The effect of lavender on mood disorders associated with the use of combined oral contraceptives (COCs): a triple-blinded randomized controlled trial.

BACKGROUND: The use of contraceptive methods is influenced by their effectiveness, availability, and minimal side effects. OCPs are one of the most effective and widely used methods of pregnancy prevention worldwide. This method not only prevents pregnancy but also helps prevent and treat other diseases. One of the main reasons for discontinuing this method is the emotional disturbances associated with its use. Lavender is an evergreen, fragrant plant that has gained significant attention for its anti-anxiety effects. This study was conducted to investigate the effect of lavender essential oil capsules on mood disorders during the use of COCs. METHODS: This triple-blinded clinical trial was conducted on 60 married women (aged 15-49 years old) who were consumers of COCs, referring to 26 health centers in Tabriz, Iran. The participants were randomly assigned to either the intervention (consuming one gelatin capsule containing 80 mg LEO daily) or control (consuming one placebo capsule daily) group. The intervention continued for 56 days. Scores for positive and negative were determined using the Positive and Negative Affect Schedule (PANAS) questionnaire; and for stress, depression, and anxiety were measured using the DASS-21 questionnaire on day's 28th and 56th post-intervention. Data analysis was conducted using the t-test and ANOVA with repeated measures, and a p-value of < 0.05 was considered significant for all analyses. RESULTS: A statistically significant difference was observed in mood disorders, stress, and depression between women receiving LEO or placebo. The consumption of LEO increased the positive mood on day 28 [MD (95% CI): 4.5 (2.1 to 7.0), p = 0.001] and day 56 [5.9 (3.4 to 8.3), p < 0.001] while decreased the negative mood on day 28 [MD (95% CI): -3.5 (-5.3 to -1.3), p < 0.001] and day 56 [-4.3 (-6.3 to -2.2), p < 0.001], stress on day 28 [MD (95% CI): -4.9 (-7.1 to -2.8), p = 0.001] and day 56 [-5.3 (-7.6 to -3.1), p < 0. 001], and depression on day 28 [MD (95% CI): -3.0 (-4.9 to 1.1), p = 0.003] and day 56 [-3.1 (-5.0 to 1.2), p = 0.002]. There was no statistically significant difference between the two groups in terms of anxiety. CONCLUSIONS: The consumption of LEO with COCs improved mood disorders and reduced stress and depression. The use of hormonal contraceptives and mood changes should be considered by providers. Therefore, regarding the possibility of mood changes, it is expected that appropriate counseling and education will be provided to women who consume COC., providing appropriate solutions, including the simultaneous use of LEO.

Programmed cell death 4: A novel player in the pathogenesis of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a pathological condition recognized by menstrual cycle irregularities, androgen excess, and polycystic ovarian morphology, affecting a significant proportion of women of childbearing age and accounting for the most prevalent cause of anovulatory sterility. In addition, PCOS is frequently accompanied by metabolic and endocrine disturbances such as obesity, dyslipidemia, insulin resistance, and hyperinsulinemia, indicating the multiplicity of mechanisms implicated in the progression of PCOS. However, the exact pathogenesis of PCOS is yet to be elucidated. Programmed cell death 4 (PDCD4) is a ubiquitously expressed protein that contributes to the regulation of various cellular processes, including gene expression, cell cycle progression, proliferation, and apoptosis. Despite some disparities concerning its exact cellular effects, PDCD4 is generally characterized as a protein that inhibits cell cycle progression and proliferation and instead drives the cell into apoptosis. The apoptosis of granulosa cells (GCs) is speculated to take a major part in the occurrence and progression of PCOS by ceasing antral follicle development and compromising oocyte competence. Given the possible involvement of GC apoptosis in the progression of PCOS, as well as the contribution of PDCD4 to the regulation of cell apoptosis and the development of metabolic diseases, the current review aimed to discuss whether or how PDCD4 can play a role in the pathogenesis of PCOS by affecting GC apoptosis.

A treatment approach of severe vulvar edema in ovarian hyperstimulation syndrome patient: A case report.

