Research Progress in the Molecular Mechanisms, Therapeutic Targets, and Drug Development of Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease. Recent studies have identified the key role of crosstalk between dysregulated epithelial cells, mesenchymal, immune, and endothelial cells in IPF. In addition, genetic mutations and environmental factors (e.g., smoking) have also been associated with the development of IPF. With the recent development of sequencing technology, epigenetics, as an intermediate link between gene expression and environmental impacts, has also been reported to be implicated in pulmonary fibrosis. Although the etiology of IPF is unknown, many novel therapeutic targets and agents have emerged from clinical trials for IPF treatment in the past years, and the successful launch of pirfenidone and nintedanib has demonstrated the promising future of anti-IPF therapy. Therefore, we aimed to gain an in-depth understanding of the underlying molecular mechanisms and pathogenic factors of IPF, which would be helpful for the diagnosis of IPF, the development of anti-fibrotic drugs, and improving the prognosis of patients with IPF. In this study, we summarized the pathogenic mechanism, therapeutic targets and clinical trials from the perspective of multiple cell types, gene mutations, epigenetic and environmental factors

An overview of hyperbaric oxygen preconditioning against ischemic stroke

Ischemic stroke (IS) has become the second leading cause of morbidity and mortality worldwide, and the prevention of IS should be given high priority. Recent studies have indicated that hyperbaric oxygen preconditioning (HBO-PC) may be a protective nonpharmacological method, but its underlying mechanisms remain poorly defined. This study comprehensively reviewed the pathophysiology of IS and revealed the underlying mechanism of HBO-PC in protection against IS. The preventive effects of HBO-PC against IS may include inducing antioxidant, anti-inflammation, and anti-apoptosis capacity; activating autophagy and immune responses; upregulating heat shock proteins, hypoxia-inducible factor-1, and erythropoietin; and exerting protective effects upon the blood-brain barrier. In addition, HBO-PC may be considered a safe and effective method to prevent IS in combination with stem cell therapy. Although the benefits of HBO-PC on IS have been widely observed in recent research, the implementation of this technique is still controversial due to regimen differences. Transferring the results to clinical application needs to be taken carefully, and screening for the optimal regimen would be a daunting task. In addition, whether we should prescribe an individualized preconditioning regimen to each stroke patient needs further exploration

Stigmatizing attitudes toward mental illness among caregivers of patients with mental disorders in China

ObjectiveThis study aimed to investigate stigmatizing attitudes toward depression, schizophrenia, and general anxiety disorder (GAD) among caregivers of patients with mental disorders in China.MethodsA cross-sectional study was conducted among 607 caregivers in China, using vignettes that described three mental illnesses. Data on the caregivers’ attitudes and other people’s attitudes toward individuals with mental disorders and their willingness to come in contact with people with mental disorders were collected.ResultsIn the three vignettes, caregivers agreed that positive outcomes outnumbered negative outcomes. The top two statements endorsing the stigma were “the person could snap out of the problem” and “people with this problem are dangerous.” In the section for perceived stigma, caregivers in the GAD vignette agreed that most people believed this problem is not a real medical illness, compared to schizophrenia. The rates of the statement endorsing unpredictability were significantly different in the schizophrenia (57.2%) and depression (45.5%) vignette, in comparison to the GAD (45.6%) vignette. For personal stigma, the caregivers tended to avoid people described in the depression vignette more often than in the GAD vignette. The caregivers were most unwilling to let the person described in the vignettes marry into their family, especially in the schizophrenia vignette.ConclusionDespite the stigma and desire for social distance associated with schizophrenia, depression, and GAD, caregivers often expect positive outcomes. Actions should be taken to improve caregivers’ knowledge about mental health and reduce the stigma

Hydroxychloroquine Potentiates Apoptosis Induced by PPARα Antagonist in 786-O Clear Cell Renal Cell Carcinoma Cells Associated with Inhibiting Autophagy

