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Handlin, L., Novembre, G., Lindholm, H., Kämpe, R., Paul, E. & Morrison, I. (2023). Human endogenous oxytocin and its neural correlates show adaptive responses to social touch based on recent social context. eLIFE, 12, Article ID e81197.
Open this publication in new window or tab >>Human endogenous oxytocin and its neural correlates show adaptive responses to social touch based on recent social context
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2023 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 12, article id e81197Article in journal (Refereed) Published
Abstract [en]

Both oxytocin (OT) and touch are key mediators of social attachment. In rodents, tactile stimulation elicits endogenous release of OT, potentially facilitating attachment and other forms of prosocial behavior, yet the relationship between endogenous OT and neural modulation remains unexplored in humans. Using serial sampling of plasma hormone levels during functional neuroimaging across two successive social interactions, we show that contextual circumstances of social touch facilitate or inhibit not only current hormonal and brain responses, but also calibrate later responses. Namely, touch from a male to his female romantic partner enhanced subsequent OT release for touch from an unfamiliar stranger, yet OT responses to partner touch were dampened following stranger touch. Hypothalamus and dorsal raphe activation reflected plasma OT changes during the initial interaction. In thesubsequent social interaction, time- and context-dependent OT changes modulated precuneus and parietal-temporal cortex pathways, including a region of medial prefrontal cortex that also covaried with plasma cortisol. These findings demonstrate that hormonal neuromodulation during successive human social interactions is adaptive to social context, and point to mechanisms that flexibly calibrate receptivity in social encounters.

Place, publisher, year, edition, pages
eLife Sciences Publications Ltd, 2023
National Category
Neurosciences
Research subject
Translational Medicine TRIM
Identifiers
urn:nbn:se:his:diva-22515 (URN)10.7554/elife.81197 (DOI)001075012600001 ()37157840 (PubMedID)2-s2.0-85158161341 (Scopus ID)
Funder
Swedish Research Council, FYF-2013-687
Note

CC BY 4.0

For correspondence: india.morrison@liu.se

The authors thank Åsa Axén and Gisela Öhnström for blood sample collection, Kerstin Uvnäs-Moberg, Maria Petersson, Stephanie Preston, and Ellen Lumpkin for valuable discussion, and Paul Hamilton and Irene Perini for assistance with AFNI software. Funding: This study was supported by Distinguished Young Investigator grant FYF-2013–687 from the Swedish Research Council to IM.

Available from: 2023-05-10 Created: 2023-05-10 Last updated: 2023-11-06Bibliographically approved
Lindholm, H. (2023). Repurposing digitoxin in the treatment of pancreatic ductal adenocarcinoma: genotypic and phenotypic features as biomarkers for digitoxin sensitivity in vitro. (Doctoral dissertation). Jönköping: Jönköping University, School of Health and Welfare
Open this publication in new window or tab >>Repurposing digitoxin in the treatment of pancreatic ductal adenocarcinoma: genotypic and phenotypic features as biomarkers for digitoxin sensitivity in vitro
2023 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The incidence of pancreatic ductal adenocarcinoma (PDAC) is increasing worldwide. The dismal prognosis and lack of effective treatments urges for increased research efforts in developing new treatment regimens. Since the development of new cancer treatments are expensive and time consuming, repurposing drugs is preferable when possible. This strategy will also be of great value for people in low income countries, to increase the availability of effective cancer treatments to affordable costs. Digitoxin, a cardiac glycoside, has been shown to have anti-cancer effects. It binds to the α subunit of the Na+/K+-ATPase, leading to increased concentrations of intracellular calcium and eventually cell death. There seems also to be other mechanisms elicited in cancer cells by digitoxin. The α subunit occurs in three isoforms, of which α3 has the highest affinity to digitoxin and frequently found over-expressed in tumor cells compared to normal cells.