Background: Ovarian hyperstimulation syndrome (OHSS) is a serious life-threatening complication of infertility treatment. Vulvar edema is a disease with various causes and frequent phenomena seen in physiological and pathologic conditions like pregnancy, inflammatory disorders, tumors, idiopathic reasons, and most importantly, in the severe form of OHSS. Case Presentation: Here, we report a 26-yr-old woman with severe OHSS, recombinant follicle-stimulating hormone therapy. 8 days later, we observed a mild and asymmetrical swelling of the vulva with severe edema in the right labia. Due to the worsening of the vulvar edema even after 15 days of conservative treatment, hand massage and compressive bandaging of the vulva were performed, which caused rapid recovery within 20 min of the case. Conclusion: Treatment with a hand massage with lubricant gel followed by compressive bandaging resolved the vulvar edema immediately; it is an easy procedure without any adverse events.

Dysregulated miRNAs in recurrent miscarriage: A systematic review.

Recurrent miscarriage (RM) is a complex reproductive medicine disease that affects many families. The cause of RM is unclear at this time; however, lifestyle and genetic variables may influence the process. The slight alteration in miRNA expression has enormous consequences for a variety of difficulties, one of which may be RM. The target of this systematic study was to provide a framework of the dysregulated miRNAs in RM. The Prisma guidelines were applied to perform current systematic review pertaining to articles in the seven databases. Thirty-nine papers out of 245 received fulfilled all inclusion requirements. From all the mentioned miRNAs, 40 were up-regulated (65.57 %), whereas 21 were down-regulated (34.43 %). These dysregulated miRNAs contributed to the pathophysiology of RM by influencing key pathways and processes such as apoptosis, angiogenesis, epithelial-mesenchymal transition, and the immune system. Understanding the dysregulation of miRNAs, as well as the pathways and processes that engage these miRNAs and impact disease pathogenesis, may aid in clarifying the unknown underlying mechanisms of RM and the development of novel molecular therapeutic targets and medical domains.

Investigating the efficacy of ultrasound-guided ethanol retention technique for endometrioma sclerotherapy and its effect on pro-inflammatory cytokine levels: A single-arm clinical trial.

BACKGROUND: Endometriosis is a chronic inflammatory disease affecting about 10% of women of reproductive age. Endometrioma is the most common presentation of endometriosis in ovaries. OBJECTIVES: Herein, the authors study the effect of the ultrasound-guided ethanol retention technique for endometrioma sclerotherapy and its effect on the plasma levels of pro-inflammatory cytokines. MATERIALS AND METHODS: Each endometrioma was aspirated and washed with 0.9% saline until clearance and then 2/3 of the cyst volume was filled with ethanol 98%. Patients were followed for 3 months. After that, changes in their cyst diameter, dyspareunia, dysmenorrhea, and antral follicular count were assessed. Also, the sera levels of Interleukin 1ß (IL-ß), IL-6, and IL-8 were assayed before and after the treatment. The primary sera levels were also compared with a control group. RESULTS: In the treatment and control groups, 23 and 25 individuals (respectively) with a matched mean age (p-value = 0.680) were enrolled in the study. Among the laboratory variables, IL-1ß (p-value = 0.035), as well as AMH (p-value = 0.002), were lower, and IL-6 (p-value = 0.011) was higher in the endometriosis group compared to the controls. Following the treatment, dysmenorrhea, dyspareunia, and the mean diameter of all cysts were significantly (p-values < 0.001) decreased in the treatment group. Also, right (p-value = 0.022) and left (p-value = 0.002) ovaries' antral follicular counts were increased following the treatment. No significant change was found among any of the investigated laboratory levels (p-value > 0.05). CONCLUSION: Ethanol retention method is proven to be safe and could improve the clinical status of patients with endometrioma. Although further studies are necessary.

Intraovarian Injection of Autologous Platelet-Rich Plasma Improves Therapeutic Approaches in The Patients with Poor Ovarian Response: A before-after Study.

In this article published in Int J Fertil Steril, Vol 16, No 2, April-June 2022, Pages: 90-94, the authors found that this sentence "Also, AMH level was not statistically significantly different after PRP treatment (0.38 ± 0.039) in comparison with before of treatment (0.39 ± 0.04, Fig.1C)" was incorrect. The corrected one is "Also, AMH level was not significantly different before PRP treatment (0.38 ± 0.039) in comparison with after of treatment (0.39 ± 0.04, Fig.1C)" in the first paragraph of the result section.
The authors would like to apologies for any inconvenience caused.

