Malignant atrophic papulosis treated with eculizumab and hirudin: a fatal case report and literature review.

Background: Malignant atrophic papulosis (MAP) is a rare obliterative vasculopathy whose etiology and pathophysiological mechanisms remain unknown, and the treatment is still empirical. It can involve multiple systems, especially the gastrointestinal tract and central nervous system, and has a poor prognosis. Case presentation: A 20-year-old Chinese male appeared to have Widespread atrophic papules and plaques, intermittent abdominal pain, recurrent bowel perforation, and psoas abscess. The clinical diagnosis of MAP was supported by skin biopsy. He was then treated with anticoagulants, antiplatelets, glucocorticoids, and immunosuppressants and started on eculizumab and hirudin after the first surgical interventions. Despite the aggressive immunosuppression, anticoagulant, antiplatelet, humanized monoclonal antibodies, and surgery therapy, he died five months after presentation. Conclusions: MAP is an extremely rare obliterative vasculopathy manifesting as benign cutaneous involvement or potentially malignant systemic involvement. MAP patients who exhibit any abdominal symptoms should undergo laparoscopy and evaluation in time and start on eculizumab and treprostinil as soon as possible, as the combination of them is presently the most effective treatment option for gastrointestinal MAP and hopefully reduce mortality.

When Natural Compounds Meet Nanotechnology: Nature-Inspired Nanomedicines for Cancer Immunotherapy.

Recent significant strides of natural compounds in immunomodulation have highlighted their great potential against cancer. Despite many attempts being made for cancer immunotherapy, the biomedical application of natural compounds encounters a bottleneck because of their unclear mechanisms, low solubility and bioavailability, and limited efficacy. Herein, we summarize the immune regulatory mechanisms of different natural compounds at each step of the cancer-immunity cycle and highlight their anti-tumor potential and current limitations. We then propose and present various drug delivery strategies based on nanotechnology, including traditional nanoparticles (NPs)-based delivery strategies (lipid-based NPs, micelles, and polysaccharide/peptide/protein-based NPs) and novel delivery strategies (cell-derived NPs and carrier-free NPs), thus providing solutions to break through existing bottlenecks. Furthermore, representative applications of nature-inspired nanomedicines are also emphasized in detail with the advantages and disadvantages discussed. Finally, the challenges and prospects of natural compounds for cancer immunotherapy are provided, hopefully, to facilitate their far-reaching development toward clinical translation.

Multiple inflammatory polyps resulted from Meckel's diverticulitis presenting with chronic abdominal pain: A case report.

INTRODUCTION AND IMPORTANCE: In most diverticulitis of Meckel's Diverticulum (MD), perforation, obstruction and hemorrhage causing acute abdomen are seen, however, multiple inflammatory polyps(IPs) are rare, which are seen in our case. CASE PRESENTATION: We present the case of 28-year-old female, who was admitted in the clinic for intermittent abdominal pain for 5 years. Histopathology suggested MD chronic diverticulitis and multiple inflammatory polyps. CLINICAL DISCUSSION: Our patient presented was diagnosed preoperatively with suspected MD, and an laparoscopy was indicated. Intraoperatively, a huge MD with multiple IPs was found and treated by surgical excision and the specimens were sent for histopathological analysis. Histopathology revealed MD's diverticulitis with IPs containing ectopic gastric mucosa. The patient had successful recovery. CONCLUSION: Meckel's diverticulitis is a rare cause of multiple IPs. This case can remind physicians that IPs caused by Meckel's diverticulum should be considered in differential diagnosis of adults presenting with the isolated symptom of chronic abdominal pain.

Bone morphogenetic protein 6-mediated crosstalk between endothelial cells and hepatocytes recapitulates the iron-sensing pathway in vitro.