PDAC cancer cells, both cell lines and tumors, differ in their genotype and in the metabolic subtype, proliferation rate and inflammatory status. To be able to individualize treatment regimens it is important to be aware of the specific vulnerabilities (genotypic or phenotypic characteristics increasing the sensitivity to digitoxin) of each PDAC tumor/cell line. This research aims to investigate the potential of using digitoxin as an anti-cancer treatment in PDAC, and analyze its effects on cell viability, metabolism and inflammatory status in PDAC cell lines in vitro with the goal to find biomarkers for digitoxin sensitivity.

The analyses of the effects of digitoxin was performed in five cell lines derived from PDAC tumors, either from primary tumors or metastases. Cell lines derived from PDAC are sensitive to digitoxin treatment to different degrees. High expression of α3 seems to be indicative for digitoxin sensitivity, as do a high proliferation rate seen in cell lines derived from primary tumors. Both subunit expression and proliferation rate should be further evaluated in PDAC tumors to confirm their potential to be used as biomarkers clinically.

In the hunt for the working mechanism behind the anti-cancer effects of digitoxin, the choline pathway, a pathway commonly affected in tumors was enlightened in the metabolomics study, affected in all five cell lines tested. Choline metabolites are important for maintaining the cell membrane and are involved in energy metabolism using lipids. Digitoxin induced an up-regulation of choline and glycerophosphocholine, which rendered us to propose a novel theory about possible interactions between two functional complexes in the cell membrane, the Na+/K+-ATPase/EGFR/c-Src and the EGFR/c-Src – Chkα. The hypothesis is that when digitoxin binds to the Na+/K+-ATPase it leads to inactivation of Chkα with a subsequent decrease in the synthesis of phosphocholine and phosphatidylcholine. Since cancer cells rely on abundance of choline metabolites, we believe an inhibition of this pathway to be deleterious for these cells.

Finally, we conclude that digitoxin has great potential as an anti-cancer treatment for some patients with pancreatic ductal adenocarcinoma. To optimize treatment results, a thorough investigation of the tumor genotype and phenotype must be done for each patient. To further increase treatment success, combination of digitoxin with other treatments for synergistic effects could be beneficial. 

Place, publisher, year, edition, pages
Jönköping: Jönköping University, School of Health and Welfare, 2023. p. 107
Series
Dissertation Series. School of Health and Welfare, ISSN 1654-3602 ; 124
Keywords
pancreatic ductal adenocarcinoma, Na+/K+-ATPase, digitoxin, cardiac glycoside, metabolomics, choline
National Category
Clinical Laboratory Medicine Cancer and Oncology
Research subject
Translational Medicine TRIM
Identifiers
urn:nbn:se:his:diva-22470 (URN)978-91-88669-23-0 (ISBN)978-91-88669-24-7 (ISBN)
Public defence
2023-05-12, G110, University of Skövde, Skövde, 13:00 (Swedish)
Opponent
Supervisors
Note

"This thesis is based on research conducted at the University of Skövde during the enrollment as a PhD-student at the School of Health and Welfare at Jönköping University."

Två av fyra delarbeten (övriga se rubriken Delarbeten/List of papers):

Paper III

Lindholm H, Herring M, Faresjö M, Haux J, Szekeres F, Ejeskär K. Inflammasomes can be formed in pancreatic cancer cells, and NLRP3 inflammasome associated genes are up-regulated in primary pancreatic tumors. (Submitted)

Paper IV

Lindholm H, Ulfenborg B, Faresjö M, Haux J, Ejeskär K, Szekeres F. Digitoxin treatment affects choline metabolism in pancreatic cancer cells (Manuscript)

Available from: 2023-04-27 Created: 2023-04-27 Last updated: 2023-04-27Bibliographically approved
Lindholm, H., Ejeskär, K. & Szekeres, F. (2022). Digitoxin Affects Metabolism, ROS Production and Proliferation in Pancreatic Cancer Cells Differently Depending on the Cell Phenotype. International Journal of Molecular Sciences, 23(15), 1-14, Article ID 8237.
Open this publication in new window or tab >>Digitoxin Affects Metabolism, ROS Production and Proliferation in Pancreatic Cancer Cells Differently Depending on the Cell Phenotype
2022 (English)In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 23, no 15, p. 1-14, article id 8237Article in journal (Refereed) Published
Abstract [en]

