Baylor Scott and White Research Institute

Singhal, N. K., S. Sternbach, S. Fleming, K. Alkhayer, J. Shelestak, D. Popescu, A. Weaver, R. Clements, B. Wasek, T. Bottiglieri, E. J. Freeman and J. McDonough (2020). “Betaine restores epigenetic control and supports neuronal mitochondria in the cuprizone mouse model of multiple sclerosis.” Epigenetics Feb 25. [Epub ahead of print].

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Methionine metabolism is dysregulated in multiple sclerosis (MS). The methyl donor betaine is depleted in the MS brain where it is linked to changes in levels of histone H3 trimethylated on lysine 4 (H3K4me3) and mitochondrial impairment. We investigated the effects of replacing this depleted betaine in the cuprizone mouse model of MS. Supplementation with betaine restored epigenetic control and alleviated neurological disability in cuprizone mice. Betaine increased the methylation potential (SAM/SAH ratio), levels of H3K4me3, enhanced neuronal respiration, and prevented axonal damage. We show that the methyl donor betaine and the betaine homocysteine methyltransferase (BHMT) enzyme can act in the nucleus to repair epigenetic control and activate neuroprotective transcriptional programs. ChIP-seq data suggest that BHMT acts on chromatin to increase the SAM/SAH ratio and histone methyltransferase activity locally to increase H3K4me3 and activate transcriptional programs that support neuronal energetics. These data suggest that the methyl donor betaine may provide neuroprotection in MS where mitochondrial impairment damages axons and causes disability.

Gu, S. X., V. K. Sonkar, P. B. Katare, R. Kumar, W. D. Kruger, E. Arning, T. Bottiglieri, S. R. Lentz and S. Dayal (2020). “Memantine Protects From Exacerbation of Ischemic Stroke and Blood Brain Barrier Disruption in Mild But Not Severe Hyperhomocysteinemia.” J Am Heart Assoc Feb 18;9(4): Epub 2020 Feb 13.

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Background Hyperhomocysteinemia is a risk factor for ischemic stroke; however, a targeted treatment strategy is lacking partly because of limited understanding of the causal role of homocysteine in cerebrovascular pathogenesis. Methods and Results In a genetic model of cystathionine beta synthase (CBS) deficiency, we tested the hypothesis that elevation in plasma total homocysteine exacerbates cerebrovascular injury and that memantine, a N-methyl-D-aspartate receptor antagonist, is protective. Mild or severe elevation in plasma total homocysteine was observed in Cbs+/- (6.1+/-0.3 mumol/L) or Cbs-/- (309+/-18 mumol/L) mice versus Cbs+/+ (3.1+/-0.6 mumol/L) mice. Surprisingly, Cbs-/- and Cbs+/- mice exhibited similar increases in cerebral infarct size following middle cerebral artery ischemia/reperfusion injury, despite the much higher total homocysteine levels in Cbs-/- mice. Likewise, disruption of the blood brain barrier was observed in both Cbs+/- and Cbs-/- mice. Administration of the N-methyl-D-aspartate receptor antagonist memantine protected Cbs+/- but not Cbs-/- mice from cerebral infarction and blood brain barrier disruption. Our data suggest that the differential effect of memantine in Cbs+/- versus Cbs-/- mice may be related to changes in expression of N-methyl-D-aspartate receptor subunits. Cbs-/-, but not Cbs+/- mice had increased expression of NR2B subunit, which is known to be relatively insensitive to homocysteine. Conclusions These data provide experimental evidence that even a mild increase in plasma total homocysteine can exacerbate cerebrovascular injury and suggest that N-methyl-D-aspartate receptor antagonism may represent a strategy to prevent reperfusion injury after acute ischemic stroke in patients with mild hyperhomocysteinemia.

Heshmati, J., F. Golab, M. Morvaridzadeh, E. Potter, M. Akbari-Fakhrabadi, F. Farsi, S. Tanbakooei and F. Shidfar (2020). “The effects of curcumin supplementation on oxidative stress, Sirtuin-1 and peroxisome proliferator activated receptor gamma coactivator 1alpha gene expression in polycystic ovarian syndrome (PCOS) patients: A randomized placebo-controlled clinical trial.” Diabetes Metab Syndr Jan 8;14(2):77-82. [Epub ahead of print].