Liver sinusoidal endothelial cell-derived bone morphogenetic protein 6 (BMP6) and the BMP6-small mothers against decapentaplegic homolog (SMAD) signaling pathway are essential for the expression of hepcidin, the secretion of which is considered the systemic master switch of iron homeostasis. However, there are continued controversies related to the strong and direct suppressive effect of iron on hepatocellular hepcidin in vitro in contrast to in vivo conditions. Here, we directly studied the crosstalk between endothelial cells (ECs) and hepatocytes using in vitro coculture models that mimic hepcidin signaling in vivo. Huh7 cells were directly cocultured with ECs, and EC conditioned media (CM) were also used to culture Huh7 cells and primary mouse hepatocytes. To explore the reactions of ECs to surrounding iron, they were grown in the presence of ferric ammonium citrate and heme, two iron-containing molecules. We found that both direct coculture with ECs and EC-CM significantly increased hepcidin expression in Huh7 cells. The upstream SMAD pathway, including phosphorylated SMAD1/5/8, SMAD1, and inhibitor of DNA binding 1, was induced by EC-CM, promoting hepcidin expression. Efficient blockage of this EC-mediated hepcidin upregulation by an inhibitor of the BMP6 receptor ALK receptor tyrosine kinase 2/3 or BMP6 siRNA identified BMP6 as a major hepcidin regulator in this coculture system, which highly fits the model of hepcidin regulation by iron in vivo. In addition, EC-derived BMP6 and hepcidin were highly sensitive to levels of not only ferric iron but also heme as low as 500 nM. We here establish a hepatocyte-endothelial coculture system to fully recapitulate iron regulation by hepcidin using EC-derived BMP6.

Direct modulation of hepatocyte hepcidin signaling by iron.

BACKGROUND: Liver-secreted hepcidin is the systemic master switch of iron homeostasis and decreased levels of hepcidin are considered to cause iron overload not only in hereditary hemochromatosis but also in hemolytic anemia and chronic liver diseases. The regulation of hepcidin is complex and its response to iron is still not completely understood. AIM: To study the direct effect of iron on various established hepcidin signaling pathways in hepatoma cells or primary hepatocytes. METHODS: Hepcidin mRNA expression was studied by quantitative real-time (qRT)-PCR in the presence of various forms of iron including ferric ammonium citrate (FAC) in hepatoma cells (Huh7), murine primary hepatocytes and an established co-culture model of phorbol myristate acetate-differentiated THP-1 monocytes and Huh7 cells. To analyze hepcidin signaling, the response to bone morphogenetic protein 6 (BMP6), interleukin (IL)-6, IL-1ß, hypoxia and lipopolysaccharide (LPS) were studied. Hepcidin and small mothers against decapentaplegic 6 (SMAD6) mRNA levels were assessed by qRT-PCR and the expression of phosphorylated signal transducer and activator of transcription 3 (phospho-STAT3), STAT3, phospho-SMAD1/5/8 and SMAD1 proteins were analyzed by western blot. RESULTS: All iron III forms including FAC efficiently blocked hepcidin mRNA expression at non-toxic dosages in Huh7 cells or primary hepatocytes in a time and dose-dependent manner (P < 0.001; P < 0.05). Hepcidin blockage could be efficiently blunted by iron chelators salicylaldehyde isonicotinoyl hydrazone (SIH) and Desferal (P < 0.001). FAC also inhibited BMP6, hypoxia, IL-1ß and IL-6-mediated hepcidin induction (P < 0.001; P < 0.001; P < 0.05; P < 0.001), and FAC also inhibited LPS-mediated hepatic hepcidin induction in co-culture model (P < 0.001). Moreover, FAC reduced SMAD6 mRNA and p-SMAD1/5/8 protein expression at basal or upon stimulation by BMP6 (P < 0.05; P < 0.01), and FAC also reduced SMAD6 and p-SMAD1/5/8 expression under hypoxia (P < 0.01; P < 0.05). However, FAC has no significant effect on p-STAT3 protein expression at basal or upon stimulation by various stimuli. Notably, in the presence of the BMP/SMAD signaling pathway inhibitor LDN193189 Hydrochloride (LDN), FAC was unable to further decrease hepcidin, SMAD6 and p-SMAD1/5/8 expression compared with LDN alone. CONCLUSION: Iron directly blocks hepatocellular hepcidin signaling through the BMP/SMAD pathway but independent of STAT3. This mechanism may contribute to continued iron overload in many pathophysiological conditions ultimately causing a vicious cycle of continued hepcidin suppression.

