Deletion of the insulin-like growth factor 1 (Igf1) gene was shown in previous studies to result in reduced numbers of Leydig cells in the testes of 35-day-old mice, and in reduced circulating testosterone levels. In the current study, we asked whether deletion of the Igf1 gene affects the number, proliferation, and/or steroidogenic function of some or all of the precursor cell types in the developmental sequence that leads to the establishment of adult Leydig cells (ALCs). Decreased numbers of cells in the Leydig cell lineage (ie, 3β-hydroxysteroid dehydrogenase–positive cells) were seen in testes of postnatal day (PND) 14–90 Igf1−/− mice compared with age-matched Igf1+/+ controls. The development of ALCs proceeds from stem Leydig cells (SLCs) through progenitor Leydig cells (PLCs) and immature Leydig cells (ILCs). The bromodeoxyuridine labeling index of putative SLCs was similar in the Igf1−/− and Igf1+/+ mice. In contrast, the labeling index of PLCs was reduced in the Igf1−/− mice on each day of PND 14 through PND 35, and that of more mature Leydig cells (referred to herein as LCs, a combination of ILCs plus ALCs) was reduced from PND 21 through PND 56. In Igf1−/− mice that received recombinant IGF-I, the labeling indices of PLCs and LCs were similar to those of age-matched Igf1+/+ mice, indicating that the reductions in the labeling indices seen in the PLCs and LCs of the Igf1−/− mice were a consequence of reduced IGF-I. On each day of PND 21 through PND 90, testicular testosterone concentrations were significantly reduced in the Igf1−/− mice, as were the expressions of testis-specific mRNAs involved in steroidogenesis, including Star, Cyp11a1, and Cyp17a1. The increased expression of the gene for 5α-reductase (Srd5a1) in adult Igf1−/− testes suggests that the depletion of Igf1 might suppress or delay Leydig cell maturation. These observations, taken together, indicate that the reduced numbers of Leydig cells in the adult testes of Igf1−/− mice result at least in part from altered proliferation and differentiation of ALC precursor cells, but not of the stem cells that give rise to these cells.

Colorectal cancer (CRC) is a common malignancy. Many reports have implicated aberrant mitochondrial activity in the progression of CRC, with particular emphasis on the dysregulation of redox signaling and oxidative stress. In this study, we focused on manganese superoxide dismutase (MnSOD/SOD2), a key antioxidant enzyme, which maintains intracellular redox homeostasis. Current literature presents conflicting mechanisms for how SOD2 influences tumorigenesis and tumor progression. Here, we explored the role of SOD2 in CRC specifically. We found high levels of SOD2 expression in CRC tissues. We carried out a series of experiments to determine whether knockdown of SOD2 expression in CRC cell lines would reverse features of tumorigenesis. We found that reduced SOD2 expression decreased cell proliferation, migration, and invasion activity in CRC cells. Results from an additional series of experiments on mitochondrial function implicated a dual role for SOD2 in promoting CRC progression. First, proper level of SOD2 helped CRC cells maintain mitochondrial function by disposal of superoxide (O2.−). Second, over‐expression of SOD2 induced H2O2‐mediated tumorigenesis by upregulating AMPK and glycolysis. Our results indicate that SOD2 may promote the occurrence and development of CRC by regulating the energy metabolism mediated by AMPK signaling pathways.

We agree with Dr. Nicolantonio and colleagues that the argument about salt and hypertension has run its course. 1 In 1937, Moritz and Oldt found narrowed visceral arterioles across the age range, in both sexes, and across races 2 (Figure 1-5A [see figure legend for column/row numbering/ lettering details]). They posed the question, "Are these injuries the cause or the consequence of hypertension?" Our finding of undiscussed "halos of hyalinisation" around uterine arterioles in pregnancy (Figure 1A), at the same periarteriolar site as "halos of injured nerves" in painful, gynecologic syndromes (Figure 1B), suggests a clear pathoanatomic relationship. 3,4 Combining these observations with historic, though obscure, discoveries of the uterorenal reflex 5 that activates a renal corticomedullary shunt 6 provides a possible mechanism for preeclampsia. 7 However, we find similar halos of injured nerves in the hila of the kidney and other viscera that also express P2X3 "stretch" receptors (Figure 1-5, A-C) that may also contribute to hypertension. Injuries to vasomotor nerves release a "cocktail" of cytokines and growth factors that cause regeneration of injured nerves and concurrent hyperplasia of denervated arteriolar walls. Narrowing of renal arterioles contributes to relative renal ischemia, providing further drive to hypertension through traditional Goldblatt mechanisms.What causes injuries to the renal vasomotor nerves to produce the epidemiologic distribution that Moritz and Oldt described? The consistent injury to uterine vasomotor nerves results from "persistent physical efforts during defecation" that occur in 20%-30% of Western bowel movements. 4 Uterus and kidneys share innervation from sympathetic segments (T10-12). Other sources may include factors that play into the epidemiology of hypertension, such as obesity, hyperglycemia, stress, smoking, and alcohol. The ragged appearances of the arteriolar adventitiae in kidney and spleen (Figure 2-3A) suggest that spikes in blood pressure may contribute to fixed, renal arteriolar injuries (eg, high blood pressures in pre-eclampsia in a first pregnancy may result in early-onset postpartum hypertension).We apologize to Dr DiNicolantonio and colleagues: in dispensing with the salt argument, might we have opened a Pandora's box of possible sources of hypertension ?

In their extensive meta-analysis, Professor Nicolaides and colleagues 1 describe a reduction of preterm (<37 weeks), although not term (37e42 weeks), preeclampsia with a daily dose of more than 100 mg aspirin starting before 16 weeks' gestation. We offer some recent observations from an entirely different source that tends to support their conclusions. In recent histological studies, we find purinergic (P2X3) "stretch" receptors in the walls of denervated uterine arterioles and myometrium in pregnancy hysterectomy specimens (Figure, AeD). Increases in uterine blood flow in the second

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