Effects of in vitro short- and long-term treatment with telomerase inhibitor in U-251 glioma cells

BACKGROUND: The inhibition of the enzyme telomerase (TERT) has been widely investigated as a new pharmacological approach for cancer treatment, but its real potential and the biochemical consequences are not totally understood. OBJECTIVE: Here, we investigated the effects of the telomerase inhibitor MST-312 on a human glioma cell line after both short- and long-term (290 days) treatments. METHODS: Effects on cell growth, viability, cell cycle, morphology, cell death and genes expression were assessed. RESULTS: We found that short-term treatment promoted cell cycle arrest followed by apoptosis. Importantly, cells with telomerase knock-down revealed that the toxic effects of MST-312 are partially TERT dependent. In contrast, although the long-term treatment decreased cell proliferation at first, it also caused adaptations potentially related to treatment resistance and tumor aggressiveness after long time of exposition. CONCLUSIONS: Despite the short-term effects of telomerase inhibition not being due to telomere erosion, they are at least partially related to the enzyme inhibition, which may represent an important strategy to pave the way for tumor growth control, especially through modulation of the non-canonical functions of telomerase. On the other hand, long-term exposure to the inhibitor had the potential to induce cell adaptations with possible negative clinical implications.

Download Full-text

Mitochondrial and Oxidative Impacts of Short and Long-term Administration of HAART on HIV Patients

Current Clinical Pharmacology ◽

10.2174/1574884714666190905162237 ◽

2020 ◽

Vol 15 (2) ◽

pp. 110-124

Author(s):

Joy E. Ikekpeazu ◽

Oliver C. Orji ◽

Ikenna K. Uchendu ◽

Lawrence U.S. Ezeanyika

Keyword(s):

Treatment Group ◽

Term Treatment ◽

Short Term ◽

Short Term Treatment ◽

Hiv Patients ◽

Long Term Treatment ◽

Term Administration ◽

Short And Long Term ◽

One Year

Background and Objective: There may be a possible link between the use of HAART and oxidative stress-related mitochondrial dysfunction in HIV patients. We evaluated the mitochondrial and oxidative impacts of short and long-term administration of HAART on HIV patients attending the Enugu State University Teaching (ESUT) Hospital, Enugu, Nigeria following short and long-term therapy. Methods: 96 patients categorized into four groups of 24 individuals were recruited for the study. Group 1 comprised of age-matched, apparently healthy, sero-negative individuals (the No HIV group); group 2 consisted of HIV sero-positive individuals who had not started any form of treatment (the Treatment naïve group). Individuals in group 3 were known HIV patients on HAART for less than one year (Short-term treatment group), while group 4 comprised of HIV patients on HAART for more than one year (Long-term treatment group). All patients were aged between 18 to 60 years and attended the HIV clinic at the time of the study. Determination of total antioxidant status (TAS in nmol/l), malondialdehyde (MDA in mmol/l), CD4+ count in cells/μl, and genomic studies were all done using standard operative procedures. Results: We found that the long-term treatment group had significantly raised the levels of MDA, as well as significantly diminished TAS compared to the Short-term treatment and No HIV groups (P<0.05). In addition, there was significantly elevated variation in the copy number of mitochondrial genes (mtDNA: D-loop, ATPase 8, TRNALEU uur) in the long-term treatment group. Interpretation and Conclusion: Long-term treatment with HAART increases oxidative stress and causes mitochondrial alterations in HIV patients.

Download Full-text

Long-term treatment with valganciclovir improves lentiviral suicide gene therapy of glioblastoma

Neuro-Oncology ◽

10.1093/neuonc/noz060 ◽

2019 ◽

Vol 21 (7) ◽

pp. 890-900 ◽

Cited By ~ 4

Author(s):

Jubayer A Hossain ◽

Md A Latif ◽

Lars A R Ystaas ◽

Sandra Ninzima ◽

Kristoffer Riecken ◽

...