Investigating the efficacy of ultrasound-guided ethanol retention technique for endometrioma sclerotherapy and its effect on pro-inflammatory cytokine levels: A single-arm clinical trial

Abstract Background Endometriosis is a chronic inflammatory disease affecting about 10% of women of reproductive age. Endometrioma is the most common presentation of endometriosis in ovaries. Objectives Herein, the authors study the effect of the ultrasound-guided ethanol retention technique for endometrioma sclerotherapy and its effect on the plasma levels of pro-inflammatory cytokines. Materials and methods Each endometrioma was aspirated and washed with 0.9% saline until clearance and then 2/3 of the cyst volume was filled with ethanol 98%. Patients were followed for 3 months. After that, changes in their cyst diameter, dyspareunia, dysmenorrhea, and antral follicular count were assessed. Also, the sera levels of Interleukin 1β (IL-β), IL-6, and IL-8 were assayed before and after the treatment. The primary sera levels were also compared with a control group. Results In the treatment and control groups, 23 and 25 individuals (respectively) with a matched mean age (p-value = 0.680) were enrolled in the study. Among the laboratory variables, IL-1β (p-value = 0.035), as well as AMH (p-value = 0.002), were lower, and IL-6 (p-value = 0.011) was higher in the endometriosis group compared to the controls. Following the treatment, dysmenorrhea, dyspareunia, and the mean diameter of all cysts were significantly (p-values < 0.001) decreased in the treatment group. Also, right (p-value = 0.022) and left (p-value = 0.002) ovaries' antral follicular counts were increased following the treatment. No significant change was found among any of the investigated laboratory levels (p-value > 0.05). Conclusion Ethanol retention method is proven to be safe and could improve the clinical status of patients with endometrioma. Although further studies are necessary.

CircRNA-Associated CeRNAs Regulatory Axes in Retinoblastoma: A Systematic Scoping Review.

Retinoblastoma (RB) is one of the most common childhood cancers caused by RB gene mutations (tumor suppressor gene in various patients). A better understanding of molecular pathways and the development of new diagnostic approaches may lead to better treatment for RB patients. The number of studies on ceRNA axes is increasing, emphasizing the significance of these axes in RB. Circular RNAs (circRNAs) play a vital role in competing endogenous RNA (ceRNA) regulatory axes by sponging microRNAs and regulating gene expression. Because of the broadness of ceRNA interaction networks, they may assist in investigating treatment targets in RB. This study conducted a systematic scoping review to evaluate verified loops of ceRNA in RB, focusing on the ceRNA axis and its relationship to circRNAs. This scoping review was carried out using a six-step strategy and the Prisma guideline, and it involved systematically searching the publications of seven databases. Out of 363 records, sixteen articles were entirely consistent with the defined inclusion criteria and were summarized in the relevant table. The majority of the studies focused on the circRNAs circ_0000527, circ_0000034, and circTET1, with approximately two-fifths of the studies focusing on a single circRNA. Understanding the many features of this regulatory structure may help elucidate RB's unknown causative factors and provide novel molecular potential therapeutic targets and medical fields.

Isolation of cfDNA from spent culture media and its association with implantation rate and maternal immunomodulation.

OBJECTIVES: This investigation aims to evaluate the association between the concentration of cell-free DNA (cfDNA) in the spent culture medium (SCM) with implantation rate and the maternal immune system in the invitro fertilization (IVF). In this study, 30 embryos were cultured and scored according to Gardner's criteria. SCM was gathered on day five from every embryo to analyze the quantity of cfDNA. The real-time PCR technique evaluated the expression level of transcription factors, including Foxp3, RORγt, GATA3, and T-bet. The percentage of Th1, Th2, Th17, Treg, NK cells, and NK cells cytotoxicity was evaluated by flow cytometry. RESULTS: The concentration of cfDNA in the ß-HCG (-), ß-HCG ( +), and ongoing pregnancy groups were 20.70 ± 9.224 ng/µL, 27.97 ± 7.990 ng/µL, and 28.91 ± 8.566 ng/µL, respectively. The ratio of Th1/Th2 and Th17/Treg reduced significantly in pregnant women, as well as the level of NK cells and NK cytotoxicity cells fell dramatically in the ongoing pregnancy group. The expression level of RORγt and T-bet declined while the expression level of Foxp3 and GATA3 increased considerably in pregnant mothers. Our investigation revealed that the concentration level of cfDNA in SCM could not be associated with implantation rate, prediction of ongoing pregnancy, and maternal immune system.

