Undesirable ER stress induced by bavachin contributed to follicular atresia in zebrafish ovary.

Fructus psoraleae (FP) is a commonly used herb with potential reproductive toxicity. Bavachin (BV), one of essential active ingredients of FP, was found to exhibit estrogenic activity, but its effect on female reproductive system remains unknown. In this study, the impact of BV on the female zebrafish reproductive system and underlying molecular mechanism were determined in vivo and ex vivo. The results showed that BV could accumulate in zebrafish ovary, leading to obvious follicular atresia and increase in gonadal index and vitellogenin content. Endoplasmic reticulum (ER) swelling and hypertrophy were observed in the BV-treated zebrafish ovary, accompanied by an increase in the expressions of ER stress and unfolded protein response (UPR) related genes, namely atf6, ire-1α and xbp1s. In the ex vivo study, BV was found to decrease the survival rate and maturation rate of oocytes, while increasing the expression of Ca2+. Additionally, BV led to an elevation in the level of estrogen receptor ESR1 and the expressions of genes involved in ER stress and UPR, including atf6, ire-1α, xbp1s, chop and perk. Moreover, molecular docking revealed that BV could directly bind to immunoglobulin heavy chain binding protein (BiP) and estrogen receptor 1 (ESR1). Besides, the alterations induced by BV could be partially reversed by fulvestrant (FULV) and 4-phenylbutyric acid (4-PBA), respectively. Thus, long-termed BV-containing medicine treatment could generate reproductive toxicity in female zebrafish by causing follicular atresia through BiP- and ESR-mediated ER stress and UPR, providing a potential target for the prevention of reproductive toxicity caused by BV.

Ferritinophagy activation and sideroflexin1-dependent mitochondrial iron overload contribute to patulin-induced cardiac inflammation and fibrosis.

Patulin (PAT) is a mycotoxin that is commonly present throughout the ecosystem where fungi grow and mainly contaminates food, soil, and water. PAT was found to be cardiotoxic in previous studies. However, the detailed mechanism has not been fully elucidated. The present study aimed to explore the role and underlying mechanism of ferroptosis in PAT-induced cardiac injury. Here, we confirmed in vivo and in vitro that ferroptosis is involved in PAT-induced myocardial inflammation and fibrosis. Mice exposed to PAT (1 and 2 mg/kg body weight/day for 14 days) exhibited myocardial inflammation and fibrosis along with disrupted iron homeostasis, elevated lipid peroxidation, depletion of glutathione peroxidase 4, and abnormal mitochondrial morphology. When primary neonatal rat cardiomyocytes (NRCMs) and H9c2 cells were exposed to PAT, ferroptosis was initiated in a dose-dependent manner, and this process could be significantly attenuated by ferrostatin-1. Mechanistically, we found that nuclear receptor coactivator (NCOA) 4, a master regulator of ferritinophagy, bound to and degraded ferritin in response to PAT treatment, thereby releasing large amounts of ferrous iron and further leading to sideroflexin (SFXN) 1-dependent mitochondrial iron overload. Conversely, knockdown of NCOA4 or SFXN1 with small interfering RNAs could effectively ameliorate ferroptotic cell death, cellular or mitochondrial iron overload and lipid peroxides accumulation. Furthermore, myocardial inflammation and fibrosis in PAT-exposed mice was alleviated by the mitochondrial iron chelator deferiprone. Overall, our findings underscore that ferritinophagy activation and SFXN1-dependent mitochondrial iron overload play critical roles in PAT-induced myocardial ferroptosis and consequent cardiotoxicity.

Ginsenoside Rb1 Ameliorated Bavachin-Induced Renal Fibrosis via Suppressing Bip/eIF2α/CHOP Signaling-Mediated EMT.