Keyword(s):

Gene Therapy ◽

Tumor Cells ◽

Suicide Gene ◽

Term Treatment ◽

Suicide Gene Therapy ◽

Short Term ◽

Short Term Treatment ◽

Long Term Treatment

Abstract Background Suicide gene therapy for malignant gliomas has shown encouraging results in the latest clinical trials. However, prodrug application was most often restricted to short-term treatment (14 days), especially when replication-defective vectors were used. We previously showed that a substantial fraction of herpes simplex virus thymidine kinase (HSV-TK) transduced tumor cells survive ganciclovir (GCV) treatment in an orthotopic glioblastoma (GBM) xenograft model. Here we analyzed whether these TK+ tumor cells are still sensitive to prodrug treatment and whether prolonged prodrug treatment can enhance treatment efficacy. Methods Glioma cells positive for TK and green fluorescent protein (GFP) were sorted from xenograft tumors recurring after suicide gene therapy, and their sensitivity to GCV was tested in vitro. GBM xenografts were treated with HSV-TK/GCV, HSV-TK/valganciclovir (valGCV), or HSV-TK/valGCV + erlotinib. Tumor growth was analyzed by MRI, and survival as well as morphological and molecular changes were assessed. Results TK-GFP+ tumor cells from recurrent xenograft tumors retained sensitivity to GCV in vitro. Importantly, a prolonged period (3 mo) of prodrug administration with valganciclovir (valGCV) resulted in a significant survival advantage compared with short-term (3 wk) application of GCV. Recurrent tumors from the treatment groups were more invasive and less angiogenic compared with primary tumors and showed significant upregulation of epidermal growth factor receptor (EGFR) expression. However, double treatment with the EGFR inhibitor erlotinib did not increase therapeutic efficacy. Conclusion Long-term treatment with valGCV should be considered as a replacement for short-term treatment with GCV in clinical trials of HSV-TK mediated suicide gene therapy.

Download Full-text

A retrospective, observational, single center study of gonadotropin-releasing hormone agonist protocols at the Reproductive Center of Farah Hospital in Jordan

International Journal of Research in Medical Sciences ◽

10.18203/2320-6012.ijrms20193402 ◽

2019 ◽

Vol 7 (8) ◽

pp. 3103

Author(s):

Zaid Kilani ◽

Mohammad Shaban

Keyword(s):

Term Treatment ◽

Gonadotropin Releasing Hormone ◽

Clinical Pregnancy ◽

Short Term ◽

Short Term Treatment ◽

Releasing Hormone ◽

Long Term Treatment ◽

Group A

Background: Data on infertility and in vitro fertilization (IVF) are incomplete and uncertain in Jordan and worldwide because of difficulties in evaluating infertility in the general population. This study aimed at comparing the effectiveness of the gonadotropin-releasing hormone agonists (GnRH-a) long and short protocols as part of IVF or intracytoplasmic sperm injection.Methods: This observational, retrospective, comparative, longitudinal study was conducted in a reproductive center in Jordan. It reviewed data charts from women who took GnRH-a for IVF, from 2010 to 2013. These were categorized in Group A (long-term GnRH-a: single 3.75 mg-monthly injection) or Group B (short-term GnRH-a: multiple daily 0.1 mg injections). The primary endpoint was the rate of ongoing clinical pregnancy (number of pregnancies/number of women) and live birth rate in fresh cycle/protocols.Results: Out of 1,946 eligible women, 471 underwent the long-term treatment of GnRH-a administration and 1,523 the short-term treatment. The women’s mean age was 29.61±3.80 years old. Out of the 471 women in Group A, 216 (45.9%) women had ongoing clinical pregnancy, of whom 69 (31.9%) had live births. In the short-protocol group, 485 (31.8%) women had ongoing clinical pregnancy, of whom 133 (27.4%) had live births.Conclusions: GnRH-a long protocol is more effective than the short protocol regardless of the agonist formulation used in subfertile women/men who underwent IVF/ intracytoplasmic sperm injection.

Download Full-text

Fluvoxamine in the Treatment of Trichotillomania: An 8-Week, Open-Label Study

CNS Spectrums ◽

10.1017/s1092852900006520 ◽

1998 ◽

Vol 3 (9) ◽

pp. 64-71 ◽

Cited By ~ 4

Author(s):

Gary A. Christenson ◽

Scott J. Crow ◽

James E. Mitchell ◽

Thomas B. Mackenzie ◽

Ross D. Crosby ◽

...