Intraovarian Injection of Autologous Platelet-Rich Plasma Improves Therapeutic Approaches in The Patients with Poor Ovarian Response: A Before-After Study.

Background: Advanced age is associated with a decline in the natural oocytes, low oocyte yield, and also increases the assisted reproductive technology (ART) failure rate, and consequently resulted in a pregnancy rate decrease. Platelet-rich plasma (PRP) is one of the proposed therapeutic strategies for women with poor ovarian response (POR). Because of the autologous source of PRP, the lowest risks of disease transmission, immunogenic and allergic reactions have been expected. This study aimed to evaluate the single-dose intraovarian injection of autologous PRP in poor ovarian reserve. Materials and Methods: We conducted a clinical trial study in the Al-Zahra hospital and Milad Infertility Clinic, Tabriz, Iran (April and May, 2021). A total of thirty-five women with a POR and mean age 40.68 ± 0.34 enrolled in this study. After injection of autologous PRP into the ovaries, the number of oocytes, antral follicles, and level of estradiol, anti-Müllerian hormone (AMH), follicle-stimulating hormone (FSH), luteal hormone (LH), FSH/LH ratio also were evaluated while, these parameters were evaluated before PRP administration. Results: At the 2-month follow-up, women treated with PRP showed a significant elevation in the number of oocytes (3.68 ± 0.24, P=0.0043) and embryos (3.17 ± 0.14, P=0.0001), as well as in the estradiol levels (404.1 ± 16.76 vs. 237.7 ± 13.14, P=0.0003). Conclusion: Single PRP injection is effective and might be a promising therapeutic approach in the patients with POR to conceive with their own oocytes, although further evidence is required to assess the influence of PRP on the live birth rate.

Toxic effect of light on oocyte and pre-implantation embryo: a systematic review.

In the female reproductive tract, oocytes and embryos are in a dark environment, while during the in vitro fertilization (IVF) they are exposed to various visible and invisible lights such as daylight, microscope, and laminar hood fluorescent lights. Studies have shown that light could damage cellular compartments of oocytes and embryos and consequently decrease rates of fertilization, development, and blastocyst formation. However, due to the lack of consensus about the effects of light on the embryos, and subsequently the inability to make definitive decisions regarding the light exposure management to improve IVF results, in the present study, we systematically reviewed the effect of light with different wavelengths and intensities on pre-implantation embryos. The toxic impact of light depends on the wavelength, intensity, and duration of light exposure and also the stage of embryo. Therefore, reducing the observation time of embryos out of the incubator and also using light filters can alleviate the detrimental effect of light in IVF labs.

Remifentanil with or without Propofol as Anesthesia Agents for Trans- Vaginal Ultrasonography Oocyte Retrieval (TUGOR) on Pregnancy and Anesthesia Outcomes: A Randomized Controlled Trial.

BACKGROUND: Transvaginal Ultrasound-Guided Oocyte Retrieval (TUGOR) is a painful procedure, which often requires the application of anesthesia agents. There is a controversy in the literature about the effects of administrated anesthetics for TUGOR on patients & pregnancy outcomes. OBJECTIVE: The current study aimed to compare the effects of remifentanil with or without propofol, administrated for TUGOR, on pregnancy and anesthesia outcomes. METHOD: In a double-blind randomized controlled trial, 180 candidates of TUGOR, aged 18-40 years old, were included in the study. All study women received midazolam 0.03 mg/kg and remifentanil 1 ug/kg as anesthesia induction; Later on, they were randomly assigned in two equalsize groups in terms of anesthesia maintenance, as the intervention group received remifentanil infusion 0.25 µg/kg/min and the control group received remifentanil infusion 1ug/kg/min with propofol 50-150 ug/kg/min. Hemodynamic symptoms, operation outcomes, including the side effects, and pregnancy outcomes, were compared between the study groups. The study is registered with the Iranian Clinical Trials Registry, number IRCT201611177013N15. RESULTS: Although the hemodynamic symptoms showed significantly better ranges in the remifentanil group, however, the study groups were not significantly different in durations of operation, anesthesia, and recovery. However, the anesthesia side effects during and after the operation were not significantly different between the groups; they were more common in control one. The reproductive outcomes (numbers of collected oocytes, fertilized oocytes and transferred embryos, pregnancy rates) showed better but non-significant ranges in the remifentanil group. CONCLUSION: Using remifentanil alone in comparison to remifentanil & propofol in the TUGOR procedure can be achieved better pregnancy outcomes without imposing the side effects of propofol; therefore, it is not recommended to use propofol as an anesthesia agent for a TUGOR procedure.