Digitoxin has repeatedly shown to have negative effects on cancer cell viability; however, the actual mechanism is still unknown. In this study, we investigated the effects of digitoxin (1-100 nM) in four pancreatic cancer cell lines, BxPC-3, CFPAC-1, Panc-1, and AsPC-1. The cell lines differ in their KRAS/BRAF mutational status and primary tumor or metastasis origin. We could detect differences in the basal rates of cell proliferation, glycolysis, and ROS production, giving the cell lines different phenotypes. Digitoxin treatment induced apoptosis in all four cell lines, but to different degrees. Cells derived from primary tumors (Panc-1 and BxPC-3) were highly proliferating with a high proportion of cells in the S/G2 phase, and were more sensitive to digitoxin treatment than the cell lines derived from metastases (CFPAC-1 and AsPC-1), with a high proportion of cells in G0/G1. In addition, the effects of digitoxin on the rate of glycolysis, ROS production, and proliferation were dependent on the basal metabolism and origin of the cells. The KRAS downstream signaling pathways were not altered by digitoxin treatment, thus the effects exerted by digitoxin were probably disconnected from these signaling pathways. We conclude that digitoxin is a promising treatment in highly proliferating pancreatic tumors.

Place, publisher, year, edition, pages
MDPI, 2022
Keywords
pancreatic cancer, digitoxin, cardiac glycosides, PDAC, KRAS, metabolism, ROS, cell proliferation
National Category
Medical and Health Sciences Clinical Laboratory Medicine
Research subject
Translational Medicine TRIM
Identifiers
urn:nbn:se:his:diva-21727 (URN)10.3390/ijms23158237 (DOI)000839229300001 ()35897809 (PubMedID)2-s2.0-85137100614 (Scopus ID)
Note

CC BY 4.0

Correspondence: ferenc.szekeres@his.se

Funding: This research was funded by Assar Gabrielsson Foundation, grant FB19-80.

Available from: 2022-08-25 Created: 2022-08-25 Last updated: 2023-04-27Bibliographically approved
Lindholm, H., Ejeskär, K. & Szekeres, F. (2022). Na+/K+‑ATPase subunit α3 expression is associated with the efficacy of digitoxin treatment in pancreatic cancer cells. Medicine International, 2(5), Article ID 27.
Open this publication in new window or tab >>Na+/K+‑ATPase subunit α3 expression is associated with the efficacy of digitoxin treatment in pancreatic cancer cells
2022 (English)In: Medicine International, ISSN 2754-3242, Vol. 2, no 5, article id 27Article in journal (Refereed) Published
Abstract [en]

The alpha subunits (ATP1A1-3) of Na+/K+-ATPase binds digitoxin with varying affinity. The expression levels of these subunits dictate the anticancer effects of digitoxin. In the present study, three pancreatic cancer cell lines, AsPC-1, Panc-1 and CFPAC-1, were used to investigate the effects of digitoxin in relation to the expression of the subunits ATP1A1 and ATP1A3. Cell viability and intracellular calcium concentrations was measured in relation to the gene and protein expression of ATP1A1 and ATP1A3. Digitoxin was used to treat the cells at concentrations of 1-100 nM, and the intracellular calcium concentrations increased in a concentration-dependent manner in the Panc-1 and in the CFPAC-1 cells with treatment at 100 nM. In the AsPC-1 cells only the supraphysiological concentration of digitoxin (100 nM) resulted in a decrease in the number of viable cells (unviable cells increased to 22%), whereas it had no effect on intracellular calcium levels. The number of viable Panc-1 and CFPAC-1 cells decreased after digitoxin treatment at 25-100 nM (unviable Panc-1 cells increased to 33-59%; unviable CFPAC-1 cells increased to 22-56%). Digitoxin treatment also affected the transcriptional expression of the ATP1A1 and ATP1A3 subunits. In Panc-1 cells, ATP1A3 gene expression was negatively associated with the digitoxin concentration (25-100 nM). In the AsPC-1 and CFPAC-1 cells, the expression of the ATP1A1 gene increased in the cells treated with the 100 nM digitoxin concentration. The protein expression of ATP1A1 and ATP1A3 was not altered with digitoxin treatment. The basal protein expression of ATP1A1 was high in the AsPC-1 and CFPAC-1 cells, compared to the Panc-1 cells, in contrast to the basal expression of ATP1A3, which was higher in the Panc-1 cells, compared to the other pancreatic cancer cells used. On the whole, the present study demonstrates that the high expression of ATP1A3 renders pancreatic cancer cells more susceptible to digitoxin-induced cell death. The findings suggest that the expression of ATP1A3 may be used as a marker for tumor sensitivity to digitoxin treatment, where a high expression of ATP1A3 is favorable for the anticancer effects of digitoxin.