Keyword(s):

Treatment Response ◽

Term Treatment ◽

Hair Pulling ◽

Short Term ◽

Open Label ◽

Short Term Treatment ◽

Open Label Study ◽

Label Study ◽

Long Term Treatment

AbstractThis short-term, open-label study investigates short- and long-term effects of the selective serotonin reuptake inhibitor (SSRI) fluvoxamine for the treatment of trichotillomania (TTM). Additionally, this study aimed to test the hypothesis that the presence of hair pulling compulsiveness is predictive of SSRI response. Nineteen subjects meeting the Diagnostic and Statistical Manual of Mental Disorders, Third Edition Revised, (DSM-III-R) criteria for TTM were treated with fluvoxamine at doses up to 300 mg/day. Random regression analysis of change across time for patients who completed the study (n=14) and those who dropped out (n=5) revealed statistically significant improvements in Physician Rating Scale, hair-pulling episodes, Trichotillomania Impairment Scale, and Trichotillomania Symptom Severity Scale, but not in estimated amount of hair pulled. In addition, the percentage of patients' focused or compulsive hair-pulling symptoms was predictive of treatment response. Unfortunately, all three subjects who entered long-term treatment displayed substantial movement back toward baseline by the end of 6 months. We concluded that fluvoxamine produces moderate reductions in symptoms during the short-term treatment of TTM and that the presence of focused or compulsive hair pulling may be predictive of treatment response. However, responses may be short lived when treatment is extended.

Download Full-text

Protein Metabolism in Acromegaly: Differential Effects of Short- and Long-Term Treatment

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2006-0664 ◽

2007 ◽

Vol 92 (4) ◽

pp. 1479-1484 ◽

Cited By ~ 17

Author(s):

James Gibney ◽

Troels Wolthers ◽

Morton G. Burt ◽

Kin-Chuen Leung ◽

A. Margot Umpleby ◽

...

Keyword(s):

Protein Oxidation ◽

Protein Metabolism ◽

Normal Subjects ◽

Term Treatment ◽

Protein Breakdown ◽

Short Term ◽

Leucine Oxidation ◽

Long Term Treatment ◽

Short And Long Term

Abstract Context: GH acutely increases body protein by stimulating protein synthesis and reducing protein oxidation. Objective: The objective of the study was to determine whether these changes in protein metabolism are sustained in long-term GH excess and reversed by correction. Design: We conducted a cross-sectional study in 16 acromegalic and 18 normal subjects and a longitudinal study in which acromegalic subjects were studied before and after short-term (n = 8) or long-term (n = 10) treatment. Setting: The study was conducted at a clinical research center. Main Outcome Measures: Whole-body rates of leucine appearance (leucine Ra; an index of protein breakdown), leucine oxidation, and nonoxidative leucine disposal (NOLD; an index of protein synthesis) estimated using infusion of 1-[13C] leucine were measured. Results: Leucine Ra and NOLD were greater (P < 0.01) in acromegalic compared with normal subjects, whereas leucine oxidation did not differ. Leucine oxidation increased significantly (P < 0.05) after short-term treatment but returned to baseline after long-term treatment. Both leucine Ra and NOLD decreased significantly (P < 0.05) after short- and long-term treatment. Adjustment for body composition did not affect results. Conclusions: In acromegalic subjects, protein breakdown and synthesis are increased, whereas protein oxidation does not differ from normal subjects. Protein oxidation increases transiently, whereas protein breakdown and synthesis are stably reduced after treatment. Because protein oxidation represents irreversible loss, we conclude that the normal state of protein oxidation found in acromegaly and after long-term treatment represents metabolic adaptation, which maintains protein mass at a steady state after stable changes in GH status.