Tacrolimus Improves the Implantation Rate in Patients with Elevated Th1/2 Helper Cell Ratio and Repeated Implantation Failure (RIF).

Introduction An abnormal endometrial immune response is involved in the pathogenesis of repeated implantation failure (RIF), so we investigated the effectiveness of tacrolimus treatment on the endometrium of RIF patients. Materials and Methods Ten RIF patients with elevated T-helper 1/T-helper 2 (Th1/Th2) cell ratios were recruited into a clinical study. The expression of p53, leukemia inhibitory factor (LIF), interleukin (IL)-4, IL-10, IL-17, and interferon gamma (IFN-γ) in the endometrium of patients with and without tacrolimus treatment and the association of these factors with assisted reproductive technology (ART) outcomes were investigated. Results Tacrolimus significantly increased the expression of LIF, IL-10, and IL-17 and decreased the expression of IL-4, IFN-γ, and the IFN-γ/IL-10 ratio in RIF patients. Tacrolimus treatment resulted in an implantation rate of 40%, a clinical pregnancy rate of 50%, and a live birth rate of 35% in RIF patients with elevated Th1/Th2 ratios who had previously failed to become pregnant despite at least three transfers of embryos. We also found a significant positive correlation between IL-10 levels and the implantation rate. Conclusions Our findings suggest that RIF patients with a higher Th1/Th2 ratio could be candidates for tacrolimus therapy and that this immunosuppressive drug could be acting through upregulation of LIF, IL-10, and IL-17.

Dual role of TGF-ß in early pregnancy: clues from tumor progression.

TGF-ß signaling in the endometrium is active during the implantation period and has a pivotal role in regulating endometrial receptivity and embryo implantation. During embryo implantation, both apoptosis and proliferation of endometrial cells happen at the same time and it seems TGF-ß is the factor that controls both of these processes. As shown in cancer cells, in special conditions this cytokine can have a dual effect and switch the action from apoptosis to proliferation. Owing to the similarity between embryo implantation and cancer development and also unusual pattern of proliferation and remodeling in the uterus, in this review we suggest the existence of such a switching in endometrium during the early pregnancy. Moreover, we address some potential mechanisms that could regulate the switching. A better understanding of the molecular mechanisms regulating TGF-ß action and signaling during the implantation period could pave the way for introducing novel therapeutic strategies in order to solve implantation-associated issues such as repeated implantation failure.

Follicular Fluid Levels of Adrenomedullin 2, Vascular Endothelial Growth Factor and its Soluble Receptors Are Associated with Ovarian Response During ART Cycles.

