Advances in Biological Regulation

Baihui Wang

Qiang Luo

Ohad Medalia

Lamins and chromatin join forces

核纤层蛋白与染色质联手

Agnieszka Gizak

Bartosz Budziak

Aleksandra Domaradzka

Łukasz Pietras

Dariusz Rakus

FRUCTOSE 1,6-BISPHOSPHATASE AS A PROMISING TARGET OF ANTICANCER TREATMENT

果糖1,6-二磷酸酶作为抗癌治疗的潜在靶点

Pancreatic cancer is devastating cancer worldwide with few if any truly effective therapies. Pancreatic cancer has an increasing incidence and may become the second leading cause of death from cancer. Novel, more effective therapeutic approaches are needed as pancreatic cancer patients usually survive for less than a year after being diagnosed. Control of blood sugar levels by the prescription drug metformin in diseases such as diabetes mellitus has been examined in association with pancreatic cancer. While the clinical trials remain inconclusive, there is hope that certain diets and medications may affect positively the outcomes of patients with pancreatic and other cancers. Other natural compounds may share some of the effects of metformin. One "medicinal" fruit consumed by millions worldwide is berberine (BBR). Metformin and BBR both activate AMP-activated protein kinase (AMPK) which is a key mediator of glucose metabolism. Glucose metabolism has been shown to be very important in cancer and its significance is increasing. In the following studies, we have examined the effects of metformin, BBR and a panel of modified BBRs (NAX compounds) and chemotherapeutic drugs on the growth of four different human pancreatic adenocarcinoma cell lines (PDAC). Interestingly, the effects of metformin could be enhanced by BBR and certain modified BBRs. Upon restoration of WT-TP53 activity in MIA-PaCa-2 cells, an altered sensitivity to the combination of certain NAX compounds and metformin was observed compared to the parental cells which normally lack WT-TP53. Certain NAX compounds may interact with WT-TP53 and metformin treatment to alter the expression of key molecules involved in cell growth. These results suggest a therapeutic approach by combining certain pharmaceutical drugs and nutraceuticals to suppress the growth of cancer cells.

Shaw M. Akula

Saverio Candido

Massimo Libra

Stephen L. Abrams

Linda S. Steelman

Kvin Lertpiriyapong

Giulia Ramazzotti

Stefano Ratti

Matilde Y. Follo

Alberto M. Martelli

Ramiro M. Murata

Pedro L. Rosalen

Bruno Bueno-Silva

Severino Matias de Alencar

Giuseppe Montalto

Melchiorre Cervello

Weifeng Mao

Heng-Liang Lin

Paolo Lombardi

James A. McCubrey

Abilities of berberine and chemically modified berberines to interact with metformin and inhibit proliferation of pancreatic cancer cells

小檗碱及其化学修饰物与二甲双胍相互作用及抑制胰腺癌细胞增殖的能力

Sphingosine phosphate lyase insufficiency syndrome (SPLIS) is a genetic disease associated with renal, endocrine, neurological, skin and immune defects. SPLIS is caused by inactivating mutations in SGPL1, which encodes sphingosine phosphate lyase (SPL). SPL catalyzes the irreversible degradation of the bioactive sphingolipid sphingosine-1-phosphate (S1P), a key regulator of lymphocyte egress. The SPL reaction represents the only exit point of sphingolipid metabolism, and SPL insufficiency causes widespread sphingolipid derangements that could additionally contribute to immunodeficiency. Herein, we review SPLIS, the sphingolipid metabolic pathway, and various roles sphingolipids play in immunity. We then explore SPLIS-related immunodeficiency by analyzing data available in the published literature supplemented by medical record reviews in ten SPLIS children. We found 93% of evaluable SPLIS patients had documented evidence of immunodeficiency. Many of the remainder of cases were unevaluable due to lack of available immunological data. Most commonly, SPLIS patients exhibited lymphopenia and T cell-specific lymphopenia, consistent with the established role of the S1P/S1P1/SPL axis in lymphocyte egress. However, low B and NK cell counts, hypogammaglobulinemia, and opportunistic infections with bacterial, viral and fungal pathogens were observed. Diminished responses to childhood vaccinations were less frequently observed. Screening blood tests quantifying recent thymic emigrants identified some lymphopenic SPLIS patients in the newborn period. Lymphopenia has been reported to improve after cofactor supplementation in some SPLIS patients, indicating upregulation of SPL activity. A variety of treatments including immunoglobulin replacement, prophylactic antimicrobials and special preparation of blood products prior to transfusion have been employed in SPLIS. The diverse immune consequences in SPLIS patients suggest that aberrant S1P signaling may not fully explain the extent of immunodeficiency. Further study will be required to fully elucidate the complex mechanisms underlying SPLIS immunodeficiency and determine the most effective prophylaxis against infection.

