1α, and mitochondrial biogenesis proteins NRF1, NRF2, and mtTFA. To assess mitochondrial content and function, reactive oxygen species levels were detected by dihydroethidium staining, and mitochondrial DNA copy number was measured by qRT-PCR. In the CLP-induced ALI mouse model, lung tissues exhibited reduced PGC-1α expression. PGZ treatment rescued PGC-1α expression and alleviated lung injury, as evidenced by decreased lung wet-to-dry weight ratio, pro-inflammatory cytokine secretion (tumor necrosis factor-α, interleukin-1β, interleukin-6), and enhanced M2 macrophage polarization. Mechanistic investigations revealed that PGZ activated the PPARγ/PGC-1α/mitochondrial protection pathway to prevent sepsis-induced ALI by inhibiting M1 macrophage polarization. These results may provide new insights and evidence for developing PGZ as a potential ALI therapy.

Exploring the mechanism of action of Xuanfei Baidu granule (XFBD) in the treatment of COVID-19 based on molecular docking and molecular dynamics.

Purpose: The Corona Virus Disease 2019 (COVID-19) pandemic has become a challenge of world. The latest research has proved that Xuanfei Baidu granule (XFBD) significantly improved patient's clinical symptoms, the compound drug improves immunity by increasing the number of white blood cells and lymphocytes, and exerts anti-inflammatory effects. However, the analysis of the effective monomer components of XFBD and its mechanism of action in the treatment of COVID-19 is currently lacking. Therefore, this study used computer simulation to study the effective monomer components of XFBD and its therapeutic mechanism. Methods: We screened out the key active ingredients in XFBD through TCMSP database. Besides GeneCards database was used to search disease gene targets and screen intersection gene targets. The intersection gene targets were analyzed by GO and KEGG. The disease-core gene target-drug network was analyzed and molecular docking was used for verification. Molecular dynamics simulation verification was carried out to combine the active ingredient and the target with a stable combination. The supercomputer platform was used to measure and analyze the number of hydrogen bonds, the binding free energy, the stability of protein target at the residue level, the solvent accessible surface area, and the radius of gyration. Results: XFBD had 1308 gene targets, COVID-19 had 4600 gene targets, the intersection gene targets were 548. GO and KEGG analysis showed that XFBD played a vital role by the signaling pathways of immune response and inflammation. Molecular docking showed that I-SPD, Pachypodol and Vestitol in XFBD played a role in treating COVID-19 by acting on NLRP3, CSF2, and relieve the clinical symptoms of SARS-CoV-2 infection. Molecular dynamics was used to prove the binding stability of active ingredients and protein targets, CSF2/I-SPD combination has the strongest binding energy. Conclusion: For the first time, it was found that the important active chemical components in XFBD, such as I-SPD, Pachypodol and Vestitol, reduce inflammatory response and apoptosis by inhibiting the activation of NLRP3, and reduce the production of inflammatory factors and chemotaxis of inflammatory cells by inhibiting the activation of CSF2. Therefore, XFBD can effectively alleviate the clinical symptoms of COVID-19 through NLRP3 and CSF2.

Antiviral Therapy for Chronic HBV Infection With Persistently Normal Alanine Aminotransferase: Controversy and Consensus.

ALT is one of the most sensitive biochemical indexes to reflect liver injury. It is generally believed that hepatitis B virus (HBV) infected patients with normal ALT levels are in either immune tolerance or low replication stage of the natural history of hepatitis B, and there is no or only mild inflammation in liver tissue, so antiviral therapy is not recommended. However, chronic HBV-infected patients with normal ALT levels are not always in a stable state. A considerable number of patients will develop active hepatitis or occult progress to liver fibrosis, cirrhosis, and hepatocellular carcinoma. Therefore, whether antiviral therapy should be recommended for chronic HBV infection with normal ALT level has been a hot topic in clinical practice. In this paper, the definition of immune tolerance, the relationship between ALT and liver inflammation, and the benefits of antiviral therapy were reviewed, and we hope it will be helpful for clinicians to have a deeper understanding of whether antiviral therapy should be considered for chronic HBV infection with normal ALT.

Efficacy and safety of sofosbuvir-based pangenotypic direct-acting antiviral agents for chronic hepatitis C patients without genotype determination: Real-world experience of a retrospective study.