The nephrotoxicity of Fructus Psoraleae, an effective traditional Chinese medicine for vitiligo treatment, has been reported. As one of the main toxic components in Fructus Psoraleae, bavachin (BV) was considered to be related to Fructus Psoraleae-caused adverse outcomes, but the direct evidence and molecular mechanism underlying BV-induced nephrotoxicity are not well elucidated. Therefore, this study was designed to confirm whether BV would cause toxic effects on the kidney and explore the possible mode of action. Our results demonstrated that days' treatment with 0.5 µM BV indeed caused obvious renal fibrosis in the zebrafish kidney. The obvious E- to N-cadherin switch and the expressions of proteins promoting epithelial-mesenchymal transition (EMT) were observed in BV-treated human renal tubular epithelial and zebrafish kidneys. In addition, elevated reactive oxygen species (ROS) levels and Bip/eIF2α/CHOP-mediated endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) were caused by BV, both of which could be reversed by ROS scavenger N-acetyl-L-cysteine (NAC). Also, blocking ER stress-caused cytoplasmic Ca2+ overload with 4-PBA notably alleviated BV-induced alterations in key molecular events related to EMT and renal fibrosis. Furthermore, of the natural compounds subjected to screening, ginsenoside Rb1 significantly downregulated BV-induced ER stress by inhibiting ROS generation and following the activation of Bip/eIF2α/CHOP signaling in HK2 cells. Subsequently, BV-triggered EMT and renal fibrosis were both ameliorated by ginsenoside Rb1. In summary, our findings suggested that BV-induced ROS promoted the appearance of EMT and renal fibrosis mainly via Bip/eIF2α/CHOP-mediated ER stress. This ER stress-related toxic pathway might be a potential intervention target for BV-caused renal fibrosis, and ginsenoside Rb1 would be a promising drug against BV- or Fructus Psoraleae-induced nephrotoxicity.

Serum Cystatin C Levels Are Associated With Obesity in Adolescents Aged 14-17 Years.

Background: The association between serum cystatin C levels and obesity has not been fully explored in adolescents. This study aimed to explore the association between serum cystatin C levels and obesity in adolescents of different sexes. Methods: We conducted a cross-sectional study including 481 adolescents aged 14-17 years. Cystatin C level was measured by immunoassay. Health examinations data, biochemical parameters, and questionnaire information were collected. The restricted cubic spline model analyzed the association between cystatin C levels and obesity in boys and girls. Results: Boys exhibited significantly higher cystatin C levels than girls, with a mean level of 0.97 ± 0.10 mg/L in boys and 0.86 ± 0.09 mg/L in girls (P < 0.001). The restricted cubic spline model suggested that low or high cystatin C levels were associated with an increased risk of obesity in boys, whereas only higher cystatin C levels were associated with an increased risk of obesity in girls. Conclusions: A U-shaped correlation was observed between serum cystatin C levels and the risk of obesity in boys. However, in girls, the risk of obesity showed a trend of initially increase and then decrease with increasing cystatin C levels. Longitudinal studies should be conducted to further investigate the diagnostic potential of cystatin C in the progression of early obesity in adolescents of different sexes.

Clinical efficacy of laparoscopic surgery used for the excision of villus tissue and the repair of uterine scar in patients with cesarean scar pregnancy-II.

The present study described the clinical presentation of patients with cesarean scar pregnancy type II (CSP)-II diagnosed by ultrasound or magnetic resonance imaging, who underwent laparoscopic surgery resection or hysteroscopic treatment. The aim of the present study was to evaluate the outcomes of different treatments for CSP. The patients with CSP-II were assigned to the laparoscopy and hysteroscopy groups according to the type of surgery performed. The general indicators and post-operative outcomes were compared between the two groups. Statistically significant differences (P<0.05) were noted in the treatment efficacy indices between the two groups. The laparoscopic group exhibited a lower value of ß-human chorionic gonadotropin (ß-HCG) following surgery (P=0.017), a shorter time required for ß-HCG to return to normal levels (P=0.001), a reduced post-operative thickness of the uterine scar (P<0.001) and a reduced menstruation recovery time (P<0.001). However, no significant differences were noted in blood loss during operation (P>0.05). On the whole, the data indicated that the laparoscopic resection of the scar with gestational tissue and wound repair may be used to preserve the uterus and may thus be an effective method for CSP-II. The appropriate treatment needs to be selected according to the condition of each patient. Based on the latter and on the available technology, priority may perhaps be given to laparoscopic surgery.

Esophageal wall thickness on CT scans: can it predict the T stage of primary thoracic esophageal squamous cell carcinoma?

