News, Notes, & Insights

Bioengineered Hair Follicles Suggests Baldness Cure

Japanese scientists have taken another step toward organ regeneration through stem cell bioengineering: successfully implanting reconstituted hair follicles into the skin of nude mice.

Last year, this same team, led by Takashi Tsuji, Ph.D., of the Tokyo University of Science, described a similar technique to transplant a bioengineered tooth unit, which included mature tooth, periodontal ligament, and bone, into the upper jawbone of a mouse.

In the new study, the researchers applied their bioengineering skills to three different types of hair. They reconstituted pelage follicle germ cells, dark and coarse hair stem cells, using mouse embryonic skin epithelial cells and mesenchymal cells. They also regenerated vibrissa follicle germs, light and fine hair stem cells, using adult mice stem cells from bulge region epithelial cells and dermal papilla cells. Harvesting small pieces of occipital scalp from human male donors, researchers repeated the method to engineer new hair follicles using intact dermal papilla cells and bulgeregion epithelial cells. The researchers rearranged the follicular cells and stem cells into their niches, grew them in culture, and then implanted them on hairless mice.

The implanted hair had the correct structures of natural hair follicles and shafts, and formed normal connections with surrounding host tissues such as the epidermis. For example, when the researchers injected the neurotransmitter acetylcholine, the hairs stood up—this piloerection ability indicated that the follicles had made functional connections to appropriate muscles and nerve fibers. The researchers even demonstrated an ability to choose cells that affected hair pigmentation.

As the researchers’ methods to regenerate ectodermal glands such as teeth and hair continue to progress, they say in their report in Nature Communications* that transplantation of these bioengineered follicle germs offers a path for hair loss treatment.

Women’s Verbal Ability Declines During Menopause

Cognitive decline is common among aging men and women, but a new study investigated whether loss of cognitive function in women can be linked to the hormonal changes of menopause.

Researchers from the University of Michigan, led by Alison Berent-Spillson, Ph.D., studied 67 women, ages 42–61 years, who were part of an ongoing menopause study. The women were grouped according to three hormonal stages: premenopause, perimenopause, and postmenopause. They were given neuropsychological assessments of their cognitive function based on visual memory tests and on their ability to process abstract and concrete meaning of words. Functional magnetic resonance imaging was used to observe the neural activation patterns during the tasks.

Menopause status affected the women’s verbal fluency independent of age. Declines in verbal cognitive functioning were observed in the women during menopause transition. In their article soon to be published in The Journal of Clinical Endocrinology & Metabolism,* the researchers conclude that their results suggest verbal functioning was affected by hormonal differences both on a behavioral and neuroanatomical level.

The researchers suggested that with the awareness that verbal fluency is vulnerable during this transitioning time of life, pharmacological and non-pharmacological interventions may be targeted to preserve function of this critical cognitive domain.

A Taste for Fat among Obese Subjects

Salty, sweet, sour, bitter, and umami. Can we add fat to this wellknown list of tastes? A new study published in the Journal of Lipid Research* suggests a sixth basic taste component for obese subjects in detection of dietary fat.

Traditionally dietary fat is thought to activate the somatosensory and olfactory systems exclusively on aromatic and textual cues. Recent research at the Washington University School of Medicine, however, finds detection of triolein and oleic acid to be higher for subjects with high expression levels of the gene CD36, commonly accepted as a lipid taste receptor. Sensitivity to triolein decreases with reductions in fatty acid release through the addition of orlistat, a tasteless lipase inhibitor and popular weight loss pill. Detection of oleic acid goes unchanged, suggesting that taste, in addition to texture, contributes to dietary fat detection.

This is especially significant for the obese. Aside from a diet high in fat content, low sensitivity to oleic acid associates with higher body mass index (BMI). Whether fat taste receptors are altered by increased BMI is unknown. Obesity may cause low oral sensitivity to fat or vice versa. Other studies show sensitivity increasing after four weeks of a low-fat diet.