Several new, pangenotypic direct-acting antiviral agents (DAAs) have been approved, may reduce the need for genotyping to guide therapy decisions for patients with chronic hepatitis C (CHC).This study aimed to investigate the efficacy and safety of Sofosbuvir (SOF)-based pangenotypic DAAs therapy for CHC patients without genotype (GT determination in the real-world practice.This retrospective cohort study included treatment-naïve CHC patients without GT determination, who received SOF-based DAAs therapy, including 400 mg SOF plus 60 mg daclatasvir (DCV) daily or 400 mg SOF plus 100 mg velpatasvir (VEL) daily for 12 or 24 weeks. Clinical and laboratory data, including sustained virologic response (SVR), were obtained at baseline, end of treatment (EOT), 12 weeks after EOT, and 48 weeks after EOT.A total of 95 CHC patients, including 30 (31.58%) had liver cirrhosis were enrolled. SVR rates after 12 weeks of treatment (SVR12) was 96.84% (92/95), including 96.20% (76/79) of patients receiving SOF plus DCV and 100% (16/16) of patients receiving SOF plus VEL. For 92 patients achieving an SVR12, no virological relapse was observed at 48 weeks after EOT. Furthermore, serum evaluation of liver fibrosis aspartate aminotransferase-to-platelet ratio index and Fibrosis-4 score were decreased significantly at EOT and 12 weeks after EOT, compared to pre-treatment values (both P < .05). Treatment was well-tolerated by our patients.SOF-based pangenotypic DAAs including SOF plus DCV and SOF plus VEL, were effective and safe for CHC patients without GT determination in this study. This may provide a potential simple strategy for CHC treatment without GT determination.

An epidemiology survey of vitamin D deficiency and its influencing factors.

BACKGROUND: There is growing evidence that vitamin D is related to the development of a variety of diseases. The current study was performed to investigate the status of serum vitamin D distribution among adult Chinese people and reveal the influence of gender, age, seasonality and residential regions on serum vitamin D levels. METHOD: This cross-sectional study included 14,302 participants aged from 18 years old to 65 years old from six major cities in China. The basic demographic information and the levels of serum vitamin D (25(OH)D) and vitamin D3 (25(OH)D3) were collected from Jan 2, 2014 to Dec 25, 2017. RESULT: The prevalence of 25(OH)D3 concentration <30ng/mL reached up to 83%, in which the rate of vitamin D insufficiency (20-29ng/mL) was 32.7%, and vitamin D deficiency (10-19ng/mL) accounted for 41.9%, and vitamin D severe shortage (<10ng/mL) accounted for 8.4%. Women were more likely to have vitamin D3 deficiency and lower serum vitamin D3 concentration than men (both p<0.001). The mean concentration of serum 25(OH)D and 25(OH)D3 in summer and autumn were higher than that in spring and winter (p<0.001), and the mean concentration of serum 25(OH)D in people from Southern China was higher than that in people from other regions (p<0.001). Although the mean concentrations of serum 25(OH)D and 25(OH)D3 were both increased by age, the percentage of patients with serum 25(OH)D3 insufficiency was also increased. CONCLUSION: Serum vitamin D deficiency is very common in adults in China. The level of serum vitamin D may be associated with age, sex, seasonality and residential regions.

Chlorhexidine-based body washing for colonization and infection of methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus: an updated meta-analysis.

BACKGROUND: The effects of chlorhexidine-based body washing (CHW) on health care-associated infections have been reported in numerous studies, while their findings remain conflicting. This study aims to update the evidence for the effects of CHW on the risk of colonization or infection with hospital-acquired methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). METHODS: Two independent authors searched PubMed, Embase, and Cochrane Library from inception through February 2018. We selected all observational studies or clinical trials for the effect of CHW on the risk of colonization and infection with hospital-acquired MRSA or VRE. Random-effects models were applied to calculate summary incidence rate ratios (IRRs) for the related associations. RESULTS: Of 140 records identified, we obtained data from 17 relevant articles for meta-analysis. Compared with patients without antiseptic bathing, patients with CHW had a significantly lower risk of MRSA colonization (IRR 0.61, 95% CI 0.48-0.77) and VRE colonization (IRR 0.58, 95% CI 0.42-0.80). Similarly, we also noted that patients with CHW had a significantly lower risk of MRSA infection (IRR 0.65, 95% CI 0.52-0.81). However, no significantly lower risk of VRE infection (IRR 0.61, 95% CI 0.30-1.25) was noted in patients with CHW. Sensitivity analyses or trim-and-fill method confirmed the robustness of the findings. CONCLUSION: Current evidence supports that patients with CHW had a significantly lower risk of MRSA or VRE colonization and a lower risk of MRSA infection. More evidence should be accumulated to reinforce these findings, especially on the effect of CHW on the risk of VRE infection.

Complete mitochondrial genome of the Siamese fighting fish (Betta splendens).