BACKGROUND: CT is the most commonly used method to stage esophageal cancer (EC). However, the reported CT T-staging criteria for EC are controversial. PURPOSE: To determine and validate the optimal esophageal wall thickness (EWT) threshold on CT to distinguish lesions with different T stages in esophageal squamous cell carcinoma (ESCC) patients. METHODS: One thousand, one hundred-two consecutive patients with histopathologically confirmed ESCC between July 2014 and April 2020 were retrospectively reviewed. All patients underwent a preoperative CT examination and surgical treatment. The maximal EWT of the lesions on CT was measured. Patients were divided into pT1, pT2, pT3 and pT4 subgroups according to the pathologic stage. We employed the support vector machine, where linear kernels were leveraged to determine the optimal threshold to classify samples with different T stages. 90% of samples from each subgroup were randomly selected as the training set, while the remainder comprised the testing set. RESULTS: The mean EWTs of the pT1, pT2, pT3 and pT4 subgroups were 4.9 ± 2.6 mm, 8.1 ± 2.3 mm, 12.4 ± 3.6 mm, and 18.6 ± 4.4 mm, respectively. Differences in the EWT between the four subgroups or between adjacent subgroups were significant (p < 0.001), and esophageal wall became thicker with increasing pT stage. We utilized MATLAB 2020a to implement the SVM model and ran the code 10 times. The accuracy of the model was 60.29 ± 2.33%. The thresholds between samples from pT1/pT2, pT2/pT3 and pT3/pT4 lesions were 5.5 ± 0.3 mm, 10.8 ± 0.8 mm and 15.9 ± 0.5 mm, respectively. CONCLUSIONS: Possibility of predicting T stage of ESCC by EWT on CT scans was limited to 60% by model examination with large sample size.

Low-dose radiation-induced demethylation of 3ß-HSD participated in the regulation of testosterone content.

The effects of low-dose radiation (LDR, ≤0.1 Gy) on living organisms have been the hot areas of radiation biology but do not reach a definitive conclusion yet. So far, few studies have adequately accounted for the male reproductive system responses to LDR, particularly the regulation of testosterone content. Hence, this study was designed to evaluate the effects of LDR on Leydig cells and testicular tissue, especially the ability to synthesize testosterone. We found that less than 0.2-Gy 60 Co gamma rays did not cause significant changes in the hemogram index and the body weight; also, pathological examination did not find obvious structural alterations in testis, epididymis, and other radiation-sensitive organs. Consistently, the results from in vitro showed that only more than 0.5-Gy gamma rays could induce remarkable DNA damage, cycle arrest, and apoptosis. Notably, LDR disturbed the contents of testosterone in mice serums and culture supernatants of TM3 cells and dose dependently increased the expression of 3ß-HSD. After cotreatment with trilostane (Tril), the inhibitor of 3ß-HSD, increased testosterone could be partially reversed. Besides, DNA damage repair-related enzymes, including DNMT1, DNMT3B, and Sirt1, were increased in irradiated TM3 cells, accompanying by evident demethylation in the gene body of 3ß-HSD. In conclusion, our results strongly suggest that LDR could induce obvious perturbation in the synthesis of testosterone without causing organic damage, during which DNA demethylation modification of 3ß-HSD might play a crucial role and would be a potential target to prevent LDR-induced male reproductive damage.

[Research progress on chemical constituents and pharmacological activities of seabuckthorn and prediction of its Q-markers].

Seabuckthorn contains flavonoids, tannins, terpenoids, polysaccharides, and vitamins, which have anti-inflammation,anti-oxidation, liver protection, anti-cardiovascular disease, anti-aging, immune enhancing, anti-tumor, and anti-bacterial activities.We reviewed the papers focusing on the chemical constituents, pharmacological activities, and utilization of seabuckthorn. The quality markers(Q-markers) of seabuckthorn were predicted and analyzed based on original plant phylogeny, chemical composition correlation, traditional medicinal properties, pharmacodynamic correlation, traditional and extended efficacy, pharmacokinetics, metabolic processes, and measurable components. With this review, we aim to provide theoretical reference for the quality control and quality standard establishment of seabuckthorn, so as to promote the rational exploitation and utilization of seabuckthorn resources, and improve the healthy and sustainable development of seabuckthorn industry.

Dual activities of ACC synthase: Novel clues regarding the molecular evolution of ACS genes.

