Tubeimoside-1 induces TFEB-dependent lysosomal degradation of PD-L1 and promotes antitumor immunity by targeting mTOR

Programmed cell death ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) cascade is an effective therapeutic target for immune checkpoint blockade (ICB) therapy. Targeting PD-L1/PD-1 axis by small-molecule drug is an attractive approach to enhance antitumor immunity. Using flow cytometry-based assay, we identify tubeimoside-1 (TBM-1) as a promising antitumor immune modulator that negatively regulates PD-L1 level. TBM-1 disrupts PD-1/PD-L1 interaction and enhances the cytotoxicity of T cells toward cancer cells through decreasing the abundance of PD-L1. Furthermore, TBM-1 exerts its antitumor effect in mice bearing Lewis lung carcinoma (LLC) and B16 melanoma tumor xenograft

Cholesterol-associated lysosomal disorder triggers cell death of hematological malignancy: Dynamic analysis on cytotoxic effects of LW-218

The integrity of lysosomes is of vital importance to survival of tumor cells. We demonstrated that LW-218, a synthetic flavonoid, induced rapid lysosomal enlargement accompanied with lysosomal membrane permeabilization in hematological malignancy. LW-218-induced lysosomal damage and lysosome-dependent cell death were mediated by cathepsin D, as the lysosomal damage and cell apoptosis could be suppressed by depletion of cathepsin D or lysosome alkalization agents, which can alter the activity of cathepsins. Lysophagy, was initiated for cell self-rescue after LW-218 treatment and correlated with calcium release and nuclei translocation of transcription factor EB. LW-218 treatment enhanced the expression of autophagy-related genes which could be inhibited by intracellular calcium chelator. Sustained exposure to LW-218 exhausted the lysosomal capacity so as to repress the normal autophagy. LW-218-induced enlargement and damage of lysosomes were triggered by abnormal cholesterol deposition on lysosome membrane which caused by interaction between LW-218 and NPC intracellular cholesterol transporter 1. Moreover, LW-218 inhibited the leukemia cell growth

Progress in the regulation of energy metabolic homeostasis by the SWI/SNF complex subunit Baf60a / 生物工程学报

Metabolic syndrome is a global chronic epidemic. Its pathogenesis is determined by genetic and environmental factors. Epigenetic modification is reported to regulate gene expression without altering its nucleotide sequences. In recent years, epigenetic modification is sensitively responded to environmental signals, further affecting the gene expression and signaling transduction. Among these regulators, chromatin remodeling SWI/SNF (SWItch/Sucrose non fermentable, SWI/SNF) complex subunit Baf60a plays an important role in maintaining energy homeostasis in mammals. In this paper, we described the pathophysiological roles of Baf60a in maintaining the balance of energy metabolism, including lipid metabolism, cholesterol metabolism, urea metabolism, as well as their rhythmicity. Therefore, in-depth understanding of Baf60a-orchestrated transcriptional network of energy metabolism will provide potential therapeutic targets and reliable theoretical supports for the treatment of metabolic syndrome.

Berberine diminishes cancer cell PD-L1 expression and facilitates antitumor immunity

Programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) blocking therapy has become a major pillar of cancer immunotherapy. Compared with antibodies targeting, small-molecule checkpoint inhibitors which have favorable pharmacokinetics are urgently needed. Here we identified berberine (BBR), a proven anti-inflammation drug, as a negative regulator of PD-L1 from a set of traditional Chinese medicine (TCM) chemical monomers. BBR enhanced the sensitivity of tumour cells to co-cultured T-cells by decreasing the level of PD-L1 in cancer cells. In addition, BBR exerted its antitumor effect in Lewis tumor xenograft mice through enhancing tumor-infiltrating T-cell immunity and attenuating the activation of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs). BBR triggered PD-L1 degradation through ubiquitin (Ub)/proteasome-dependent pathway. Remarkably, BBR selectively bound to the glutamic acid 76 of constitutive photomorphogenic-9 signalosome 5 (CSN5) and inhibited PD-1/PD-L1 axis through its deubiquitination activity, resulting in ubiquitination and degradation of PD-L1. Our data reveals a previously unrecognized antitumor mechanism of BBR, suggesting BBR is small-molecule immune checkpoint inhibitor for cancer treatment.

