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Pulmonary diseases are main causes of morbidity and mortality worldwide. Current studies show that though specific pulmonary diseases and correlative lung-metabolic deviance own unique pathophysiology and clinical manifestations, they always tend to exhibit common characteristics including reactive oxygen species (ROS) signaling and disruptions of proteostasis bringing about accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER). ER is generated by the unfolded protein response. When the adaptive unfolded protein response (UPR) fails to preserve ER homeostasis, a maladaptive or terminal UPR is engaged, leading to the disruption of ER integrity and to apoptosis, which is called ER stress. The ER stress mainly includes the accumulation of misfolded and unfolded proteins in lumen and the disorder of Ca 2+ balance. ROS mediates several critical aspects of the ER stress response. We summarize the latest advances in of the UPR and ER stress in the pathogenesis of pulmonary disease and discuss potential therapeutic strategies aimed at restoring ER proteostasis in pulmonary disease.

Myocardial ischemia is a disease with high morbidity and mortality, for which reperfusion is currently the standard intervention. However, the reperfusion may lead to further myocardial damage, known as myocardial ischemia/reperfusion injury (MI/RI). Oxidative stress is one of the most important pathological mechanisms in reperfusion injury, which causes apoptosis, autophagy, inflammation, and some other damage in cardiomyocytes through multiple pathways, thus causing irreversible cardiomyocyte damage and cardiac dysfunction. This article reviews the pathological mechanisms of oxidative stress involved in reperfusion injury and the interventions for different pathways and targets, so as to form systematic treatments for oxidative stress-induced myocardial reperfusion injury and make up for the lack of monotherapy.

Background/Aims: Qiliqiangxin (QL), a traditional Chinese medicine, has been demonstrated to be effective and safe for the treatment of chronic heart failure. Left ventricular (LV) remodeling causes depressed cardiac performance and is an independent determinant of morbidity and mortality after myocardial infarction (MI). Our previous studies have shown that QL exhibits cardiac protective effects against heart failure after MI. The objective of this study was to explore the effects of QL on myocardial fibrosis in rats with MI and to investigate the underlying mechanism of these effects. Methods: A rat model of acute myocardial infarction was induced by ligating the left anterior descending coronary artery. The rats were treated with QL (1.0 g/kg/day) for 4 weeks after surgery. Echocardiography and histology examination were performed to evaluate heart function and fibrosis, respectively. Protein levels of transforming growth factor-β1 (TGF-β1), phosphorylated Smad3 (p-Smad3), phosphorylated Smad7 (p-Smad7), collagen I (Col- I), alpha smooth muscle actin (a-SMA), tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), nuclear factor κB (NF-κB), and phosphorylated inhibitor of kappa B alpha (p-IκBα) were measured by western blot analysis. Results: QL treatment ameliorated adverse cardiac remodeling 8 weeks after AMI, including better preservation of cardiac function, decreased inflammation, and reduced fibrosis. In addition, QL treatment reduced Col-I, a-SMA, TGF-β1, and p-Smad3 expression levels but increased p-Smad7 levels in postmyocardial infarct rat hearts. QL administration also reduced the elevated levels of cardiac inflammation mediators, such as TNF-α and IL-6, as well as NF-κB and p-IκBα expression. Conclusions: QL therapy exerted protective effects against cardiac remodeling potentially by inhibiting TGF-β1/Smad3 and NF-κB signaling pathways, thereby preserving cardiac function, as well as reducing myocardial inflammation and fibrosis.

Cardiovascular diseases (CVDs) is the leading cause of high morbidity and mortality worldwide, which emphasizes the urgent necessity to develop new pharmacotherapies. In eastern countries, traditional Chinese medicine Scutellaria baicalensis Georgi has been used clinically for thousands of years. Baicalin is one of the main active ingredients extracted from Chinese herbal medicine S. baicalensis . Emerging evidence has established that baicalin improves chronic inflammation, immune imbalance, disturbances in lipid metabolism, apoptosis and oxidative stress. Thereby it offers beneficial roles against the initiation and progression of CVDs such as atherosclerosis, hypertension, myocardial infarction and reperfusion, and heart failure. In this review, we summarize the pharmacological features and relevant mechanisms by which baicalin regulates CVDs in the hope to reveal its application for CVDs prevention and/or therapy.