Ethylene plays profound roles in plant development. The rate-limiting enzyme of ethylene biosynthesis is 1-aminocyclopropane-1-carboxylate (ACC) synthase (ACS), which is generally believed to be a single-activity enzyme evolving from aspartate aminotransferases. Here, we demonstrate that, in addition to catalyzing the conversion of S-adenosyl-methionine to the ethylene precursor ACC, genuine ACSs widely have Cß-S lyase activity. Two N-terminal motifs, including a glutamine residue, are essential for conferring ACS activity to ACS-like proteins. Motif and activity analyses of ACS-like proteins from plants at different evolutionary stages suggest that the ACC-dependent pathway is uniquely developed in seed plants. A putative catalytic mechanism for the dual activities of ACSs is proposed on the basis of the crystal structure and biochemical data. These findings not only expand our current understanding of ACS functions but also provide novel insights into the evolutionary origin of ACS genes.

Emodin-Induced Oxidative Inhibition of Mitochondrial Function Assists BiP/IRE1α/CHOP Signaling-Mediated ER-Related Apoptosis.

Cassiae Semen is a widely used herbal medicine and a popular edible variety in many dietary or health beverage. Emerging evidence disclosed that improper administration of Cassiae Semen could induce obvious liver injury, which is possibly attributed to emodin, one of the bioactive anthraquinone compounds in Cassiae Semen, which caused hepatotoxicity, but the underlying mechanisms are not completely understood. Hence, the present study firstly explored the possible role of oxidative stress-mediated mitochondrial dysfunction and ER stress in emodin-cause apoptosis of L02 cells, aiming to elaborate possible toxic mechanisms involved in emodin-induced hepatotoxicity. Our results showed that emodin-induced ROS activated ER stress and the UPR via the BiP/IRE1α/CHOP signaling pathway, followed by ER Ca2+ release and cytoplasmic Ca2+ overloading. At the same time, emodin-caused redox imbalance increased mtROS while decreased MMP and mitochondrial function, resulting in the leaks of mitochondrial-related proapoptotic factors. Interestingly, blocking Ca2+ release from ER by 2-APB could inhibit emodin-induced apoptosis of L02, but the restored mitochondrial function did not reduce the apoptosis rates of emodin-treated cells. Besides, tunicamycin (TM) and doxorubicin (DOX) were used to activate ER stress and mitochondrial injury at a dosage where obvious apoptosis was not observed, respectively. We found that cotreatment with TM and DOX significantly induced apoptosis of L02 cells. Thus, all the results indicated that emodin-induced excessive ROS generation and redox imbalance promoted apoptosis, which was mainly associated with BiP/IRE1α/CHOP signaling-mediated ER stress and would be enhanced by oxidative stress-mediated mitochondrial dysfunction. Altogether, this finding has implicated that redox imbalance-mediated ER stress could be an alternative target for the treatment of Cassiae Semen or other medicine-food homologous varieties containing emodin-induced liver injury.

Nickel-promoted oxidative domino Csp3-H/N-H bond double-isocyanide insertion reaction to construct pyrrolin-2-ones.

The first nickel-catalyzed oxidative domino Csp3-H/N-H double isocyanide insertion reaction of acetamides with isocyanides has been developed for the synthesis of pyrrolin-2-one derivatives. A wide range of acetamides bearing various functional groups are compatible with this reaction system by utilizing Ni(acac)2 as a catalyst. In this transformation, isocyanide could serve as a C1 connector and insert into the inactive Csp3-H bond, representing an effective way to construct heterocycles.

Tongxinluo Ameliorates Myocardial Ischemia-Reperfusion Injury Mainly via Activating Parkin-Mediated Mitophagy and Downregulating Ubiquitin-Proteasome System.