The SWI/SNF chromatin-remodeling factors BAF60a, b, and c in nutrient signaling and metabolic control

Metabolic syndrome has become a global epidemic that adversely affects human health. Both genetic and environmental factors contribute to the pathogenesis of metabolic disorders; however, the mechanisms that integrate these cues to regulate metabolic physiology and the development of metabolic disorders remain incompletely defined. Emerging evidence suggests that SWI/SNF chromatin-remodeling complexes are critical for directing metabolic reprogramming and adaptation in response to nutritional and other physiological signals. The ATP-dependent SWI/SNF chromatin-remodeling complexes comprise up to 11 subunits, among which the BAF60 subunit serves as a key link between the core complexes and specific transcriptional factors. The BAF60 subunit has three members, BAF60a, b, and c. The distinct tissue distribution patterns and regulatory mechanisms of BAF60 proteins confer each isoform with specialized functions in different metabolic cell types. In this review, we summarize the emerging roles and mechanisms of BAF60 proteins in the regulation of nutrient sensing and energy metabolism under physiological and disease conditions.

Textual research of origin and development of bronze acupuncture figure / 中国针灸

The origin, development and duplication history of bronze acupuncture figure (BAF) were explored by textual research of related literature. BAF was firstly recorded in period of North dynasty, which was made by under emperor's summons. It was a standard bronze figure with acupuncture points, so it was also called BAF. Thereafter, BAF was duplicated in different dynasties or even oversea, such as BAF made in period of Dynasty, self-made BAF made by , BAF made as rewards for the writers of in period of Dynasty, and BAF made by 's family of . In addition, BAF was made after the BAF was robbed by the Russian invasion army. Japan and Korea also made their own BAF. After the founding of China, the national government and scientific research institutes made new BAFs and donated it to World Health Organization as a gift in 2017.

Marcadores moleculares en el cáncer de tiroides / Molecular markers for thyroid cancer

La importancia del estudio del nódulo tiroideo es excluir una lesión maligna, ya que, aunque la mayoría son lesiones benignas, existe un riesgo de malignidad de un 5-10 por ciento. La mayoría de estos son carcinomas bien diferenciados, que se originan del epitelio folicular. A pesar de que la mayoría de las lesiones son benignas, la distinción entre estas y los carcinomas, es crucial para un tratamiento y seguimiento apropiado. La biopsia por punción con aguja fina permite realizar el diagnóstico en la mayoría de los casos, sin embargo, esta presenta limitaciones, particularmente referidas al diagnóstico de las lesiones foliculares. En un esfuerzo por mejorar la precisión diagnóstica de la biopsia y ofrecer nuevos criterios para el diagnóstico, múltiples marcadores moleculares han sido propuestos, algunos de los cuales presentan gran aprobación, mientras que otros requieren aún validación para su implementación. En este artículo se realiza una revisión actualizada de los marcadores moleculares que presentan mayor número de evidencias, los que son metodológicamente más asequibles y potencialmente utilizables para el diagnóstico prequirúrgico del nódulo tiroideo(AU)

The importance of the study of the thyroid nodule lies in excluding the possibility of a malignant lesion because the majority of lesions are benign but there is a malignancy risk of 5 to 10 percent. Most of them are well differentiated carcinomas originating in the follicular epithelium. In spite of the fact that the majority are benign lesions, distinguishing them from carcinomas is crucial to treatment and adequate follow-up. Fine-needle biopsy allows making the diagnosis in most of cases. However, this method is restricted, particularly when diagnosing follicular lesions. In an effort to improve the diagnostic accuracy of biopsy and to provide new diagnosing criteria, a number of molecular markers have been put forward, some of which has wide range of approval whereas others still awaits to be validated for further implementation. This article presented an updated review of molecular markers with higher number of evidence, more accessible and potentially usable from a methodological viewpoint for diagnosis of the thyroid nodule before surgery(AU)

Avaliação de fatores associados à invasão, migração celular e transformação maligna em mulheres com endometriose profunda / Evaluation of factors related to invasion, cell migration and malignant transformation in women with deep endometriosis