Dear Editor, The rat is an important laboratory model and has many advantages over mouse models especially in toxicol- ogy and pharmacology studies. Several genome-editing technologies, such as zinc-finger nucleases （ZFNs） [1-2], transcription activator-like effector nucleases （TALENs） [3] and the Clustered Regularly Interspaced Short Palin- dromic Repeats （CRISPR）/CRISPR-associated 9 （Cas9） system [4-5],

The CRISPR/Cas9 system has been proven to be an efficient gene-editing tool for genome modification of cells and organisms. Multiplex genetic engineering in rat holds a bright future for the study of complex disease. Here, we show that this system enables the simultaneous disruption of four genes (ApoE, B2m, Prf1, and Prkdc) in rats in one-step, by co-injection of Cas9 mRNA and sgRNAs into fertilized eggs. We further observed the gene modifications are germline transmittable, and confirmed the off-target mutagenesis and mosaicism are rarely detected by comprehensive analysis. Thus, the CRISPR/Cas9 system makes it possible to efficiently and reliably generate gene knock-out rats.

Aims : Pathological left ventricular (LV) remodeling induced by multiple causes often triggers fatal cardiac dysfunction, heart failure (HF), and even cardiac death. This study is aimed to investigate whether qiliqiangxin (QL) could improve LV remodeling and protect against HF via modulating gut microbiota and inhibiting nod-like receptor pyrin domain 3 (NLRP3) inflammasome activation. Methods: Rats were respectively treated with QL (100 mg/kg/day) or valsartan (1.6 mg/kg/day) by oral gavage after transverse aortic constriction or sham surgery for 13 weeks. Cardiac functions and myocardial fibrosis were assessed. In addition, gut microbial composition was assessed by 16S rDNA sequencing. Furthermore, rats’ hearts were harvested for histopathological and molecular analyses including immunohistochemistry, immunofluorescence, terminal-deoxynucleotidyl transferase-mediated 2’-deoxyuridine 5’-triphosphated nick end labeling, and Western blot. Key findings: QL treatment preserved cardiac functions including LV ejection fractions and fractional shortening and markedly improved the LV remodeling. Moreover, HF was related to the gut microbial community reorganization like a reduction in Lactobacillus , while QL reversed it. Additionally, the protein expression levels like IL-1β, TNF-α, NF-κB, and NLRP3 were decreased in the QL treatment group compared to the model one. Conclusion: QL ameliorates ventricular remodeling to some extent in rats with HF by modulating the gut microbiota and NLRP3 inflammasome, which indicates the potential therapeutic effects of QL on those who suffer from HF.

Emodin alleviates renal interstitial fibrosis (RIF) and reduces inflammation by inhibiting the TGF-β1/Smad pathway, thus improving CKD outcomes. However, its clinical use is limited due to poor solubility and side effects. This study developed a targeted drug delivery system using αKIM-1 modified microbubbles carrying Emodin to enhance accumulation in renal tissues with high KIM-1 expression. Emo@KP MBs were characterized by TEM and DLS, and their drug loading and encapsulation rates were measured by UV-VIS-NIR spectroscopy. Biocompatibility was assessed in vitro with HK-2 cells and in vivo via hematological and pathological markers. Contrast-enhanced ultrasound (CEUS) and fluorescence imaging were used for real-time visualization of treatment. Therapeutic experiments were performed on a unilateral ureteral obstruction (UUO) mouse model treated with Emo@KP MBs + US on days 1 and 3 post-surgery. Renal function, cytokine levels, and histological analysis were detected to evaluate therapeutic effects. Emo@KP MBs exhibited spherical structures (2 ~ 4 μm) with good stability. Ultrasound targeted microbubble destruction (UTMD) enabled controlled release of Emodin. CEUS and fluorescence imaging showed enhanced drug accumulation in diseased kidneys. In the UUO + Emo@KP MBs/US group, renal function was improved, inflammatory cytokines (IL-1β, TNF-α) were decreased, and renal lesions and collagen deposition were reduced. Immunohistochemistry revealed the downregulation of TGF-β, Smad2/3, and α-SMA, and upregulation of E-cadherin. Emo@KP MBs enhanced drug delivery efficiency and therapeutic efficacy through αKIM-1 targeting and UTMD, while providing real-time imaging capabilities, suggesting good potential as a therapeutic approach to reduce renal inflammation and fibrosis in UUO.

This paper analyzes a class of common-component allocation rules, termed no-holdback (NHB) rules, in continuous-review assemble-to-order (ATO) systems with positive lead times. The inventory of each component is replenished following an independent base-stock policy. In contrast to the usually assumed first-come-first-served (FCFS) component allocation rule in the literature, an NHB rule allocates a component to a product demand only if it will yield immediate fulfillment of that demand. We identify metrics as well as cost and product structures under which NHB rules outperform all other component allocation rules. For systems with certain product structures, we obtain key performance expressions and compare them to those under FCFS. For general product structures, we present performance bounds and approximations. Finally, we discuss the applicability of these results to more general ATO systems.

We study a single server queue under a processor-sharing type of scheduling policy, where the weights for determining the sharing are given by functions of each job's remaining service (processing) amount, and obtain a fluid limit for the scaled measure-valued system descriptors.