In measuring triacylglycerols and fatty acids together, the new study makes further understanding of the body’s ability to directly taste fat. Future studies of lipase inhibition and genetic variance of lipid taste reception may provide inroads to improving dietary therapy for obesity.

Resveratrol’s Role in Treating PCOS

The beneficial effects of red wine, grape juice, and peanuts might extend to ameliorating the excess androgen production in patients with polycystic ovary syndrome (PCOS).

Resveratrol is a naturally occurring polyphenol found in these foods and some medicinal plants. It has anti-inflammatory, antioxidant, cardioprotective, and neuroprotective effects—and studies in rats have shown it can inhibit steroidogenesis. Researchers led by Antoni J. Duleba, M.D., of the University of California, Davis, explored whether this latter effect could be useful in women with the androgen-overproducing disorder, PCOS.

Theca cells play an important role in ovarian steroidogenesis; ovaries of women with PCOS are enlarged and characterized by theca-interstitial hyperplasia. Researchers cultured rat theca-interstitial cells and tested the effects of adding resveratrol.

The polyphenol reduced androgen production in these cells but did not affect progesterone levels. This inhibitory effect correlated with a decrease in mRNA expression of genes regulating androgen production, especially Cyp17a1. Resveratrol decreased activity of a cellsignaling pathway involved in ovarian steroidogenesis, apparently by decreasing phosphorylation in the pathway.

Resveratrol can activate sirtuins, a family of deacetylases involved in cellular processes such as genomic stability and DNA repair. This activation has been shown to extend lifespan in mice. To test whether sirtuins were involved in the steroid effects, the researchers added sirtuin inhibitors to the culture, which did not reverse the resveratrolinduced inhibition of steroidogenesis.

In an article accepted for publication in Endocrinology,* the researchers say this study is the first they know of for evaluating the role of resveratrol on theca-interstitial cell steroidogenesis. Their results could be of clinical relevance for treating conditions associated with excessive production of androgens by theca cells such as PCOS.

Bees Provide Key to Anesthesia Jet Lag

Surgery can have a disorienting effect on patients. The altered perception of time that often follows anesthesia has been described as post-operative jet lag by researchers at the University of Auckland in New Zealand. Using honeybees as subjects, the researchers studied the effects of anesthesia. Dosing honeybees with the common anesthetic, isoflurane, the research team saw marked significant delays in timed behavior and circadian rhythms.

Bees keep to an obsessively controlled schedule with highly timed field behaviors. Their circadian clocks are molecularly similar to mammals, oscillating through mRNA and protein levels to regulate a 24-hour rhythm. A sixhour administration of isoflurane inhalant during the bees’ subjective day, as published in the Proceedings of the National Academy of Sciences,* produced a four- to five-hour delay in field behavior and clock gene expression.

Night dosing had little to no effect, and the reason may be found in the mRNA oscillations during this time. Isoflurane is thought to increase mRNA expression, causing a time shift forward when levels are rising and a delay when levels are declining. When levels hold steady at their highest point, as at night, isoflurane and similar anesthetics cause no shift.

Isoflurane is known to increase GABA reception, which forms much of the brain’s daily rhythm. Manipulation of the GABA receptors modifies circadian clock responses to light. Although isoflurane had no effect at night, a night-time light pulse causes a circadian phase delay. Administered during the day, light causes a phase advance.

Administration of light and isoflurane together may be an important next step possibly making postop jet lag treatable during anesthesia, the researchers suggested.

How Dietary Fiber Fights Type 2 Diabetes Mellitus

Studies show that a high-fiber diet helps people maintain a healthy body weight, suggesting a possible role in the prevention and control of type 2 diabetes mellitus (T2DM). Specifically, researchers wanted to test the efficacy of an insoluble dietary fiber derived from maize, high-amylose maize-resistant starch 2 (HAM-R2), which has been shown both to increase insulin sensitivity and reduce adipose tissue.