OBJECTIVE: To investigate the protective effects and mechanism of Chinese herbal compound Tongxinluo Capsule (, TXL) on the Parkin-mediated mitophagy and the ubiquitin-proteasome system in a rat model of myocardial ischemia-reperfusion injury (MIRI). METHODS: Seventy adult male Sprague-Dawley rats were randomly divided into 7 groups: sham group, MIRI group, low- and high-dose TXL (0.5 and 1 g·kg-1·d-1, respectively) groups, atorvastatin (ATV) group (7.2 g·kg-1·d-1), chloroquine (CQ) group (10 g·kg-1·d-1), and highdose TXL + CQ group. After pharmacological administration for 7 days, rats underwent left anterior descending artery ligation surgery to establish the MIRI models with 50 min ischemia followed by 4 h reperfusion. Blood was taken for cardiac troponin I (cTnI) detection and hearts were harvested for infarct staining and apoptosis detection. The autophagy or mitophagy proteins and ubiquitinated proteins were detected by Western blotting. RESULTS: Compared with the sham group, the MIRI group exhibited a larger infarcted area (27.13%±0.01%, P<0.01), a higher apoptotic index (34.33%±2.03% vs.1.81%±0.03%, P<0.01), and higher cTnI expression (14.18±1.01 vs. 7.96±0.32, P<0.01). The mitochondrial integrity was damaged in the MIRI group, while TXL and ATV alleviated the damage of MIRI. More autophagosomes were observed in the high-dose TXL group than in the MIRI group (7.00±0.58 vs. 4.33±1.15, P<0.05). More amounts of PTEN-induced putative kinase protein 1 (PINK1) and Parkin translocated onto the mitochondria were detected in the high-dose TXL group than in the MIRI group (P<0.05). The ubiquitin response was signifificantly downregulated in the high-dose TXL group relative to the MIRI group (P<0.05). CQ administration abolished the activation of autophagy flux and the PINK1/ Parkin pathway induced by high-dose of TXL. CONCLUSIONS: TXL ameliorates MIRI via activating Parkin-mediated mitophagy in rats. The downregulation of the ubiquitin-proteasome system is also involved.

Penfluridol triggers mitochondrial-mediated apoptosis and suppresses glycolysis in colorectal cancer cells through down-regulating hexokinase-2.

Penfluridol, a commonly used antipsychotic agent in a clinical setting, exhibits potential anticancer properties against various human malignancies. Here, we investigated the effect of penfluridol on the biological behavior of colorectal cancer (CRC) cells. Cell viability and clonogenic potential were detected by the cell counting kit-8 and colony formation assay. The cell apoptosis and cell cycle distribution were quantified through flow cytometry. Caspase-3 activity, glucose consumption, lactate production, and intracellular ATP levels were evaluated using the corresponding commercial detection kits. The protein levels of related genes were detected through western blotting. Mitochondrial membrane potential was detected using JC-1 staining. A CRC xenograft tumor model was used to validate the antitumor activity of penfluridol in vivo. Penfluridol reduced cell survival and promoted apoptotic cell death effectively through the mitochondria-mediated intrinsic pathway in a dose-dependent manner. Furthermore, the process of glycolysis in HCT-116 and HT-29 cells was inhibited upon penfluridol treatment, as evidenced by the decrease in glucose consumption, lactate production, and intracellular ATP levels. Further mechanistic studies revealed that penfluridol influenced cell apoptosis and glycolysis in CRC cells by downregulating hexokinase-2 (HK-2). The proapoptotic effect and glycolytic inhibition-induced by penfluridol were effectively reversed by HK-2 overexpression. Consistent with in vitro results, penfluridol could also suppress tumor growth and trigger apoptosis in vivo. Penfluridol triggers mitochondrial-mediated apoptosis and induces glycolysis inhibition via modulating HK-2 in CRC and provides a theoretical basis to support penfluridol as a repurposed drug for CRC patients.

Sharing and Helping: Regularity and Characteristics of Pathogenesis of a Widely Used Transgene Initiated Murine Acute Promyelocytic Leukemia Model.

A transgenic acute promyelocytic leukemia (APL) murine model established by Michael Bishop by cloning a human PML-RARα cDNA into the hMRP8 expression cassette has been widely used in the all-trans retinoid acid and arsenic preparations for the research of APL. However, in the existing literature, the data of regularity and characteristics of the pathogenesis of this model were still missing, which hinder the development of many studies, especially application of new technologies such as single-cell sequencing. Therefore, in this article, we have made up this part of the missing data using an improved APL murine model. We clarified the effects of different inoculation doses on the onset time, latency, morbidity, life span, and proportion of APL cells in peripheral blood (PB), spleen, bone marrow, and so on. The relationship between the proportion of APL cells in the bone marrow, spleen, and PB and organ histological changes was also revealed. These results were a supplement and refinement of this APL model. It would add to the knowledge base of the field and aid in ensuring that accurate models are used for directed interventions. It also provides a great convenience for the researchers who will carry out similar research.