Introduction Adrenomedullin 2 (ADM2) and vascular endothelial growth factor (VEGF) affect ovarian function, especially angiogenesis and follicular development. The actions of VEGF can be antagonized by its soluble receptors, soluble Fms-like tyrosine kinase-1 (sFlt-1) and soluble VEGF receptor 2 (sVEGFR-2), as they decrease its free form. In the present study, we evaluated the relationship between follicular fluid (FF) levels of AMD2, VEGF and its soluble receptors, and ICSI outcomes. Materials and Methods ICSI cycle outcomes were evaluated and FF levels of VEGF, sFlt-1, sVEGFR-2 and ADM2 were determined using ELISA kits. Results FF levels of ADM2, VEGF, and sVEGFR-2 were significantly higher in non-responders compared to other ovarian response groups (p < 0.05). There were significant correlations between ADM2, VEGF and sVEGFR-2 levels as well as VEGF/sFlt-1 and VEGF/sVEGFR-2 ratios (r = 0.586, 0.482, 0.260, and - 0.366, respectively). Based on the ROC curve, the cutoff value for ADM2 as a non-responder predictor was 348.55 (pg/ml) with a sensitivity of 67.7% and a specificity of 94.6%. Conclusions For the first time we measured FF ADM2 levels to determine the relationship to VEGF and its soluble receptors. We suggest that ADM2 could be a potential predictive marker for non-responders. Although the exact function of ADM2 in ovarian angiogenesis is not yet understood, our study may shed light on the possible role of ADM2 in folliculogenesis and ovulation.

Altered T-cell subpopulations in recurrent pregnancy loss patients with cellular immune abnormalities.

Recurrent pregnancy loss (RPL) is a multifactorial disorder of women in reproductive age, which in some cases is caused by immunologic abnormalities. In this study, we aimed to evaluate cellular and molecular components of the immune system like different T-cell subsets and their regulating microRNAs (miRNAs) in RPL women and control group. Fifty RPL and 50 healthy subjects were recruited. Subsets of T cells, including regulatory T (Treg) cells, helper T (Th) 17 cells, exhausted T cells, exhausted Treg cells were evaluated by flow cytometry. Transcription factors of T cells and related miRNA profile were quantified using real-time polymerase chain reaction (RT-PCR). Assessment showed that Treg and exhausted T cells, were decreased in RPL patients (p = 0.009 and 0.02, respectively), while an increase was observed in Th17 and exhausted Treg frequency ( p = 0.013 and 0.0037, respectively). Messenger RNA expression level of T-bet and IRF4 was upregulated in RPL patients ( p = 0.011 and 0.0001, respectively), while Th2- and Treg-related transcription factors, GATA3 and GITR, were downregulated in these patients compared with the healthy subjects ( p = 0.0008 and <0.000, respectively). Treg-associated miRNAs, the miR-106b-25-93 cluster, showed a higher rate in RPL patients ( P = 0.007, 0.001, and 0.029, respectively), however, we observed no significant difference in the expression level of Th17-associated miRNA, mir-326. According to the results, we concluded that unbalanced immune responses and deregulated function of T-cell subsets may lead to reproduction-related failure like a miscarriage. Therefore, evaluation of immune cells and related miRNA profile may serve as prognostic biomarker for the treatment of RPL patients.

Effect of oral Utrogestan in comparison with Cetrotide on preventing luteinizing hormone surge in IVF cycles: A randomized controlled trial.

BACKGROUND: Oral progesterone is recommended as an alternative to gonadotropin-releasing hormone (GnRH) agonists and antagonists to prevent luteinizing hormone (LH) surge in assisted reproductive technology (ART) cycles. However, there are little data regarding its use. OBJECTIVE: We aimed to compare the effect of oral Utrogestan and Cetrotide (a GnRH antagonist) on preventing LH surge in ART cycles. MATERIALS AND METHODS: In this randomized clinical trial, 100 infertile women undergoing ART who received recombinant follicle-stimulating hormone (FSH) at 150-225 IU/day were randomly assigned to receive either Utrogestan 100 mg twice a day (case group) or GnRH antagonist protocol (control group) from cycle day 3 until the trigger day. Triggering was performed with 10,000 IU hCG) when there were at least three mature follicles. Viable embryos were cryopreserved for transfer in the next cycle for both groups. The number of oocytes retrieved and transferred embryos were compared between groups. RESULTS: The case group had significantly higher progesterone levels on triggering day, more follicles of > 14 mm with higher maturity, and more oocytes retrieved with a higher rate of embryos transferred. A small increase in the pregnancy rate was observed in the case group, with no significant between-group differences. The most important result was the lack of premature LH surge in either group upon serum LH assessment on the triggering day. CONCLUSION: Utrogestan is an alternative treatment that could reduce the LH surge rate and increase the ART outcomes including the number of oocytes retrieved and transferred embryos compared with GnRH agonists and antagonists.

