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Author

Anna Kirstein

Bio: Anna Kirstein is an academic researcher from Leipzig University. The author has contributed to research in topics: PTEN & Medicine. The author has an hindex of 2, co-authored 10 publications receiving 16 citations.
Topics: PTEN, Medicine, Adipogenesis, Tensin, Biology

Papers
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Journal ArticleDOI
29 Sep 2021
TL;DR: In this paper, the authors reviewed the pathophysiology and pharmacotherapy of obesity including intersection points to the new generation of antidiabetic drugs and provided insight into the effectiveness of currently approved anti-obesity drugs and other therapeutic avenues that can be explored.
Abstract: Obesity represents a major public health problem with a prevalence increasing at an alarming rate worldwide. Continuous intensive efforts to elucidate the complex pathophysiology and improve clinical management have led to a better understanding of biomolecules like gut hormones, antagonists of orexigenic signals, stimulants of fat utilization, and/or inhibitors of fat absorption. In this article, we will review the pathophysiology and pharmacotherapy of obesity including intersection points to the new generation of antidiabetic drugs. We provide insight into the effectiveness of currently approved anti-obesity drugs and other therapeutic avenues that can be explored.

21 citations

Journal ArticleDOI
17 Oct 2019-Cancers
TL;DR: Since alpelisib was well tolerated in first clinical trials, this drug alone or in combination with rapamycin is a potential new treatment option for PHTS-related adipose tissue overgrowth.
Abstract: Germline mutations in the tumor suppressor gene PTEN cause PTEN Hamartoma Tumor Syndrome (PHTS). Pediatric patients with PHTS frequently develop lipomas. Treatment attempts with the mTORC1 inhibitor rapamycin were unable to reverse lipoma growth. Recently, lipomas associated with PIK3CA-related overgrowth syndrome were successfully treated with the novel PI3K inhibitor alpelisib. Here, we tested whether alpelisib has growth-restrictive effects and induces cell death in lipoma cells. We used PTEN-haploinsufficient lipoma cells from three patients and treated them with alpelisib alone or in combination with rapamycin. We tested the effect of alpelisib on viability, proliferation, cell death, induction of senescence, adipocyte differentiation, and signaling at 1–100 µM alpelisib. Alpelisib alone or in combination with rapamycin reduced proliferation in a concentration- and time-dependent manner. No cell death but an induction of senescence was detected after alpelisib incubation for 72 h. Alpelisib treatment led to a reduced phosphorylation of AKT, mTOR, and ribosomal protein S6. Rapamycin treatment alone led to increased AKT phosphorylation. This effect could be reversed by combining rapamycin with alpelisib. Alpelisib reduced the size of lipoma spheroids by attenuating adipocyte differentiation. Since alpelisib was well tolerated in first clinical trials, this drug alone or in combination with rapamycin is a potential new treatment option for PHTS-related adipose tissue overgrowth.

15 citations

Journal ArticleDOI
24 Jun 2020
TL;DR: It was found that both cellular life span and the capacity for adipocyte differentiation as well as adipocyte-specific functions were preserved in LipPD1 and comparable to SGBS adipocytes.
Abstract: Few human cell strains are suitable and readily available as in vitro adipocyte models We used resected lipoma tissue from a patient with germline phosphatase and tensin homolog (PTEN) haploinsuff

8 citations

Journal ArticleDOI
TL;DR: In this article, the role of PTEN in adipose tissue development was investigated and RNA-Seq of control and PTEN knockdown APCs was performed. And the results provided evidence that PTEN is involved in the regulation of APC proliferation, differentiation, and senescence.

7 citations

Posted ContentDOI
28 May 2021-bioRxiv
TL;DR: In this article, the role of PTEN in adipose tissue development was investigated and RNA sequencing of control and PTEN knockdown APCs was performed and it was shown that reducing PTEN levels using siRNA or CRISPR leads to an enhanced proliferation and differentiation of APCs.
Abstract: The tumor suppressor phosphatase and tensin homolog (PTEN) negatively regulates the insulin signaling pathway. Germline PTEN pathogenic variants cause PTEN Hamartoma Tumor Syndrome (PHTS), associated with lipoma development in children. It remains unclear which mechanisms trigger this aberrant adipose tissue growth. Adipocyte progenitor cells (APCs) lose their capacity to differentiate into adipocytes during continuous culture, while APCs from PHTS patients’ lipomas retain their adipogenic potential over a prolonged period. To investigate the role of PTEN in adipose tissue development we performed functional assays and RNA sequencing of control and PTEN knockdown APCs. Reduction of PTEN levels using siRNA or CRISPR lead to an enhanced proliferation and differentiation of APCs. FOXO1 was downregulated on the mRNA level while inactivation through phosphorylation increased. FOXO1 phosphorylation initiates the expression of the lipogenesis activating transcription factor SREBP1. SREBP1 levels were higher after PTEN knockdown and may account for the enhanced adipogenesis. To validate this we overexpressed constitutively active FOXO1 in PTEN CRISPR cells and found reduced adipogenesis, accompanied by a SREBP1 downregulation. We observed that PTEN levels were upregulated during long term culture of wild type APCs. PTEN CRISPR cells showed less senescence compared to controls and the senescence marker CDKN1A (p21) was downregulated in PTEN knockdown cells. Cellular senescence was the most significantly enriched pathway found in RNA sequencing of PTEN knockdown vs. control cells. These results provide evidence that PTEN is involved in the regulation of APCs proliferation, differentiation and senescence, thereby contributing to aberrant adipose tissue growth in PHTS patients.