Clear cell renal cell carcinoma (ccRCC) is the major pathological pattern of renal cell carcinoma. The ccRCC cells exhibit a certain degree of inherent drug resistance due to some genetic mutations. In recent years, peroxisome proliferator-activated receptor-α (PPARα) antagonists have been reported as a targeted therapeutic drug capable of inducing apoptosis and cell cycle arrest in the ccRCC cell line. Autophagy, which can be induced by stress in eukaryotic cells, plays a complex role in the proliferation, survival, and death of tumor cells. In our study, we found that the expression of PPARα was low in highly differentiated ccRCC tissues and 786-O cell line but high in poorly differentiated ccRCC tissues. The level of PPARα expression in ccRCC tissues is correlated to the grade of differentiation, but not to the sex or age of ccRCC patients. The findings also revealed that the PPARα antagonist GW6471 can lower cell viability and induce autophagy in the 786-O ccRCC cell line. This autophagy can be inhibited by hydroxychloroquine. When treated with a combination of hydroxychloroquine and GW6471, the viability of the 786-O cells was decreased further when compared to the treatment with GW6471 or hydroxychloroquine alone, and apoptosis was promoted. Meanwhile, when human kidney 2 cells were cotreated with hydroxychloroquine and GW6471, cell viability was only slightly influenced. Hence, our finding indicates that the combination of GW6471 and hydroxychloroquine may constitute a novel and potentially effective treatment for ccRCC. Furthermore, this approach is likely to be safe owing to its minimal effects on normal renal tissues

Development of a new damping ratio prediction model for recycled aggregate concrete: Incorporating modified admixtures and carbonation effects

Recycled aggregate concrete (RAC) has been widely used in practical engineering construction. However, the ability of buildings to resist wind-induced vibration and earthquake effects plays an important role in building safety. It is urgent to ensure that recycled concrete still has good anti-vibration ability within the allowable strength range. By conducting damping tests on recycled concrete specimens, the results show that the damping performance of RAC is better improved compared with natural aggregate concrete. Moreover, the influence of internal factors of recycled aggregates and external environmental conditions on damping performance can be determined, and corresponding damping ratio prediction models can be constructed. However, the current prediction models still have limitations in theory and practice. The existing damping ratio prediction models have a large span of independent variables and do not consider the gradual carbonation effect in the actual environment over time. To overcome these limitations, a new damping ratio prediction model is proposed. Based on the replacement rate of recycled aggregates (RAs) and the amplitude of excitation force, the influence of modified admixtures and carbonation on damping performance is considered, and the corresponding model prediction formula is constructed. In addition, the influence mechanism is further demonstrated and explained from the macroscopic aspect of specimen profile and the microscopic aspect of electron microscopy tests. It is found that, considering both strength and cost factors, recycled concrete still has good damping performance when the replacement rate of recycled aggregates (RAs) is 40%

Characterization of the complete chloroplast genome of Taxus wallichiana as the medicinal plant from China

Taxus wallichiana is a member of the family Taxaceae, which is a unique and endangered species in China and is widely used for ornamental, material and medicinal purposes. The complete chloroplast genome of T. wallichiana was found to possess a total size of 128,168 bp. The GC content of T. wallichiana chloroplast genome sequence is 37.3%, the overall nucleotide composition of chloroplast genome sequence is: A of 30.7%, T of 32.0%, C of 19.0% and G of 18.3%. The total of 116 genes were successfully annotated, which contained 83 protein-coding genes, 29 transfer RNA genes, and 4 ribosomal RNA genes. The ML phylogenetic analysis result showed that T. wallichiana was closely related to Taxus baccata in the phylogenetic relationship using the neighbour-joining (NJ) method in this study

Construction of cellulose-degrading microbial consortium and evaluation of their ability to degrade spent mushroom substrate

IntroductionSpent mushroom substrate (SMS) is a solid waste in agricultural production that contains abundant lignocellulosic fibers. The indiscriminate disposal of SMS will lead to significant resource waste and pollution of the surrounding environment.The isolation and screening of microorganisms with high cellulase degradation capacity is the key to improving SMS utilization.MethodsThe cellulose-degrading microbial consortiums were constructed through antagonism and enzyme activity test. The effect of microbial consortiums on lignocellulose degradation was systematically evaluated by SMS liquid fermentation experiments.ResultsIn this study, four strains of cellulose-degrading bacteria were screened, and F16, F, and F7 were identified as B. amyloliquefaciens, PX1 identified as B. velezensis. At the same time, two groups of cellulose efficient degrading microbial consortiums (PX1 + F7 and F16 + F) were successfully constructed. When SMS was used as the sole carbon source, their carboxymethyl cellulase (CMCase) activities were 225.16 and 156.63 U/mL, respectively, and the filter paper enzyme (FPase) activities were 1.91 and 1.64 U/mL, respectively. PX1 + F7 had the highest degradation rate of hemicellulose and lignin, reaching 52.96% and 52.13%, respectively, and the degradation rate of F16 + F was as high as 56.30%. Field emission scanning electron microscopy (FESEM) analysis showed that the surface microstructure of SMS changed significantly after microbial consortiums treatment, and the change of absorption peak in Fourier transform infrared spectroscopy (FTIR) and the increase of crystallinity in X-ray diffraction (XRD) confirmed that the microbial consortiums had an actual degradation effect on SMS. The results showed that PX1 + F7 and F16 + F could effectively secrete cellulase and degrade cellulose, which had practical significance for the degradation of SMS.DiscussionIn this study, the constructed PX1 + F7 and F16 + F strains can effectively secrete cellulase and degrade cellulose, which holds practical significance in the degradation of SMS. The results can provide technical support for treating high-cellulose solid waste and for the comprehensive utilization of biomass resources

