Targeting ABCB6 with nitidine chloride inhibits PI3K/AKT signaling pathway to promote ferroptosis in multiple myeloma.

Since multiple myeloma (MM) remains a cureless malignancy of plasma cells to date, it becomes imperative to develop novel drugs and therapeutic targets for MM. We screened a small molecule library comprising 3633 natural product drugs, which demonstrated that Nitidine Chloride (NC), an extract from traditional Chinese medicine Zanthoxylum nitidum. We used Surface Plasmon Resonance-High Performance Liquid Chromatography-Protein Mass Spectrometry (SPR-HPLC-MS), Cellular Thermal Shift Assay (CETSA), molecular docking, and SPR assay to identify the potential targets of NC, in which ABCB6 was the unique target of NC. The effects of ABCB6 on cellular proliferation and drug resistance were determined by CCK8, western blot, flow cytometry, site-mutation cells, transmission electron microscopy, immunohistochemistry staining and xenograft model in vitro and in vivo. NC induced MM cell death by promoting ferroptosis. ABCB6 is the direct target of NC. ABCB6 expression was increased in MM samples compared to normal controls, which was significantly associated with MM relapse and poor outcomes. VGSK was the inferred binding epitope of NC on the ABCB6 protein. In the ABCB6-mutated MM cells, NC did not display cancer resistance, implying the vital role of ABCB6 in NC's bioactivity. Moreover, the silencing of ABCB6 significantly inhibited MM cell growth. Mechanistically, the direct binding of NC to ABCB6 suppressed PI3K/AKT signaling pathway to promote ferroptosis. In conclusion, ABCB6 can be a potential therapeutic target and prognostic biomarker in MM, while NC can be considered a novel drug for MM treatment.

Dyslipidemia may be a risk factor for progression in children with IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is often chronically progressive and commonly accompanied by dyslipidemia. However, the intrinsic relationship between dyslipidemia and IgAN remains to be elucidated. This study aimed to investigate the impact of different types of dyslipidemia on clinical and pathological characteristics in children with IgAN. METHODS: In our retrospective cohort study from January 2006 to January 2021, 276 children with IgAN were ultimately included in the baseline analysis, and 169 were included in the follow-up analysis. The clinical and pathological features of different types of dyslipidemia and their effect on kidney prognosis were analyzed. RESULTS: Children in the dyslipidemia group had more severe clinical characteristics (higher blood urea nitrogen, serum uric acid, and 24-h proteinuria; higher proportion of hypertension; and lower serum albumin and estimated glomerular filtration rate) and pathological changes (higher proportion of Lee grades IV-V and E1, S1, and C2 in MEST-C). Furthermore, the clinical and pathological characteristics were worse in the mixed hyperlipidemia group. Multivariate logistic analysis showed that hypertension, steroid treatment, lower serum albumin, severe proteinuria, and segmental glomerulosclerosis were independent risk factors for dyslipidemia in children with IgAN. The Kaplan-Meier analysis revealed that the probability of kidney survival in children with dyslipidemia was lower than that in those without dyslipidemia, with a median follow-up of 5.9 years. CONCLUSIONS: Children with IgAN and dyslipidemia, especially mixed hyperlipidemia, are prone to more severe clinical and pathological changes. Our study provides further insight into dyslipidemia as a potential risk factor in children with IgAN. A higher resolution version of the Graphical abstract is available as Supplementary information.

Effects of alternative remission criteria on outcome of pediatric proliferative lupus nephritis: a multi-center retrospective study of pediatric proliferative lupus nephritis.