Saber Gharagozlou

NicolaA M Wright

Luis Murguila-Favela

Juliette Eshleman

Julian Midgley

Seha Saygili

Georgie Mathew

Harry Lesmana

Nadia Makkoukdji

Melissa Gans

Julie D Saba

Sphingosine Phosphate Lyase Insufficiency Syndrome As a Primary Immunodeficiency State

鞘氨醇磷酸酯裂解酶不足综合征作为原发性免疫缺陷状态

The transcription factor NF-κB plays a critical role in the control of innate and adaptive immunity and inflammation. Several recent studies have demonstrated that the mutation of different splicing factor genes, including SF3B1, SRSF2 and U2AF1, in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) result in hyperactive NF-κB signaling through the aberrant splicing of different target genes. The presence of U2AF1 and SF3B1 mutations in the bone marrow cells of MDS and AML patients induces oncogenic isoforms of the target gene IRAK4, leading to hyperactivation of NF-κB signaling and an increase in the fitness of leukemic stem and progenitor cells (LSPCs). The potent IRAK4 inhibitor CA-4948 has shown efficacy in both pre-clinical studies and MDS clinical trials, with splicing factor mutant patients showing the higher response rates. Emerging data has, however, revealed that co-targeting of IRAK4 and its paralog IRAK1 is required to maximally suppress LSPC function in vitro and in vivo by inducing cellular differentiation. These findings provide a link between the presence of the commonly mutated splicing factor genes and activation of innate immune signaling pathways in myeloid malignancies and have important implications for targeted therapy in these disorders.

Andrea Pellagatti

Jacqueline Boultwood

Hyperactivation of NF-κB signaling in splicing factor mutant myelodysplastic syndromes and therapeutic approaches

剪接因子突变型骨髓增生异常综合征中NF-κB信号通路的超激活及治疗策略

PITPNC1 was the last of the PITPs to be identified and has been characterized as a binding protein for phosphatidylinositol and phosphatidate. In mammals, PITPNC1 is expressed as two splice variants whilst in zebrafish is expressed from two separate genes. The two splice variants have different expression profiles with the long splice variant having a prominent role in the brain. Several physiological functions have been identified including neuronal and metabolic functions. PITPNC1 also plays a significant role in cancer and has been identified as a risk factor in type 2 diabetes. Here, we review our current understanding of PITPNC1 in cell physiology and pathology.

Shamshad Cockcroft

Expanding functions of the phosphatidylinositol/phosphatidate lipid transporter, PITPNC1 in physiology and in pathology

磷脂酰肌醇/磷脂酸脂质转运蛋白PITPNC1在生理与病理中的功能扩展

ISSN	2212-4926, 2212-4934
h-index	69

涉及主题	生物化学遗传学生物化学医学细胞生物学内科学信号转导基因物理有机化学核磁共振酶受体磷酸化癌症研究激酶免疫学癌症细胞凋亡
出版信息	出版商: Elsevier Ltd，出版周期: ，期刊类型: book-series，开源期刊: 否
基本数据	创刊年份: 2012，原创研究文献占比: 0.00%，自引率:N.A.， Gold OA占比: 0.00%

Advances in Biological Regulation

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Lamins and chromatin join forces

FRUCTOSE 1,6-BISPHOSPHATASE AS A PROMISING TARGET OF ANTICANCER TREATMENT

Abilities of berberine and chemically modified berberines to interact with metformin and inhibit proliferation of pancreatic cancer cells

Sphingosine Phosphate Lyase Insufficiency Syndrome As a Primary Immunodeficiency State

Hyperactivation of NF-κB signaling in splicing factor mutant myelodysplastic syndromes and therapeutic approaches

Lamins and chromatin join forces

Sphingosine Phosphate Lyase Insufficiency Syndrome As a Primary Immunodeficiency State

FRUCTOSE 1,6-BISPHOSPHATASE AS A PROMISING TARGET OF ANTICANCER TREATMENT

Hyperactivation of NF-κB signaling in splicing factor mutant myelodysplastic syndromes and therapeutic approaches

Expanding functions of the phosphatidylinositol/phosphatidate lipid transporter, PITPNC1 in physiology and in pathology