Mitochondrial Iron Overload-Mediated Inhibition of Nrf2-HO-1/GPX4 Assisted ALI-Induced Nephrotoxicity.

Aristolactam I (ALI) is an active component derived from some Traditional Chinese medicines (TCMs), and also the important metabolite of aristolochic acid. Long-term administration of medicine-containing ALI was reported to be related to aristolochic acid nephropathy (AAN), which was attributed to ALI-induced nephrotoxicity. However, the toxic mechanism of action involved is still unclear. Recently, pathogenic ferroptosis mediated lipid peroxidation was demonstrated to cause kidney injury. Therefore, this study explored the role of ferroptosis induced by mitochondrial iron overload in ALI-induced nephrotoxicity, aiming to identify the possible toxic mechanism of ALI-induced chronic nephropathy. Our results showed that ALI inhibited HK-2 cell activity in a dose-dependent manner and significantly suppressed glutathione (GSH) levels, accompanying by significant increases in intracellular 4-hydroxynonenal (4-HNE) and intracellular iron ions. Moreover, the ALI-mediated cytotoxicity could be reversed by deferoxamine mesylate (DFO). Compared with other inhibitors, Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, obviously alleviated ALI-induced cytotoxicity. Furthermore, we have shown that ALI could remarkably increase the levels of superoxide anion and ferrous ions in mitochondria, and induce mitochondrial damage and condensed mitochondrial membrane density, the morphological characteristics of ferroptosis, all of which could be reversed by DFO. Interestingly, ALI dose-dependently inhibited these protein contents of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and glutathione peroxidase 4 (GPX4), which could be partly rescued by Tin-protoporphyrin IX (SnPP) and mitoTEMPO co-treatment. In conclusion, our results demonstrated that mitochondrial iron overload-mediated antioxidant system inhibition would assist ALI-induced ferroptosis in renal tubular epithelial cells, and Nrf2-HO-1/GPX4 antioxidative system could be an important intervention target to prevent medicine containing ALI-induced nephropathy.

Robust, Lightweight, Hydrophobic, and Fire-Retarded Polyimide/MXene Aerogels for Effective Oil/Water Separation.

Polyimide (PI) aerogels have attracted great attention owing to their low density and excellent thermal stability. However, hydrophobic surface modification is required for PI aerogels to improve their ability in oil/water separation due to their amphiphilic characteristic. Two-dimensional MXenes (transition metal carbides/nitrides) can be utilized as nanofillers to enhance the properties of polymers because of their unique layered structure and versatile interface chemistry. Herein, the robust, lightweight, and hydrophobic PI/MXene three-dimensional architectures were fabricated via freeze-drying of polyamide acid/MXene suspensions and thermal imidization. Polyamide acid was synthesized using N-N-dimethylacetamide and 4,4'-oxydianiline. MXene (Ti3C2Tx) dispersion was obtained via the etching of Ti3AlC2 and ultrasonic exfoliation. Taking advantage of the strong interaction between PI chains and MXene nanosheets, the interconnected, highly porous, and hydrophobic PI/MXene aerogels with low density were fabricated, resulting in the improved compressive performance, remarkable oil absorption capacity, and efficient separation of oil and water. For the PI/MXene-3 aerogel (weight ratio, 5.2:1) without any surface modification, the water contact angle was 119° with a density of 23 mg/cm3. This aerogel can completely recover to its original height after 50 compression-release cycles, exhibiting superelasticity and exceptional fatigue-resistant ability. It also showed high absorption capacities to various organic liquids ranging from approximately 18 to 58 times of their own weight. This hybrid aerogel can rapidly separate the chloroform, soybean oil, and liquid paraffin from the water-oil system. The thermally stable hybrid aerogel also exhibited excellent fire safety properties and outstanding reusability under an extreme environment.

[Study of macrophage polarization on pulmonary fibrosis and signaling pathway].