INTRODUÇÃO: A endometriose é uma doença crônica de natureza benigna e de alta prevalência, definida pela presença de tecido endometrial fora da cavidade uterina. Dentre os principais sintomas, destacam-se a dor pélvica crônica, dismenorreia e infertilidade. Clinicamente, apresenta-se de três formas distintas: endometriose peritoneal ou superficial, endometriose ovariana - endometrioma - e endometriose profunda (EP). A EP apresenta um padrão de comportamento semelhante ao das doenças malignas, com capacidade de crescimento infiltrativo e destrutivo em diferentes sítios. Lesões endometrióticas já foram identificadas em linfonodos pélvicos, evidenciando a disseminação linfática das células endometrióticas. Em neoplasias malignas, as quimiocinas e seus receptores desempenham papel soberano no processo de metástase e na disseminação linfática das células tumorais. OBJETIVOS: 1) avaliar a expressão das quimiocinas que no câncer estão relacionadas ao processo de metástase - CXCL12-CXCR4, CCL19/CCL21-CCR7 - na EP do compartimento posterior da pelve e nos respectivos linfonodos-sentinela (LS); 2) avaliar a concentração dessas quimiocinas no líquido peritoneal (LP) de pacientes com e sem endometriose; 3) avaliar a expressão da proteína BAF250a, relacionada à transformação maligna, na endometriose, com ênfase na EP do compartimento posterior da pelve. MÉTODOS: 123 pacientes foram incluídas neste estudo. Nós realizamos a coloração imuno-histoquímica para avaliar a expressão das quimiocinas - ligantes e receptores - nas lesões de EP retovaginal/do compartimento posterior da pelve (n=27), nos respectivos LS (n=27) e no endométrio de pacientes-controle sem endometriose (n=20); a concentração das quimiocinas no LP foi avaliada por meio da tecnologia multiplex - Luminex® xMAP® Technology - em um subgrupo de pacientes com (n=36) e sem (n=27) endometriose; a possibilidade de transformação maligna também foi avaliada por meio da imuno-histoquímica para analisar a expressão...

INTRODUCTION: Endometriosis is a chronic disease of benign nature and of high prevalence, defined by the presence of endometrial tissue outside the uterine cavity. Among the main symptoms are highlighted chronic pelvic pain, dysmenorrhea and infertility; clinically, it may appear in three distinct ways: peritoneal endometriosis, ovarian endometriosis - endometriomas - and deep infiltrating endometriosis (DIE). DIE presents a behavioral pattern in many ways similar to that of malignancies, as capacity of infiltrative and destructive growth in different sites. Endometriotic lesions have already been identified in pelvic lymph nodes, showing the possibility of lymphatic dissemination of endometriotic cells. In malignancies, chemokines play a sovereign role in the process of metastasis and lymphatic spread of tumor cells. OBJECTIVES: 1) to evaluate the expression of cancer-related chemokines - CXCL12-CXCR4, CCL19/CCL21-CCR7 - in rectovaginal DIE (or endometriosis of the posterior compartment of the pelvis) and the respective pelvic sentinel lymph node (PSLN); 2) to evaluate the concentration levels of those chemokines in the peritoneal fluid (PF) of patients with and without endometriosis; 3) to evaluate the expression of protein BAF250a, related to malignant transformation, in endometriosis, with emphasis in rectovaginal DIE. METHODS: 123 patients were enrolled in this study. We performed immunohistochemical staining to assess the expression of all chemokines - ligands and receptors - in rectovaginal DIE (n=27), PSLN (n=27) and eutopic endometrium (EE) from patients without endometriosis as controls (n=20); chemokine concentration in the PF was assessed with multiplexing technology - Luminex® x-MAP® Technology - in a subgroup of patients with (n=36) and without (n=27) endometriosis; the possibility of malignant transformation was also assessed by means of immunohistochemistry to evaluate the expression of BAF250a protein among endometriosis lesions...