Scientists led by Denise Robertson, Ph.D., at the University of Surrey, Guilford, United Kingdom, investigated just how HAM-R2 affects metabolism and precisely where. Fifteen obese, insulin-resistant men and women consumed a daily diet with powdered HAM-R2 supplements (Hi-Maize) or control (Amioca starch) for eight weeks. Researchers then measured glucose levels, discriminating between hepatic and peripheral insulin sensitivity. They also biopsied adipose tissue from the participants’ buttocks to quantify gene expression there. In their paper, to be published soon in The Journal of Clinical Endocrinology & Metabolism,* the researchers report a 65 percent increase in postprandial glucose uptake and 10 percent less fasting insulin resistance among the HAM-R2 group, which also demonstrated increased expression of hormone-sensitive lipase and lipoprotein lipase mRNA. Expression of these enzymes, in turn, indicates increased adipose tissue differentiation.

The researchers conclude that HAM-RS2 intake increased peripheral, but not hepatic, insulin sensitivity. These findings represent a big step toward an intervention for obese patients at risk of developing T2DM, they reported.

Thyroid Hormone Finds Alternative Paths into Growth Cells

Like commuters finding their way around a closed road, thyroid hormones can sometimes find alternative routes for getting to work.

Patients with the low hormone levels of congenital hypothyroidism suffer from short stature, but those with problems related to thyroid hormone transport may not. Thyroid hormone must find its way into a cell via transporter proteins to exert its actions on the nucleus, a process that is disrupted in conditions such as Allan-Herndon-Dudley syndrome (AHDS), which features mutations that interfere with the workings of a main thyroid hormone transporter, monocarboxylate transporter 8 (MCT8). AHDS patients grow to a fairly normal size but have severe neurological symptoms, including mental and motor retardation.

AHDS patients have high T3 levels, indicating that the thyroid is producing hormone that is not always getting where it needs to be. Researchers led by Noriyuki Namba, M.D., Ph.D., of Osaka University in Japan, hypothesized that AHDS patients grow because the thyroid hormone gains access to growth plate cartilage cells via transporters other than MCT8.

When the scientists analyzed thyroid hormone transporter mRNA expression in mouse chondrogenic ATDC5 cells, they found that monocarboxylate transporter 10 (MCT10) was abundantly expressed. MCT10 mRNA was also expressed abundantly in the growth plate resting zone chrondrocytes.

When the researchers silenced MCT10 mRNA expression in ATDC5 cells, they detected a significant decrease in T3 influx and reduced effects of the hormone. The results demonstrate that MCT10 serves as a thyroid hormone transporter into these cells.

In an article slated for publication in Endocrinology,* the researchers say that the role of MCT10 in bone growth warrants further investigation for potential application in addressing unresolved causes of short stature and skeletal dysplasias.

Regulating the Human Birth Clock

The placenta is thought to be the site of the hormonal clock that coordinates the complex gestational interplay of biologic processes between mother and fetus, resulting in the timing of parturition. Corticotropinreleasing hormone (CRH) of placental origin is one such substance that steadily increases during gestation, culminating with delivery. Based on the demonstration of nuclear factor κB (NF-κB) in term cytotrophoblastic nuclei coupled with NF- κB’s known roles in cell survival, differentiation, and proliferation, a new study investigated NF-κB as the possible positive placental CRH regulator.

Scientists led by Bingbing Wang, M.D., Ph.D., at the UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey, performed chromatin immunoprecipitation assays, among other tests, in primary cytotrophoblasts to determine whether the RelB/NF-κB2 complex, the alternate NF-κB pathway, is activated in the placenta at term. In their paper, to be published soon in Molecular Endocrinology,* the researchers report that RelB/NF-κB2 binds to a newly discovered NF-κB enhancer of CRH gene promoter to stimulate CRH transcription, thereby positively regulating CRH expression.