Macrophages are a group of immune cells with pluripotency and plasticity that can differentiate into different phenotypes under different microenvironments in vitro and in vivo. In the development of pulmonary fibrosis, there are alveolar macrophages and interstitial macrophages, which are polarized to different cell phenotypes at different stages of development. And their polarized phenotypes include M1 macrophages and M2 macrophages. In the inflammation early stages of pulmonary fibrosis, the increase of classical activated macrophages are helpful to clear pathogenic microorganisms and promote the progress of inflammation. In the fibrosis stage, the alternatively activated macrophages increased, which inhibiting the inflammatory reaction or directly promoting tissue fibrosis, on the other hand, it also promoting the fibrosis degradation. To clarify the polarization and polarization mechanisms of macrophages in pulmonary fibrosis will be conducive to the treatment of pulmonary fibrosis. In IPF, the polarization mechanism of M1 and M2 is closely related to TGF-ß1/Smad. TGF-ß1/Smad pathway plays an important regulatory role in liver fibrosis, renal fibrosis, myocardial fibrosis, scars, tumors and other diseases. Blocking the signaling of TGF-ß1 by Smad3 and Smad4 is beneficial to inhibit the polarization of AM, which in turn helps to inhibit the progression of IPF.

HAMdb: a database of human autophagy modulators with specific pathway and disease information.

Autophagy is an important homeostatic cellular recycling mechanism responsible for degrading unnecessary or dysfunctional cellular organelles and proteins in all living cells. In addition to its vital homeostatic role, this degradation pathway also involves in various human disorders, including metabolic conditions, neurodegenerative diseases, cancers and infectious diseases. Therefore, the comprehensive understanding of autophagy process, autophagy-related modulators and corresponding pathway and disease information will be of great help for identifying the new autophagy modulators, potential drug candidates, new diagnostic and therapeutic targets. In recent years, some autophagy databases providing structural and functional information were developed, but the specific databases covering autophagy modulator (proteins, chemicals and microRNAs)-related target, pathway and disease information do not exist. Hence, we developed an online resource, Human Autophagy Modulator Database (HAMdb, http://hamdb.scbdd.com ), to provide researchers related pathway and disease information as many as possible. HAMdb contains 796 proteins, 841 chemicals and 132 microRNAs. Their specific effects on autophagy, physicochemical information, biological information and disease information were manually collected and compiled. Additionally, lots of external links were available for more information covering extensive biomedical knowledge. HAMdb provides a user-friendly interface to query, search, browse autophagy modulators and their comprehensive related information. HAMdb will help researchers understand the whole autophagy process and provide detailed information about related diseases. Furthermore, it can give hints for the identification of new diagnostic and therapeutic targets and the discovery of new autophagy modulators. In a word, we hope that HAMdb has the potential to promote the autophagy research in pharmacological and pathophysiological area.

N-Terminus-Mediated Degradation of ACS7 Is Negatively Regulated by Senescence Signaling to Allow Optimal Ethylene Production during Leaf Development in Arabidopsis.

Senescence is the final phase of leaf development, characterized by key processes by which resources trapped in deteriorating leaves are degraded and recycled to sustain the growth of newly formed organs. As the gaseous hormone ethylene exerts a profound effect on the progression of leaf senescence, both the optimal timing and amount of its biosynthesis are essential for controlled leaf development. The rate-limiting enzyme that controls ethylene synthesis in higher plants is ACC synthase (ACS). In this study, we evaluated the production of ethylene and revealed an up-regulation of ACS7 during leaf senescence in Arabidopsis. We further showed that the promoter activity of ACS7 was maintained at a relatively high level throughout the whole rosette development process. However, the accumulation level of ACS7 protein was extremely low in the light-grown young seedlings, and it was gradually restored as plants aging. We previously demonstrated that degradation of ACS7 is regulated by its first 14 N-terminal residues, here we compared the phenotypes of transgenic Arabidopsis overexpressing a truncated ACS7 lacking the 14 residues with transgenic plants overexpressing the full-length protein. Results showed that seedlings overexpressing the truncated ACS7 exhibited a senescence phenotype much earlier than their counterparts overexpressing the full-length gene. Fusion of the 14 residues to SSPP, a PP2C-type senescence-suppressed protein phosphatase, effectively rescued the SSPP-induced suppression of rosette growth and development but had no effect on the delayed senescence. This observation further supported that N-terminus-mediated degradation of ACS7 is negatively regulated by leaf senescence signaling. All results of this study therefore suggest that ACS7 is one of the major contributors to the synthesis of 'senescence ethylene'. And more importantly, the N-terminal 14 residue-mediated degradation of this protein is highly regulated by senescence signaling to enable plants to produce the appropriate levels of ethylene required.