Homozygous p.Ser267Phe in SLC10A1 is associated with a new type of hypercholanemia and implications for personalized medicine.

SLC10A1 codes for the sodium-taurocholate cotransporting polypeptide (NTCP), which is a hepatocellular transporter for bile acids (BAs) and the receptor for hepatitis B and D viruses. NTCP is also a target of multiple drugs. We aimed to evaluate the medical consequences of the loss of function mutation p.Ser267Phe in SLC10A1. We identified eight individuals with homozygous p.Ser267Phe mutation in SLC10A1 and followed up for 8-90 months. We compared their total serum BAs and 6 species of BAs with 170 wild-type and 107 heterozygous healthy individuals. We performed in-depth medical examinations and exome sequencing in the homozygous individuals. All homozygous individuals had persistent hypercholanemia (P = 5.8 × 10-29). Exome sequencing excluded the involvement of other BA metabolism-associated genes in the hypercholanemia. Although asymptomatic, all individuals had low vitamin D levels. Of six adults that were subjected to bone mineral density analysis, three presented with osteoporosis/osteopenia. Sex hormones and blood lipids were deviated in all subjects. Homozygosity of p.Ser267Phe in SLC10A1 is associated with asymptomatic hypercholanemia. Individuals with homozygous p.Ser267Phe in SLC10A1 are prone to vitamin D deficiency, deviated sex hormones and blood lipids. Surveillance of these parameters may also be needed in patients treated with drugs targeting NTCP.This project is supported by the National Natural Science Foundation of China (31471193, 81570539, 81370535, 91331204 and 31525014). S.X. acknowledges financial support from the Strategic Priority Research Program (XDB13040100) and Key Research Program of Frontier Sciences (QYZDJ-SSW-SYS009) of the Chinese Academy of Sciences (CAS)

Prognosis of sepsis induced by cecal ligation and puncture in mice improved by anti-Clonorchis Sinensis cyclopholin a antibodies

Abstract Background Cyclophilin A (CyPA), a ubiquitously distributed intracellular protein, is thought to be one of the important inflammatory factors and plays a significant role in the development process of sepsis. In the form of cytokine, CyPA deteriorates sepsis by promoting intercellular communication, apoptosis of endothelial cells and chemotactic effect on inflammatory cells. In our previous study, cyclophilin A of Clonorchis sinensis (CsCyPA), a type of excretory-secretory antigen, could induce the patients infected with Clonorchis sinensis to produce specific anti-CsCyPA antibodies. In this study, we investigated whether anti-CsCyPA antibodies could cross-react with CyPA and then play a protective role against sepsis, just like other anti-cytokine antagonists. Methods The mice model with sepsis was established with cecal ligation and puncture (CLP). Fifty mg/kg purified anti-CsCyPA antibodies were injected via the caudal vein 6 h after the CLP operation, and persistent observation was performed for 72 h. Blood samples and tissues were collected at 6 h, 12 h, 24 h, 48 h and 72 h after CLP. Cytokines in serum were measured by ELISA. Lung and mesentery tissues were stained with hematoxylin-eosin. Endothelial cells (ECs) isolated from murine aorta were co-cultured with CyPA of mice (MuCyPA) and anti-CsCyPAs for 24 h, then, viability was measured by Cell Counting Kit-8. Results Anti-CsCyPA antibodies could combine with MuCyPA and inhibite its peptidyl prolyl isomerase (PPIase) activity. In the antibodies treatment group, blood coagulation indicators including PT, aPTT, D-dimer and platelet count were obviously more ameliorative, the proinflammary factors like IL-6, TNF-α, IL-1β were significantly lower at 12 h and 24 h after surgery and the viability of ECs was significantly improved compared to those in the control group. Furthermore, the survival rate was elevated, ranging from 10.0 % to 45.0 % compared to the control group. Conclusions These antibodies may have a favorable effect on sepsis via inhibition of enzymic activity or protection of endothelial cells