Reciprocal Changes in Phosphoenolpyruvate Carboxykinase and Pyruvate Kinase with Age Are a Determinant of Aging in Caenorhabditis elegans.

Aging involves progressive loss of cellular function and integrity, presumably caused by accumulated stochastic damage to cells. Alterations in energy metabolism contribute to aging, but how energy metabolism changes with age, how these changes affect aging, and whether they can be modified to modulate aging remain unclear. In locomotory muscle of post-fertile Caenorhabditis elegans, we identified a progressive decrease in cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C), a longevity-associated metabolic enzyme, and a reciprocal increase in glycolytic pyruvate kinase (PK) that were necessary and sufficient to limit lifespan. Decline in PEPCK-C with age also led to loss of cellular function and integrity including muscle activity, and cellular senescence. Genetic and pharmacologic interventions of PEPCK-C, muscle activity, and AMPK signaling demonstrate that declines in PEPCK-C and muscle function with age interacted to limit reproductive life and lifespan via disrupted energy homeostasis. Quantifications of metabolic flux show that reciprocal changes in PEPCK-C and PK with age shunted energy metabolism toward glycolysis, reducing mitochondrial bioenergetics. Last, calorie restriction countered changes in PEPCK-C and PK with age to elicit anti-aging effects via TOR inhibition. Thus, a programmed metabolic event involving PEPCK-C and PK is a determinant of aging that can be modified to modulate aging.

Three rare diseases in one Sib pair: RAI1, PCK1, GRIN2B mutations associated with Smith-Magenis Syndrome, cytosolic PEPCK deficiency and NMDA receptor glutamate insensitivity.

The National Institutes of Health Undiagnosed Diseases Program evaluates patients for whom no diagnosis has been discovered despite a comprehensive diagnostic workup. Failure to diagnose a condition may arise from the mutation of genes previously unassociated with disease. However, we hypothesized that this could also co-occur with multiple genetic disorders. Demonstrating a complex syndrome caused by multiple disorders, we report two siblings manifesting both similar and disparate signs and symptoms. They shared a history of episodes of hypoglycemia and lactic acidosis, but had differing exam findings and developmental courses. Clinical acumen and exome sequencing combined with biochemical and functional studies identified three genetic conditions. One sibling had Smith-Magenis Syndrome and a nonsense mutation in the RAI1 gene. The second sibling had a de novo mutation in GRIN2B, which resulted in markedly reduced glutamate potency of the encoded receptor. Both siblings had a protein-destabilizing homozygous mutation in PCK1, which encodes the cytosolic isoform of phosphoenolpyruvate carboxykinase (PEPCK-C). In summary, we present the first clinically-characterized mutation of PCK1 and demonstrate that complex medical disorders can represent the co-occurrence of multiple diseases.

Cited2, a transcriptional modulator protein, regulates metabolism in murine embryonic stem cells.

CREB-binding protein (CBP)/p300 interacting transactivator with glutamic acid (Glu) and aspartic acid (Asp)-tail 2 (Cited2) was recently shown to be essential for gluconeogenesis in the adult mouse. The metabolic function of Cited2 in mouse embryonic stem cells (mESCs) remains elusive. In the current study, the metabolism of glucose was investigated in mESCs, which contained a deletion in the gene for Cited2 (Cited2(Δ/-)). Compared with its parental wild type counterpart, Cited2(Δ/-) ESCs have enhanced glycolysis, alternations in mitochondria morphology, reduced glucose oxidation, and decreased ATP content. Cited2 is recruited to the hexokinase 1 (HK1) gene promoter to regulate transcription of HK1, which coordinates glucose metabolism in wild type ESCs. Reduced glucose oxidation and enhanced glycolytic activity in Cited2(Δ/-) ESCs correlates with defective differentiation during hypoxia, which is reflected in an increased expression of pluripotency marker (Oct4) and epiblast marker (Fgf5) and decreased expression of lineage specification markers (T, Gata-6, and Cdx2). Knockdown of hypoxia inducible factor-1α in Cited2(Δ/-) ESCs re-initiates the expression of differentiation markers T and Gata-6. Taken together, a deletion of Cited2 in mESCs results in abnormal mitochondrial morphology and impaired glucose metabolism, which correlates with a defective cell fate decision.