The roles of ARID1A in gynecologic cancer / 부인종양

One of the exciting findings in recent cancer genome studies is the discovery of somatic mutations in several chromatin remodeling genes. These studies not only illuminate the emerging roles of chromatin remodeling in the pathogenesis of human cancer but also provide molecular genetic basis of aberrant epigenomic regulation as one of the key mechanisms driving cancer development. This is because chromatin remodeling influences a variety of DNA activities such as replication, transcription, repair, methylation, and recombination. Among the mutated chromatin remodeling genes reported, ARID1A is frequently mutated in a variety of human cancers, especially in endometrium-related neoplasms including ovarian clear cell carcinoma, ovarian endometrioid carcinomas, and uterine endometrioid carcinomas, all of which arise from endometrial epithelium. This review will summarize the recent advances in studying the roles of ARID1A mutations in gynecologic cancers with special emphasis on how this new knowledge will further extend our understanding of the pathogenesis of endometrium-related carcinomas.

Increased HoxB4 Inhibits Apoptotic Cell Death in Pro-B Cells

HoxB4, a homeodomain-containing transcription factor, is involved in the expansion of hematopoietic stem cells and progenitor cells in vivo and in vitro, and plays a key role in regulating the balance between hematopoietic stem cell renewal and cell differentiation. However, the biological activity of HoxB4 in other cells has not been reported. In this study, we investigated the effect of overexpressed HoxB4 on cell survival under various conditions that induce death, using the Ba/F3 cell line. Analysis of phenotypical characteristics showed that HoxB4 overexpression in Ba/F3 cells reduced cell size, death, and proliferation rate. Moreover, the progression from early to late apoptotic stages was inhibited in Ba/F3 cells subjected to HoxB4 overexpression under removal of interleukin-3-mediated signal, leading to the induction of cell cycle arrest at the G2/M phase and attenuated cell death by Fas protein stimulation in vitro. Furthermore, apoptotic cell death induced by doxorubicin-treated G2/M phase cell-cycle arrest also decreased with HoxB4 overexpression in Ba/F3 cells. From these data, we suggest that HoxB4 may play an important role in the regulation of pro-B cell survival under various apoptotic death environments.

IFN-gamma Regulates Expression of BRG1 Associated Factor 155/170 and Sensitivity to Steroid in Astrocytes

BACKGROUND: The expression of BRG1 associated factors (BAF) 155 and BAF 170 in response to IFN-gamma or TNF-alpha was studied in astrocytoma cell lines and primary astrocytes. BAFs are complexed with BRG1 and are also associated with activated glucocorticoid for glucocorticoid trans-activation. METHODS: IFN-gamma was pretreated for 18 hrs and cells were incubated with IL-1 or TNF-alpha for 72 hrs or 96 hrs with different concentrations of steroid. Cell death was measured by LDH assay. BAF expression was assayed by RT-PCR. RESULTS: IFN-gamma increased cell death by dexamethasone in LN215 cells but not in LN319 cells. The IFN-gamma increased the expression of BAF 155 and BAF 170 in adult astrocytes and LN215 cells, but IFN-gamma decreased the expression of BAF 155/170 in LN319 cells. The effect of IFN-gamma on the expression of BAF was not as clear in fetal astrocytes as it was in adult astrocytes. CONCLUSION: Our results suggest cytokines produced during immune reaction or immunotherapy may modulate steroid susceptibility of astrocytes and astrocytoma cells by influencing the expression of BAFs.

Construction of BaF3-P210 cell line stably expressing BCR/ABL protein and its biological activity / 第三军医大学学报

Objective To construct the transformed mouse BaF3-P210 cell line stably expressing BCR/ABL and to initially investigate the influence of BCR/ABL on the cell biological characteristics of BaF3 cell line. Methods The retroviral vector with bcr/abl gene was transfected into the packaging cell line. The BaF3 cells were infected with the collected viral supernatant. The transgenic BaF3-P210 cell line stably expressing BCR/ABL were screened and subcloned. The integration of the bcr/abl gene in the genome of the target cell was determined by PCR and DNA sequencing,trypan blue staining assay,flow cytometry and MTT assay. Results The bcr/abl gene was integrated into the BaF3 cell genome; RT-PCR and Western blot verified the stable expression of the bcr/abl gene and protein in the screened subclone cell line BaF3-P210. Compared with the control group,the cell proliferation rate was promoted (P