Place, publisher, year, edition, pages
Spandidos Publications, 2022
Keywords
Na+/K+-ATPase, Na+/K+-ATPase alpha subunits 1 and 3, calcium, digitoxin, pancreatic cancer
National Category
Clinical Laboratory Medicine Cell and Molecular Biology Cell Biology Cancer and Oncology
Research subject
Translational Medicine TRIM
Identifiers
urn:nbn:se:his:diva-22471 (URN)10.3892/mi.2022.52 (DOI)36698913 (PubMedID)
Note

CC BY-NC-ND 4.0

Correspondence to: Dr Ferenc Szekeres, Department of Biomedicine, Translational Medicine, School of Health Sciences, University of Skövde, Högskolevägen 1, 54145 Skövde, Sweden E‑mail: ferenc.szekeres@his.se

No funding was received.

Available from: 2023-04-19 Created: 2023-04-27 Last updated: 2023-07-14Bibliographically approved
Lindholm, H., Morrison, I., Krettek, A., Malm, D., Novembre, G. & Handlin, L. (2020). Genetic risk-factors for anxiety in healthy individuals: polymorphisms in gene simportant for the HPA axis. BMC Medical Genetics, 21, Article ID 184.
Open this publication in new window or tab >>Genetic risk-factors for anxiety in healthy individuals: polymorphisms in gene simportant for the HPA axis
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2020 (English)In: BMC Medical Genetics, E-ISSN 1471-2350, Vol. 21, article id 184Article in journal (Refereed) Published
Abstract [en]

Background

Two important aspects for the development of anxiety disorders are genetic predisposition and alterations in the hypothalamic-pituitary-adrenal (HPA) axis. In order to identify genetic risk-factors for anxiety, the aim of this exploratory study was to investigate possible relationships between genetic polymorphisms in genes important for the regulation and activity of the HPA axis and self-assessed anxiety in healthy individuals.

Methods

DNA from 72 healthy participants, 37 women and 35 men, were included in the analyses. Their DNA was extracted and analysed for the following Single Nucleotide Polymorphisms (SNP)s: rs41423247 in the NR3C1 gene, rs1360780 in the FKBP5 gene, rs53576 in the OXTR gene, 5-HTTLPR in SLC6A4 gene and rs6295 in the HTR1A gene. Self-assessed anxiety was measured by the State and Trait Anxiety Inventory (STAI) questionnaire.

Results

Self-assessed measure of both STAI-S and STAI-T were significantly higher in female than in male participants (p = 0.030 and p = 0.036, respectively). For SNP rs41423247 in the NR3C1 gene, there was a significant difference in females in the score for STAI-S, where carriers of the G allele had higher scores compared to the females that were homozygous for the C allele (p < 0.01). For the SNP rs53576 in the OXTR gene, there was a significant difference in males, where carriers of the A allele had higher scores in STAI-T compared to the males that were homozygous for the G allele (p < 0.01).