1 citations


Cited by
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Journal ArticleDOI
TL;DR: This review article profiles 13 new tailor-made AA-derived pharmaceuticals introduced to the market in 2019, and discusses the development form drug-candidates, total synthesis, with emphasis on the core-AA, therapeutic area, and the mode of biological activity.
Abstract: Amino acids (AAs) are among a handful of paramount classes of compounds innately involved in the origin and evolution of all known life-forms. Along with basic scientific explorations, the major goal of medicinal chemistry research in the area of tailor-made AAs is the development of more selective and potent pharmaceuticals. The growing acceptance of peptides and peptidomimetics as drugs clearly indicates that AA-based molecules become the most successful structural motif in the modern drug design. In fact, among 24 small-molecule drugs approved by FDA in 2019, 13 of them contain a residue of AA or di-amines or amino-alcohols, which are commonly considered to be derived from the parent AAs. In the present review article, we profile 13 new tailor-made AA-derived pharmaceuticals introduced to the market in 2019. Where it is possible, we will discuss the development form drug-candidates, total synthesis, with emphasis on the core-AA, therapeutic area, and the mode of biological activity.

21 citations

Journal ArticleDOI
29 Sep 2021
TL;DR: In this paper, the authors reviewed the pathophysiology and pharmacotherapy of obesity including intersection points to the new generation of antidiabetic drugs and provided insight into the effectiveness of currently approved anti-obesity drugs and other therapeutic avenues that can be explored.
Abstract: Obesity represents a major public health problem with a prevalence increasing at an alarming rate worldwide. Continuous intensive efforts to elucidate the complex pathophysiology and improve clinical management have led to a better understanding of biomolecules like gut hormones, antagonists of orexigenic signals, stimulants of fat utilization, and/or inhibitors of fat absorption. In this article, we will review the pathophysiology and pharmacotherapy of obesity including intersection points to the new generation of antidiabetic drugs. We provide insight into the effectiveness of currently approved anti-obesity drugs and other therapeutic avenues that can be explored.

21 citations

Journal ArticleDOI
TL;DR: PTEN is proposed as the likely gene as it has functions that span metabolism, cancer and reproduction, all of which are deranged in obesity and insulin resistance and is tuned like a metabolic rheostat proportional to the availability of specific nutrients.
Abstract: The modern obesity epidemic with associated disorders of metabolism and cancer has been attributed to the presence of "thrifty genes". In the distant past, these genes helped the organism to improve energy efficiency and store excess energy safely as fat to survive periods of famine, but in the present day obesogenic environment, have turned detrimental. I propose PTEN as the likely gene as it has functions that span metabolism, cancer and reproduction, all of which are deranged in obesity and insulin resistance. The activity of PTEN can be calibrated in utero by availability of nutrients by the methylation arm of the epigenetic pathway. Deficiency of protein and choline has been shown to upregulate DNA methyltransferases (DNMT), especially 1 and 3a; these can then methylate promoter region of PTEN and suppress its expression. Thus, the gene is tuned like a metabolic rheostat proportional to the availability of specific nutrients, and the resultant "dose" of the protein, which sits astride and negatively regulates the insulin-PI3K/AKT/mTOR pathway, decides energy usage and proliferation. This "fixes" the metabolic capacity of the organism periconceptionally to a specific postnatal level of nutrition, but when faced with a discordant environment, leads to obesity related diseases.

16 citations

Journal ArticleDOI
24 Jun 2020
TL;DR: It was found that both cellular life span and the capacity for adipocyte differentiation as well as adipocyte-specific functions were preserved in LipPD1 and comparable to SGBS adipocytes.
Abstract: Few human cell strains are suitable and readily available as in vitro adipocyte models We used resected lipoma tissue from a patient with germline phosphatase and tensin homolog (PTEN) haploinsuff

8 citations

Journal ArticleDOI
TL;DR: In this article, the role of PTEN in adipose tissue development was investigated and RNA-Seq of control and PTEN knockdown APCs was performed. And the results provided evidence that PTEN is involved in the regulation of APC proliferation, differentiation, and senescence.

7 citations