The Siamese fighting fish (Betta splendens) is one of the popular aquarium fish. Serious attentions have been paid to the biodiversity of the fish. The mitochondrial genome of the Siamese fighting fish is reported to be 17 099 bp and includes 37 genes. The gene organization is similar to other fish mitogenomes. The control region is AT-rich and includes three tandem repeats. Phylogenetic analysis reveals that the fish is close to fish in the Macropodus genus. This mitogenome will assist in studying the mitochondrial variations and population structure in this fish and examine the evolutionary relationship among fish in the Osphronemidae family.

Complete mitochondrial genome of the penguin tetra, Thayeria boehlkei.

The penguin tetra (Thayeria boehlkei) is one of the most popular aquarium fish and belongs to the family of Characidae. The composition, phylogeny, and classification of this family are uncertain. Here, the complete mitogenome of T. boehlkei was reported to be 16,524 bp in length. It contains 13 protein-coding genes, 22 transfer RNA genes and 2 ribosomal RNA genes. Comparing the mitochondrial genome of T. boehlkei with its congener Astyanax mexicanus revealed high-sequence similarity. The mitochondrial genome of T. boehlkei will contribute to conservation studies and evolution analysis of Characidae family.

Gene Expression Variations of Red-White Skin Coloration in Common Carp (Cyprinus carpio).

Teleosts have more types of chromatophores than other vertebrates and the genetic basis for pigmentation is highly conserved among vertebrates. Therefore, teleosts are important models to study the mechanism of pigmentation. Although functional genes and genetic variations of pigmentation have been studied, the mechanisms of different skin coloration remains poorly understood. The koi strain of common carp has various colors and patterns, making it a good model for studying the genetic basis of pigmentation. We performed RNA-sequencing for red skin and white skin and identified 62 differentially expressed genes (DEGs). Most of them were validated with RT-qPCR. The up-regulated DEGs in red skin were enriched in Kupffer's vesicle development while the up-regulated DEGs in white skin were involved in cytoskeletal protein binding, sarcomere organization and glycogen phosphorylase activity. The distinct enriched activity might be associated with different structures and functions in erythrophores and iridophores. The DNA methylation levels of two selected DEGs inversely correlated with gene expression, indicating the participation of DNA methylation in the coloration. This expression characterization of red-white skin along with the accompanying transcriptome-wide expression data will be a useful resource for further studies of pigment cell biology.

Oscillator death induced by amplitude-dependent coupling in repulsively coupled oscillators.

The effects of amplitude-dependent coupling on oscillator death (OD) are investigated for two repulsively coupled Lorenz oscillators. Based on numerical simulations, it is shown that as constraint strengths on the amplitude-dependent coupling change, an oscillatory state may undergo a transition to an OD state. The parameter regimes of the OD domain are theoretically determined, which coincide well with the numerical results. An electronic circuit is set up to exhibit the transition process to the OD state with an amplitude-dependent coupling. These findings may have practical importance on chaos control and oscillation depression.

The fate of recent duplicated genes following a fourth-round whole genome duplication in a tetraploid fish, common carp (Cyprinus carpio).

Whole genome duplication (WGD) results in extensive genetic redundancy. In plants and yeast, WGD is followed by rapid gene deletions and intense expression differentiation with slow functional divergence. However, the early evolution of the gene differentiation processes is poorly understood in vertebrates because almost all studied WGDs are extremely ancient, and the genomes have returned to a diploid status. Common carp had a very recent fourth round of WGD dated to 8 million years ago. It therefore constitutes an ideal model to study early-stage functional divergence and expression differentiation in vertebrates. We identified 1,757 pairs of recently duplicated genes (RDGs) originating from this specific WGD and found that most ancestral genes were retained in duplicate. Most RDGs were conserved and under selective pressure. Gene expression analysis across six tissues revealed that 92.5% of RDG pairs were co-expressed in at least one tissue and that the expression of nearly half pairs ceased to be strongly correlated, indicating slow spatial divergence but rapid expression dissociation. Functional comparison revealed that 25% of pairs had functional divergence, of which neo- and sub-functionalization were the main outcomes. Our analysis revealed slow gene loss but rapid and intense expression and function differentiation after WGD.

Complete mitochondrial genome of the kissing gourami, Helostoma temminkii.

The kissing gourami (Helostoma temminkii) belongs to the Labyrinth fishes (Perciformes: Anabantoidei), which exhibits a wide variety of behavioral traits. In this study the complete mitogenome of H. temminkii was determined to be 16,740 bp in length. It contains 13 protein-coding genes, 22 transfer RNA genes and 2 ribosomal RNA genes. The sequence structure of non-coding control region was also analyzed. Comparing the mitochondrial genome of H. temminkii with its closely related species Colisa lalia showed the similarity of 78%. The complete mitochondrial genome of H. temminkii provides resource for phylogenetic analysis on Anabantoidei.