OBJECTIVES: To observe the induction efficacy of mycophenolate mofetil and cyclophosphamide under different complete remission (CR) criteria in children with proliferative lupus nephritis, and to further explore the factors influencing the judgment of remission. METHODS: From 2003 to 2019, children who diagnosed proliferative lupus nephritis underwent induction therapy of MMF or CYC in three hospitals were consecutively collected. Based on this population, we compared CR rates between two groups under six CR criteria selected from related recommendations and clinical trials. Then degrees and impact factors of disagreement among CR rates evaluated by selected criteria would be analyzed by Kappa test and multivariable logistic-regression models. RESULTS: A total of 161 children were included in this study, 27 patients received induction therapy of mycophenolate mofetil (MMF) and 134 patients recieved cyclophosphamide (CYC). Under different CR criteria, CR rates in MMF group fluctuated between 18.5%-74.1% and that in CYC group ranged from 16.4%-73.9%. Moreover, comparison between the two drugs in induction treatment under different criteria showed an opposite trend in efficacy. The results of six criteria were inconsistent, with pair-to-pair Kappa values ranging from 0.118 to 0.858. The most important factors leading to disagreement in judgment were urinary protein and urinary red blood cells. CONCLUSIONS: The definition of complete response, especially the factors of the urinary protein and urinary red blood cells, significantly impacts the clinical judgment of children with lupus nephritis.

[Anti-depression effect of acupunctrue and moxibustion based on SSRIs medication].

OBJECTIVE: To verify the anti-depression effect of acupuncture and moxibustion based on the medication with selective serotonin reuptake inhibitors (SSRIs). METHODS: Eighty cases of depression were randomly divided into an acupuncture-moxibustion-medication group (25 cases), an acupuncture-medication group (25 cases) and a medication group (30 cases). SSRIs medication was administered in all of the three groups. Complementarily, in acupuncture-moxibustion-medication group, the needling technique of qi conduction in the Governor Vessel was applied to Baihui (GV 20), Fengfu (GV 16), Dazhui (GV 14), etc. Additionally, mild moxibustion was added at Dazhui (GV 14) and Baihui (GV 20). In acupuncture-medication group, acupuncture for qi conduction in the Governor Vessel was only adopted. Hamilton Depression Scale (HAMD) was used for the evaluation of the total score, the score of each factor before and after treatment separately, and the therapeutic effects were observed among 3 groups. RESULTS: Compared with medication group, the scores of the factors as retardation, sleep, and anxiety/somatization, as well as the total score were all apparently improved in the other two groups (P < 0.05, P < 0.01). Compared with acupuncture-medication group, the scores of sleep and cognition factors as well as the total score in HAMD were much improved in acupuncture-moxibustion-medication group (P < 0.05, P < 0.01). The remarkable effective rates were 100.0% (25/25), 84.0% (21/25) and 56.7% (17/30) in the three groups separately, in which, the result in acupuncture-moxibustion-medication group was superior to acupuncture-medication group (P < 0.05), and the results of these two groups were superior to medication group (both P < 0.01). CONCLUSION: Either acupunctrure or moxibustion has a definite anti-depression effect based on SSRIs medication, but the coordination of acupuncture and moxibustion achieves a superior efficacy as compared with simple acupuncture therapy.

[Application of "regulating spirit and conducting qi" therapy in treatment of psychological diseases].

Taking the clinical curative effects of psychological diseases treated with "regulating spirit and conducting qi" therapy as the starting point, the manipulation and technology method of "regulating spirit and conducting qi" therapy are introduced in the paper. Based on analysis of "conducting qi" therapy of Neijing (Internal Classic), it is summarized that, in "regulating spirit and conducting qi" therapy, tardiness and tenderness are taken as technical core of manipulation, individualization of patients is taken as basis, and regulation on spirit as key issue of technology, so as to rapidly, effectively and safely regulate the functional status of emotion and organism. It is aq effective technology method for treating psychological diseases, especially for insomnia, anxiety and somatic symptoms, with better curative effects.

Semiquantitative multielemental analysis of biological samples by a laser ionization orthogonal time-of-flight mass spectrometer.

Semiquantitative multielemental analyses of biological samples (tea leaf standard, Laminaria japonica, and pig skin) were demonstrated with a newly developed laser ionization orthogonal time-of-flight mass spectrometer (LI-O-TOFMS). The sample was directly ablated and ionized with high irradiance after simple sample preparation. Relative sensitivity coefficients (RSC) were calculated and evaluated for sensitivity differences. Due to the employment of a collisional cooling device and the orthogonal geometry of the TOF system, high resolving power can be obtained, such that elemental peaks and interferential peaks with the same nominal mass can be distinguished. The detection limit of microg g(-1) levels can be commonly achieved for elemental determination.