Conclusion

This study shows that SNP rs41423247 in the NR3C1 gene and SNP rs53576 in the OXTR gene are associated with self-assessed anxiety in healthy individuals in a gender-specific manner. This suggests that these SNP candidates are possible genetic risk-factors for anxiety.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2020
Keywords
Anxiety, Stress, HPA axis, Polymorphism, STAI
National Category
Medical and Health Sciences Psychiatry Medical Genetics Neurosciences
Research subject
Translational Medicine TRIM; Individual and Society VIDSOC
Identifiers
urn:nbn:se:his:diva-19078 (URN)10.1186/s12881-020-01123-w (DOI)000574511800002 ()32957930 (PubMedID)2-s2.0-85091472288 (Scopus ID)
Funder
Swedish Research CouncilUniversity of Skövde
Note

CC BY 4.0 [artikel], CC0 1.0 [data]

* Correspondence: linda.handlin@his.se

The study was supported by the Swedish Research Council and the School of Health Sciences, University of Skövde, Sweden. Open access funding provided by University of Skövde.

Available from: 2020-09-22 Created: 2020-09-22 Last updated: 2024-01-17Bibliographically approved
Sjöling, Å., Lindholm, H., Samuelson, E., Yamasaki, Y., Watanabe, T. K., Tanigami, A. & Levan, G. (2001). Analysis of chromosomal aberrations involving chromosome 1q31-->q53 in a DMBA-induced rat fibrosarcoma cell line: amplification and overexpression of Jak2. Cytogenetics and Cell Genetics, 95(3-4), 202-209
Open this publication in new window or tab >>Analysis of chromosomal aberrations involving chromosome 1q31-->q53 in a DMBA-induced rat fibrosarcoma cell line: amplification and overexpression of Jak2
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2001 (English)In: Cytogenetics and Cell Genetics, ISSN 0301-0171, E-ISSN 1421-9816, Vol. 95, no 3-4, p. 202-209Article in journal (Refereed) Published
Abstract [en]

In a study of DMBA-induced rat fibrosarcomas we repeatedly found deletions and/or amplifications in the long arm of rat chromosome 1 (RNO1). Comparative genome hybridization showed that there was amplification involving RNO1q31-->q53 in one of the DMBA-induced rat fibrosarcoma tumors (LB31) and a cell culture derived from it. To identify the amplified genes we physically mapped rat genes implicated in cancer and analyzed them for signs of amplification. The genes were selected based on their locations in comparative maps between rat and man. The rat proto-oncogenes Ccnd1, Fgf4, and Fgf3 (HSA11q13.3), were mapped to RNO1q43 by fluorescence in situ hybridization (FISH). The Ems1 gene was mapped by radiation hybrid (RH) mapping to the same rat chromosome region and shown to be situated centromeric to Ccnd1 and Fgf4. In addition, the proto-oncogenes Hras (HSA11p15.5) and Igf1r (HSA15q25-->q26) were mapped to RNO1q43 and RNO1q32 by FISH and Omp (HSA11q13.5) was assigned to RNO1q34. PCR probes for the above genes together with PCR probes for the previously mapped rat genes Bax (RNO1q31) and Jak2 (RNO1q51-->q53) were analyzed for signs of amplification by Southern blot hybridization. Low copy number increases of the Omp and Jak2 genes were detected in the LB31 cell culture. Dual color FISH analysis of tumor cells confirmed that chromosome regions containing Omp and Jak2 were amplified and were situated in long marker chromosomes showing an aberrant banding pattern. The configuration of the signals in the marker chromosomes suggested that they had arisen by a break-fusion-bridge (BFB) mechanism.

Place, publisher, year, edition, pages
S. Karger, 2001
National Category
Medical Genetics
Identifiers
urn:nbn:se:his:diva-22163 (URN)10.1159/000059347 (DOI)000176408300014 ()12063401 (PubMedID)2-s2.0-0036281577 (Scopus ID)
Available from: 2022-12-28 Created: 2022-12-28 Last updated: 2022-12-28Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-2462-0178

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