Synergistic effect of terbinafine and amphotericin B in killing Fonsecaea nubica in vitro and in vivo

ABSTRACT Chromoblastomycosis is a chronic fungal infection. Itraconazole and terbinafine are the most recommended antifungal drugs for chromoblastomycosis, while amphotericin B is not usually recommended. A patient with chromoblastomycosis in our hospital showed poor clinical responses to itraconazole and terbinafine. The fungus isolated from the lesions of this patient was identified as Fonsecaea nubica and numbered zssy0803. In vitro antifungal susceptibilities of F. nubica zssy0803 to terbinafine, amphotericin B, itraconazole, voriconazole and caspofungin were evaluated, as well as the combinations of terbinafine with the other four antifungals. The combined effect of terbinafine and amphotericin B on other 20 clinical F. nubica strains was also evaluated. The minimal inhibitory concentrations of terbinafine, amphotericin B, itraconazole, voriconazole and caspofungin on F. nubica zssy0803 were 0.25 μg/mL, 2 μg/mL, 1 μg/mL, 4 μg/mL and 8 μg/mL, respectively. The combination of terbinafine and amphotericin B showed the lowest fractional inhibitory concentration index of 0.28 to F. nubica zssy0803 in comparison with combinations of terbinafine and the other four antifungal drugs. The combination of terbinafine and amphotericin B was also synergistic for all the other 20 F. nubica strains. Then, the combination of oral terbinafine (500 mg/day) and intralesional injections of amphotericin B (1 mg/mL) was used to treat this patient. After this combined therapy for 25 weeks and terbinafine monotherapy for additional 12 weeks, the patient was cured. These findings indicate for the first time that terbinafine and amphotericin B are synergistic in killing F. nubica both in vitro and in vivo

Taenia taeniaeformis in rat favors protracted skin lesions caused by Sporothrix schenckii infection: Dectin-1 and IL-17 are dispensable for clearance of this fungus.

We occasionally found that cestode Taenia taeniaeformis in rats favored Sporothrix schenckii infection and survival, causing protracted cutaneous lesions. In this study, we compared the pathology and cytokines profile of rats co-infected with the two pathogens and infected with S. schenckii alone to explore underlying mechanisms. In the co-infection group, there was high expression of β-glucan receptor Dectin-1 in the cutaneous lesions and no multinucleated giant cells, but in the S. schenckii infection group the opposite was observed. Cytokines profiles demonstrated an expected finding that IL-4, commonly expressed in helminth and fungus infection, is undetectable in the two infection groups. In the single fungal infection group, cytokines IFN-γ, IL-10 and IL-17 kept increasing in the first few weeks of infection to a peak which was followed by gradual decrease. This study showed that Dectin-1 and IL-17, which were believed to be the major anti-fungus mechanisms, are Th2 independent and dispensable for clearance of S. schenckii infection, suggesting that S. schenckii has a different molecular recognition pattern and evokes anti-infection mechanisms other than Dectin-1 and IL-17

Morphology of <i>Taenia taeniaeformis</i>.

<p>(A) Taenia cyst covered the entire liver; (B) <i>Taenia taeniaeformis</i> larva with large scolex, long neck and pseudo segmentation of entire body length with terminal bulged portion. (C) Histology of a <i>Taenia</i> cyst revealed armed rostellum characterized by 2 rows of hooks and four suckers.</p

Cytokines IFN-γ, IL-10 and IL-17 released during <i>S. schenckii</i> infection and co-infection with <i>Taenia taeniaeformis</i> (A, B and C).

<p>IFN-γ and IL-10 (A and B) productions occurred in large amounts in the 1^st, 2^nd and 3^rd weeks after <i>S. schenckii</i> infection in fungus-infected group, and reached the peak in the 2^nd week PI. IL-17 productions (C) of the co-infected group. There was a significant difference between the two groups for IL-17 levels (P<0.05).</p