H2O2-mediated autophagy during ethanol metabolism.

BACKGROUND: Alcoholic liver disease (ALD) is the most common liver disease worldwide and its underlying molecular mechanisms are still poorly understood. Moreover, conflicting data have been reported on potentially protective autophagy, the exact role of ethanol-metabolizing enzymes and ROS. METHODS: Expression of LC3B, CYP2E1, and NOX4 was studied in a mouse model of acute ethanol exposure by immunoblotting and immunohistochemistry. Autophagy was further studied in primary mouse hepatocytes and huh7 cells in response to ethanol and its major intermediator acetaldehyde. Experiments were carried out in cells overexpressing CYP2E1 and knock down of NOX4 using siRNA. The response to external H2O2 was studied by using the GOX/CAT system. Autophagic flux was monitored using the mRFP-GFP-LC3 plasmid, while rapamycin and chloroquine served as positive and negative controls. RESULTS: Acute ethanol exposure of mice over 24 h significantly induced autophagy as measured by LC3B expression but also induced the ROS-generating CYP2E1 and NOX4 enzymes. Notably, ethanol but not its downstream metabolite acetaldehyde induced autophagy in primary mouse hepatocytes. In contrast, autophagy could only be induced in huh7 cells in the presence of overexpressed CYP2E1. In addition, overexpression of NOX4 also significantly increased autophagy, which could be blocked by siRNA mediated knock down. The antioxidant N-acetylcysteine (NAC) also efficiently blocked CYP2E1-and NOX4-mediated induction of autophagy. Finally, specific and non-toxic production of H2O2 by the GOX/CAT system as evidenced by elevated peroxiredoxin (Prx-2) also induced LC3B which was efficiently blocked by NAC. H2O2 strongly increased the autophagic flux as measured by mRFP-GFP-LC3 plasmid. CONCLUSION: We here provide evidence that short-term ethanol exposure induces autophagy in hepatocytes both in vivo and in vitro through the generation of ROS. These data suggest that suppression of autophagy by ethanol is most likely due to longer alcohol exposure during chronic alcohol consumption with the accumulation of e.g. misfolded proteins.

Reduction-sensitive N, N'-Bis(acryloyl) cystinamide-polymerized Nanohydrogel as a Potential Nanocarrier for Paclitaxel Delivery.

Novel monomer, N, N'-bis(acryloyl) cystinamide (NBACA), was designed and synthesized with L-cystine as row material. By using this NBACA both as the monomer and crosslinker, reduction-sensitive nanohydrogel was prepared in ethanol via distillation-precipitation polymerization. The obtained nanohydrogel can provide a relatively hydrophobic environment and hydrogen-bonding sites inside the gel; therefore, it is suitable for loading hydrophobic drug. When paclitaxel that possess poor water-solubility was used as a model drug, the nanohydrogel represented a high drug-loading capacity, and dispersed well in aqueous solutions. Furthermore, the disulfide-group-containing nanohydrogel exhibited good reduction-sensitive drug-release behavior. The nanohydrogel biodegraded rapidly in a reducing environment, and released approximately 80% of the PTX within 24 h. Cytotoxicity assays showed that the PTX-loaded nanohydrogel exhibited high cytotoxicity against MCF-7 breast cancer cells, while blank nanohydrogels displayed a negligible cytotoxicity.

[Application of differential proteomics in mechanism research of acupuncture].

Proteomics, a new branch of science, has been used to study protein expressions on the molecular level with a dynamic perspective. Organisms under varying states may express different proteins, which results in the set-up of differential proteomics. Research methods of differential proteomics include the separation and identification of proteins. Differential proteomics has a rapid development in recent years. In the study of acupuncture, researchers have reached certain achievements using differential proteomics to investigate the mechanisms of acupuncture treatment for some diseases, including acute spinal cord injury, ischemic cerebrovascular disease, Parkinson's disease and neuralgia.