pH-Sensitive Fluorescent Dyes: Are They Really pH-Sensitive in Cells?

National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health; NIBIB; National Institute of Standards and TechnologyChemically synthesized near-infrared aza-BODIPY dyes displayed off-on fluorescence at acidic pH (pK(a) = 6.2-6.6) through the suppression of the photoinduced electron transfer and/or internal charge transfer process. The apparent pK(a)s of the dyes were shifted well above physiological pH in a hydrophobic microenvironment, which led to "turned-on" fluorescence in micelles and liposomes at neutral and basic pH. Bovine serum albumin also activated the fluorescence, though to a much lesser extent. When these small molecular dyes entered cells, instead of being fluorescent only in acidic organelles, the whole cytoplasm exhibited fluorescence, with a signal/background ratio as high as similar to 10 in no-wash live-cell imaging. The dye 1-labeled cells remained highly fluorescent even after 3 days. Moreover, slight variations of the dye structure resulted in significantly different intracellular fluorescence behaviors, possibly because of their different cellular uptake and intracellular activation capabilities. After the separation of cellular components, the fraction of plasma membrane and endoplasmic reticulum showed the highest fluorescence, further confirming the fluorescence activation by membrane structures. The fluorescence intensity of these dyes at different intracellular pHs (6.80 and 8.00) did not differ significantly, indicating that intracellular pH did not play a critical role. Altogether, we showed here for the first time that the fluorescence of pH-sensitive aza-BODIPY dyes was switched intracellularly not by acidic pH, but by intracellular membranes (and proteins as well). The excellent membrane permeability, ultrahigh fluorescence contrast ratio, persistent fluorescent signal, and minimal biological interference of dye 1 make it an ideal choice for live-cell imaging and in vivo cell tracking. These findings also imply that the intracellular fluorescence properties of pH-sensitive dyes should be carefully examined before they are used as pH indicators

pH-Sensitive Fluorescent Dyes: Are They Really pH-Sensitive in Cells?

Chemically synthesized near-infrared aza-BODIPY dyes displayed off–on fluorescence at acidic pH (p<i>K</i>_a = 6.2–6.6) through the suppression of the photoinduced electron transfer and/or internal charge transfer process. The apparent p<i>K</i>_as of the dyes were shifted well above physiological pH in a hydrophobic microenvironment, which led to “turned-on” fluorescence in micelles and liposomes at neutral and basic pH. Bovine serum albumin also activated the fluorescence, though to a much lesser extent. When these small molecular dyes entered cells, instead of being fluorescent only in acidic organelles, the whole cytoplasm exhibited fluorescence, with a signal/background ratio as high as ∼10 in no-wash live-cell imaging. The dye <b>1</b>-labeled cells remained highly fluorescent even after 3 days. Moreover, slight variations of the dye structure resulted in significantly different intracellular fluorescence behaviors, possibly because of their different cellular uptake and intracellular activation capabilities. After the separation of cellular components, the fraction of plasma membrane and endoplasmic reticulum showed the highest fluorescence, further confirming the fluorescence activation by membrane structures. The fluorescence intensity of these dyes at different intracellular pHs (6.80 and 8.00) did not differ significantly, indicating that intracellular pH did not play a critical role. Altogether, we showed here for the first time that the fluorescence of pH-sensitive aza-BODIPY dyes was switched intracellularly not by acidic pH, but by intracellular membranes (and proteins as well). The excellent membrane permeability, ultrahigh fluorescence contrast ratio, persistent fluorescent signal, and minimal biological interference of dye <b>1</b> make it an ideal choice for live-cell imaging and in vivo cell tracking. These findings also imply that the intracellular fluorescence properties of pH-sensitive dyes should be carefully examined before they are used as pH indicators