Download Full-text

Direct upregulation of parathyroid calcium-sensing receptor and vitamin D receptor by calcimimetics in uremic rats

AJP Renal Physiology ◽

10.1152/ajprenal.90272.2008 ◽

2009 ◽

Vol 296 (3) ◽

pp. F605-F613 ◽

Cited By ~ 41

Author(s):

Francisco J. Mendoza ◽

Ignacio Lopez ◽

Rocio Canalejo ◽

Yolanda Almaden ◽

David Martin ◽

...

Keyword(s):

Cell Proliferation ◽

Term Treatment ◽

Parathyroid Cell ◽

Calcium Sensing Receptor ◽

Short Term ◽

Calcium Sensing ◽

Long Term Treatment ◽

Acute Increase

To investigate whether the effect of the calcimimetic AMG 641 and calcitriol on CaSR and VDR expression could be separated from their ability to reduce parathyroid cell proliferation, five-sixth nephrectomized (5/6 Nx) rats received vehicle, AMG 641, calcitriol, or AMG 641+calcitriol either daily for 13 days (long-term protocol) or in a single dose (short-term protocol). In the long-term protocol, AMG 641, calcitriol, and their combination significantly reduced the percentage of proliferating parathyroid cells. Proliferation was uncontrolled in the short-term protocol. A significant increase in CaSR mRNA (% vs. β-actin) was detected in rats treated with both calcitriol (1.60 ± 0.30) and AMG 641 (1.66 ± 0.25) for 13 days ( P = 0.01 vs. 5/6 Nx+vehicle, 0.89 ± 0.09); and there was a further increase when both drugs were administered simultaneously (2.46 ± 0.33). In the short-term protocol, only rats receiving AMG 641 alone (2.01 ± 0.33, P < 0.001) showed increased expression of CaSR mRNA, whereas the combination (1.81 ± 0.20) produced no additional benefit. AMG 641 also increased CaSR mRNA expression in vitro. Changes in VDR mRNA paralleled those of CaSR mRNA. In the long-term treatment, both AMG 641 (0.87 ± 0.14) and calcitriol (0.99 ± 0.12) increased VDR mRNA ( P < 0.05 vs. 5/6 Nx+vehicle, 0.49 ± 0.10), and the increase was more accentuated when the drugs were combined (1.49 ± 0.45). In the short-term protocol, only treatment with AMG 641, alone (1.52 ± 0.41) or combined with calcitriol (1.86 ± 0.24), increased VDR mRNA. In conclusion, our results demonstrate an acute increase in CaSR mRNA and VDR mRNA in the parathyroid glands of uremic rats treated with AMG 641, in which cell proliferation was uncontrolled, thus supporting a direct effect of calcimimetics on CaSR and VDR expression by hyperplastic parathyroid cells.

Download Full-text

Brushing Influences Transplant Growth and Subsequent Yield of Four Cultivars of Tomato and Their Hybrid Lines

Journal of the American Society for Horticultural Science ◽

10.21273/jashs.117.3.384 ◽

1992 ◽

Vol 117 (3) ◽

pp. 384-388 ◽

Cited By ~ 11

Author(s):

Tomio Johjima ◽

Joyce G. Latimer ◽

Hiroshi Wakita

Keyword(s):

Mechanical Stress ◽

Stem Elongation ◽

Total Yield ◽

Term Treatment ◽

Short Term ◽

Short Term Treatment ◽

Long Term Treatment ◽

Growth Habits ◽

Hybrid Lines

Pot-grown seedlings of seven lines [`Red Cherry' (RC), `Moneymaker' (MM), `Dantobi-yohzu' (DY), `Furikoma' (FK), RC × FK, MM × DY, and MM × FK] of tomato (Lycopersicon esculentum Mill.) were brushed with a suspended steel bar for 1.5 minutes twice daily for 18 days (short-term treatment) before being transplanted to beds in a plastic greenhouse. Brushing was continued on a selected group of plants for an additional 10 days (long-term treatment). Short-term brushing slightly reduced the number of leaves, but markedly reduced leaf size and stem elongation of all lines. Dry weights of lamina, petioles, and stems of brushed plants of each cultivar except FK were less than those of the respective controls. However, the ratios of root: shoot dry weight of brushed plants were unchanged or higher than those of the respective controls. Short-term brushing did not increase the total number or weight of tomato fruits harvested over 1 month and did not improve fruit quality, size, or color. Long-term brushing reduced the total yield (number and weight) of fruits of RC and total fruit weight of DY. With respect to sensitivity to mechanical stress, cultivars with taller growth habits were more responsive to brushing than were those with shorter growth habits. These characteristic responses to mechanical stress also were exhibited by the hybrid lines.

