Metabolite Profiling of Swertia cincta Extract in Rats and Pharmacokinetics Study of Three Bioactive Compounds Using UHPLC-MS/MS.

Swertia cincta, a plant of the genus Swertia in Gentianceae, has "heat-clearing" and detoxifying effects that normalize the gallbladder function in the treatment of jaundice. Although numerous studies on Swertia cincta have been performed, the absorption and pharmacokinetic behaviors remain unclear. In this study, the compounds of Swertia cincta in serum, bile, feces, and urine of rats were analyzed using a ultra-high-performance liquid chromatography-tandem mass spectrometry. A total of 9 prototype components and 48 metabolites were detected in biological samples. Furthermore, we determined the main components absorbed in the blood of Swertia cincta and established a method for simultaneously determining these components (sweroside, swertiamarin, and gentiopicroside) in positive ionization mode within 6 min. The quantitative method was successfully applied for the multiple-component pharmacokinetic study of Swertia cincta.

PPARα: A potential therapeutic target of cholestasis.

The accumulation of bile acids in the liver leads to the development of cholestasis and hepatocyte injury. Nuclear receptors control the synthesis and transport of bile acids in the liver. Among them, the farnesoid X receptor (FXR) is the most common receptor studied in treating cholestasis. The activation of this receptor can reduce the amount of bile acid synthesis and decrease the bile acid content in the liver, alleviating cholestasis. Ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) have a FXR excitatory effect, but the unresponsiveness of some patients and the side effect of pruritus seriously affect the results of UDCA or OCA treatment. The activator of peroxisome proliferator-activated receptor alpha (PPARα) has emerged as a new target for controlling the synthesis and transport of bile acids during cholestasis. Moreover, the anti-inflammatory effect of PPARα can effectively reduce cholestatic liver injury, thereby improving patients' physiological status. Here, we will focus on the function of PPARα and its involvement in the regulation of bile acid transport and metabolism. In addition, the anti-inflammatory effects of PPARα will be discussed in some detail. Finally, we will discuss the application of PPARα agonists for cholestatic liver disorders.

A transgene-encoded truncated human epidermal growth factor receptor for depletion of anti- B-cell maturation antigen CAR-T cells.

BACKGROUND: Chimeric antigen receptor T cells (CAR-T) against B-cell maturation antigen (BCMA) has been used to treat multiple myeloma (MM). CAR-T cells co-expressing a truncated human EGFR (tEGFR) has been proposed for in vivo cell ablation. METHODS: We designed and tested a novel anti-BCMA CAR. We transduced T cells with retroviral vectors encoding CAR and tEGFR. The anti-BCMA-CAR-transduced T cells were evaluated for the functions including cytokine production, proliferation, cytotoxicity, and in vivo tumor eradication of BCMA. Cetuximab was used for in vivo cell ablation. RESULTS: The CAR-T cells could specifically recognize BCMA, and anti-BCMA CAR-T cells could exhibit interferon-γ and cytotoxicity specifically produced by BCMA and eradicate tumor in vivo. Cetuximab could mediate antibody-dependent cellular cytotoxicity and in vivo elimination. CONCLUSIONS: We confirm that BCMA is a suitable target for CAR- T cells and tEGFR is a effective tool for cellular ablation.

High glucose induces alternative activation of macrophages via PI3K/Akt signaling pathway.

OBJECTIVE: It has been proved that lactate-4.25% dialysate could result in peritoneal fibrosis by inducing alternative activation of macrophages in our previous study, but the mechanism of high glucose-induced alternative activation has not been elucidated. This study was, therefore, to investigate the mechanism by high glucose stimuli. METHODS: In this study, Raw264.7 (murine macrophage cell line) cells were cultured and stimulated by 4.25% glucose medium, and mannitol medium was used as osmotic pressure control. Cells were harvested at 0 h, 4 h, 8 h, and 12 h to examine the expression of Arg-1, CD206, and p-Akt. After blocking PI3K by LY294002, the expression of Arg-1, CD206, and p-Akt was examined again. RESULTS: The expression of Arg-1 and CD206 was increased in a time-dependent manner induced by high glucose medium. On the contrary, there was mainly no Agr-1 or CD206 expressed in cells cultured in the mannitol medium with the same osmotic pressure. What's more, Akt was phosphorylated at the eighth hour stimulated by high glucose medium, and LY294002 inhibited the expression of Arg-1 and CD206 by blocking the phosphorylation of Akt. CONCLUSIONS: Our study indicated that high glucose rather than high osmotic pressure induced M2 phenotype via PI3K/Akt signaling pathway.

Jadassohn-Pellizzari anetoderma: study of multiphoton microscopy based on two-photon excited fluorescence and second harmonic generation.

Anetoderma is a rare skin disease with loss of dermal elastic tissue resulting in clinically localized areas of flaccid or herniated sack-like skin. In this study, we report a case of Jadassohn-Pellizzari anetoderma, in a 21-year-old Chinese female with an 18-year history of progressively generalized wrinkled skin lesions. Multiphoton microscopy based on two-photon excited fluorescence (TPEF) and second harmonic generation (SHG) was firstly employed to investigate the pathological process from unaffected skin to the erythematous phase and finally with affected skin of this case. The results showed that the normal elastic fibers in unaffected skin were almost completely absent in erythematous skin tissue, then replaced by a lot of elastic fibers with granular morphology in affected skin, which was consistent with the histopathological results. The obvious changes in collagen fibers and the occurrence of inflammatory cell infiltration in erythematous tissue suggested that the variations of these two components were also the main pathogenesis of anetoderma, except for the deficiency of elastic fibers. Based on these data, we demonstrated that multiphoton microscopy was a promising tool for non-invasive investigation of the pathology of anetoderma at nearly histological resolution, and has potential for observing the dermatological dynamic processes for living specimens because it is based on the intrinsic signals of tissue components.