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MARIA MARJORETTE O. (Marj) PENA, Ph.D
Mehl
KA, Davis JM, Clements JM, Berger FG, Pena MM, Carson JA.
Decreased intestinal polyp multiplicity is related to
exercise mode and gender in ApcMin/+ mice. J Appl Physiol.
2005 Jun;98(6):2219-25
Moderate-intensity treadmill running can
alter male Apc(Min/+) mouse polyp formation. This purpose of
this study was to examine whether exercise mode
differentially affects Apc(Min/+) mouse intestinal polyp
development in male and female mice. Male and female Apc(Min/+)
mice were randomly assigned to control, treadmill (18 m/min;
60 min/day; 6 days/wk), or voluntary wheel running (24-h
access) groups. Nine weeks of training decreased total
intestinal polyps by 29% in male treadmill runners (66 +/-
9; P = 0.038) compared with male controls (93 +/- 7). The
number of large polyps (>/=1-mm diameter) were also reduced
by 38% in male treadmill runners (49 +/- 6; P = 0.005)
compared with male controls (79 +/- 6). Treadmill running in
female Apc(Min/+) mice and wheel running in both genders did
not affect polyp number or size. Spleen weight decreased in
male treadmill runners (91 +/- 9 mg; P = 0.011) and wheel
runners (75 +/- 6 mg; P = 0.004) compared with controls (141
+/- 13 mg). Plasma IL-6 was reduced by 96% in male treadmill
runners (1.2 +/- 0.6 pg/ml) and 78% in male wheel runners
(6.6 +/- 3.3 pg/ml) compared with control mice (27.9 +/- 2.8
pg/ml; P < 0.05). Female mice responded similarly with an
86% decrease in plasma IL-6 with treadmill running (3.2 +/-
1.2 pg/ml) and 90% decrease with wheel running (2.9 +/- 2.0
pg/ml) compared with control mice (21.1 +/- 5.3 pg/ml; P <
0.05). The crypt depth-to-villus height ratio in the
intestine, an indirect marker of intestinal inflammation,
decreased by 21 (P = 0.024) and 24% (P = 0.029),
respectively, in male and female treadmill runners but not
wheel runners. Physical activity-induced attenuation of
intestinal polyp number and size is dependent on exercise
mode and differs between genders. The modulation of systemic
and intestinal inflammation may also depend on exercise
mode.
Altemir FH, Montero SH, Montero SH,
Pena MM, Montero EH. Avoiding tracheostomy: submental
intubation in faciomaxillary trauma surgery. Plast Reconstr
Surg. 2005 Jan;115(1):349-51
Author reply 351. No abstract available.
Forsthoefel AM, Pena MM, Xing YY,
Rafique Z, Berger FG. Structural determinants for the
intracellular degradation of human thymidylate synthase.
Biochemistry. 2004 Feb 24;43(7):1972-9
Thymidylate synthase (EC 2.1.1.45) (TS)
catalyzes the conversion of dUMP to dTMP and is therefore
indispensable for DNA replication in actively dividing
cells. The enzyme is a critical target at which
chemotherapeutic agents such as fluoropyrimidines (e.g.,
5-fluorouracil and 5-fluoro-2'-deoxyuridine) and folic acid
analogues (e.g., raltitrexed, LY231514, ZD9331, and
BW1843U89) are directed. These agents exert their effects
through the generation of metabolites that bind the active
site of TS and inhibit catalytic activity. The binding of
ligands to the TS molecule leads to dramatic changes in the
conformation of the enzyme, particularly within the
C-terminal domain. Stabilization of the enzyme and an
increase in its intracellular level are associated with
ligand binding and may be important in cellular response to
TS-directed drugs. In the present study, we have examined
molecular features of the TS molecule that control its
degradation. We find that the C-terminal conformational
shift is not required for ligand-mediated stabilization of
the enzyme. In addition, we demonstrate that the N-terminus
of the TS polypeptide, which is extended in the mammalian
enzyme and is disordered in crystal structures, is a primary
determinant of the enzyme's half-life. Finally, we show that
TS turnover is carried out by the 26S proteasome in a
ubiquitin-independent manner. These findings provide the
basis for a mechanistic understanding of TS degradation and
its regulation by antimetabolites.
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