Download Full-text

Construction of effective induction of immune tolerance to rheumatoid arthritis using fingolimod

Impact ◽

10.21820/23987073.2021.5.51 ◽

2021 ◽

Vol 2021 (5) ◽

pp. 51-53

Author(s):

Yuya Yoshida

Keyword(s):

Rheumatoid Arthritis ◽

Autoimmune Diseases ◽

Immune Tolerance ◽

Term Treatment ◽

The Body ◽

Short Term ◽

Short Term Treatment ◽

Long Term Treatment ◽

New Treatments

Autoimmune diseases occur when the body begins to attack normal cells instead of fighting off diseases and infections. There are ways of treating autoimmune diseases, but these provide only short-term relief, and there is no cure. Therefore, relapse tends to be an inevitable part of autoimmune diseases. Dr Yuya Yoshida is a specialist in immunology based in the Department of Pathological Biochemistry, Faculty of Pharmaceutical Sciences, Setsunan University, Japan, who is investigating the possibility of inducing immune tolerance and, in doing so, eliminating the need for long-term treatment. He and his team are working to devise a treatment strategy that enables complete short-term treatment and can then maintain long-term remission without the need for drug treatment. The ultimate goal for the team is a breakthrough in the treatment of autoimmune diseases, which would have far-reaching benefits for patients and the field of medicine. A key focus for Yoshida and his team is how an immunomodulating medication called fingolimod (FTY720) could be used to induce immune tolerance and, in doing so, stop the cycle of remission and relapse. There is potential for FTY720 to be used to develop new treatments and eliminate the need for patients to rely on long-term treatment. In particular, the researchers are focusing on multiple sclerosis and rheumatoid arthritis. One investigation involves the use of animal models to explore the construction of effective induction of immune tolerance to rheumatoid arthritis using FTY720.

Download Full-text

Stable Colonization of Orally Administered Lactobacillus casei SY13 Alters the Gut Microbiota

BioMed Research International ◽

10.1155/2020/5281639 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8 ◽

Cited By ~ 3

Author(s):

Yuanchun Yue ◽

Xiaoxi Xu ◽

Baoyu Yang ◽

Jing Lu ◽

Shuwen Zhang ◽

...

Keyword(s):

Gut Microbiota ◽

Oral Administration ◽

Lactobacillus Casei ◽

Illumina Miseq ◽

Term Treatment ◽

Short Term ◽

Short Term Treatment ◽

Long Term Treatment ◽

Colonization Ability

The gut microbiota plays an important role in intestinal health. Probiotics such as Lactobacillus are known to regulate gut microbes and prevent diseases. However, most of them are unable to colonize their stability in hosts’ intestinal tracts. In this study, we investigated the ability of Lactobacillus casei SY13 (SY13) to colonize the intestinal tract of BALB/c mice, after its oral administration for a short-term (once for a day) and long-term (once daily for 27 days) duration. Furthermore, we also evaluated the influence of its administration on the gut microbial structure and diversity in mice. Male BALB/c mice were gavaged with 108 colony-forming units (CFU) of SY13, and TaqMan-MGB probe and Illumina MiSeq sequencing were performed to assess the colonization ability and bacterial community structure in the cecum contents. The results showed that long-term treatment with SY13 enhanced its ability to form a colony in the intestine tract in contrast to the short-term treatment group, whose colony was retained for only 3 days. Oral administration of SY13 also significantly enhanced the gut microbial diversity. Short-term treatment with SY13 (SSY13) elevated Firmicutes and diminished Bacteroidetes phyla compared with long-term treatment (LSY13) and controls. The findings laid the foundation for the study of probiotic colonization ability and improvement of microbiota for the prevention of gut diseases.

Download Full-text