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BACKGROUND & AIMS: Curcumin is a biologically active phytochemical ingredient found in turmeric and has antioxidant pharmacologic actions that may benefit patients with polycystic ovarian syndrome (PCOS). The aim in this trial was to evaluate the efficacy of curcumin supplementation on oxidative stress enzymes, sirtuin-1 (SIRT1) and Peroxisome proliferator activated receptor gamma coactivator 1alpha (PGC1alpha) gene expression in PCOS patients. METHODS: Seventy-two patients with PCOS were recruited for this randomized, double-blinded, clinical trial. Thirty-six patients received curcumin, 1500 mg (three times per day), and 36 patients received placebo for 3 months. Gene expression of SIRT1, PGC1alpha and serum activity of glutathione peroxidase (Gpx) and superoxide dismutase (SOD) enzymes were evaluated at the beginning of trial and at 3-month follow-up. RESULTS: Sixty-seven patients with PCOS completed the trial. Curcumin supplementation significantly increased gene expression of PGC1alpha (p = 0.011) and activity of the Gpx enzyme (p = 0.045). Curcumin also non-significantly increased gene expression of SIRT1 and activity of the SOD enzyme. CONCLUSIONS: Curcumin seems to be an efficient reducer of oxidative stress related complications in patients with PCOS. Further studies on curcumin should strengthen our findings.

Nakase-Richardson, R., D. J. Schwartz, L. Drasher-Phillips, J. M. Ketchum, K. Calero, M. N. Dahdah, K. R. Monden, K. Bell, U. Magalang, J. M. Hoffman, J. Whyte, J. Bogner and J. M. Zeitzer (2020). “Comparative Effectiveness of Sleep Apnea Screening Instruments During Inpatient Rehabilitation Following Moderate to Severe TBI.” Arch Phys Med Rehabil 101(2): 283-296.

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OBJECTIVE: To determine the diagnostic sensitivity and specificity and comparative effectiveness of traditional sleep apnea screening tools in traumatic brain injury (TBI) neurorehabilitation admissions. DESIGN: Prospective diagnostic comparative effectiveness trial of sleep apnea screening tools relative to the criterion standard, attended level 1 polysomnography including encephalography. SETTING: Six TBI Model System Inpatient Rehabilitation Centers. PARTICIPANTS: Between May 2017 and February 2019, 449 of 896 screened were eligible for the trial with 345 consented (77% consented). Additional screening left 263 eligible for and completing polysomnography with final analyses completed on 248. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Area under the curve (AUC) of screening tools relative to total apnea hypopnea index>/=15 (AHI, moderate to severe apnea) measured at a median of 47 days post-TBI (interquartile range, 29-47). RESULTS: The Berlin high-risk score (receiving operating curve [ROC] AUC=0.634) was inferior to the Multivariable Apnea Prediction Index (MAPI) (ROC AUC=0.780) (P=.0211; CI, 0.018-0.223) and Snoring, Tired, Observed, Blood Pressure, Body Mass Index, Age, Neck Circumference, and Gender (STOPBANG) score (ROC AUC=0.785) (P=.001; CI, 0.063-0.230), both of which had comparable AUC (P=.7245; CI, -0.047 to 0.068). Findings were similar for AHI>/=30 (severe apnea); however, no differences across scales was observed at AHI>/=5. The pattern was similar across TBI severity subgroups except for posttraumatic amnesia (PTA) status wherein the MAPI outperformed the Berlin. Youden’s index to determine risk yielded lower sensitivities but higher specificities relative to non-TBI samples. CONCLUSION: This study is the first to provide clinicians with data to support a choice for which sleep apnea screening tools are more effective during inpatient rehabilitation for TBI (STOPBANG, MAPI vs Berlin) to help reduce comorbidity and possibly improve neurologic outcome.

Kumano, K., M. Takita, S. Vasu, C. Darden, M. Lawrence, E. Beecherl, A. Gupta, N. Onaca and B. Naziruddin (2020). “Impact of microbial contamination of the islet product during total pancreatectomy with islet autotransplantation.” J Hepatobiliary Pancreat Sci Jan 16. [Epub ahead of print].

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BACKGROUND: The combined use of interleukin-1beta and tumor necrosis factor-alpha blockers in the peritransplant period has improved outcomes of total pancreatectomy with islet autotransplantation (TPIAT). However, these drugs may suppress the immune system, resulting in severe infection. METHODS: We retrospectively investigated the impact of microbial-contaminated islet product on posttransplant complications and metabolic outcomes of TPIAT patients receiving the IL-1 and TNF-blockade treatment at our center. RESULTS: Among 108 TPIAT patients, 37 patients (34%) received contaminated products. Preoperative stent treatment and fibrosis score were independent risk factors for the contamination. There were no significant differences between the contaminated and noncontaminated product groups in posttransplant infectious complication rate, length of hospitalization, or readmission rate. However, islet equivalents (P < 0.0001) and insulin independence rate (P = 0.036) at 6 months were significantly lower for patients receiving contaminated product. CONCLUSIONS: These results suggest that combined anti-inflammatory drug use is safe and well tolerated in TPIAT patients who receive contaminated islet product and does not increase the rate of infectious complications; however, contaminated islet product is associated with poor metabolic outcomes.