The researchers conclude that the noncanonical NF-κB pathway is necessary for CRH expression. Moreover, impairment in placental CRH regulation likely correlates with incongruous gestational duration and leads to preterm labor and birth, they said.

Low Testosterone Is Not a Natural Result of Aging

A new population-based study shows that testosterone levels can be more or less sustained throughout a man’s lifespan if he is healthy. Declining testosterone, the study said, is likely to be the result of lifestyle and chronic disease-related factors rather than aging.

Led by Gary Wittert, M.D., Freemasons Foundation Centre for Men’s Health, University of Adelaide in Australia, scientists took blood testosterone measurements from 1,382 men ages 35–80 years during two separate clinic visits 5 years apart. Of the total population studied, about 290 of the men were bachelors, about 162 smoked, about 414 were overweight or obese, nearly half had central obesity, and about 110 suffered from depression. In their paper, presented at ENDO 2012* by Andre B. Araujo, Ph.D., Department of Epidemiology, New England Research Institutes, Inc., Watertown, Massachusetts, the researchers reported that on average, testosterone levels decreased less than one percent each year. The men who revealed significant declines in serum measurements were those who became obese, had chronic cardiovascular disease, were depressed, quit smoking, or were unmarried.

The researchers concluded that testosterone decline is caused by health and lifestyle factors rather than a de facto result of aging. Making health care providers aware of this fact is critical for targeting the problems underlying the decline in testosterone, they added.

Zebrafish, a Big Catch for Vitamin D Studies

The tiny zebrafish (Danio rerio), a popular organism for scientific experiments because of its transparency and rapidly progressive embryonic state, is helping researchers unlock the role of the hormonal form of vitamin D, 1a,25-dihydroxyvitamin3 D (1a,25(OH)2 D3 ), during early development.

Based on previous findings that 1a,25(OH)2 D3 regulates hundreds of genes in vitro and that zebrafish abundantly begin to express the vitamin D receptor just 48 hours post-fertilization, scientists led by Rajiv Kumar, M.D., at the Mayo Clinic, Rochester, Minnesota, investigated vitamin D’s effects on gene expression patterns and metabolic pathways in vivo. After administering 1a,25(OH)2 D3 in ethanol or ethanol only for control, to the medium of groups of 25–30 zebrafish larvae 24 hours after fertilization, the scientists shotgun-sequenced these larvae’s whole transcriptomes. In their paper, to be published soon in Molecular Endocrinology,* the researchers report altered expression in more than 2,000 genes in response to 1a,25(OH)2 D3 .

The hormonal form of vitamin D regulates several mechanisms it was not previously known to influence, including transcription factors, fatty acid, amino acid, and xenobiotic metabolic pathways, and peptide hormones. Vitamin D, it turns out, is crucial for more than just calcium homeostasis and bone.

Benefits of Soy Diet for Prostate Cancer Linked to Estrogen

The mighty soybean is full of antioxidants and has been linked to a lower risk of prostate cancer. Soy contains genistein, a phytoestrogen shown to be an anti-cancer compound, and a new study looks at whether genistein relies on estrogen receptors to provide its shield against cancer.

A team of researchers, led by Anna Slusarz, Ph.D., and Glenn Jackson, D.V.M., from the Department of Biochemistry at the University of Missouri in Columbia bred mice lacking estrogen receptors alpha or beta (ERa and ERβ) and randomly assigned them to three different diet groups: casein alone, casein with 300 mg genistein/kg, or casein with 750 mg genistein/kg. The mice were fed these diets from 6 weeks of age until 5 months of age and then euthanized for tissue examination.

The researchers found that genistein consumption reduced the incidence of cancer in the mice with normal estrogen receptors (ERWT/TRAMP). Cancer occurred in 70 percent of the ERWT mice fed only casein, while the cancer incidence in ERWT mice fed low-dose genistein (300 mg/kg) was 47 percent and only 32 percent in the 750- mg/kg genistein group. Genistein had no effect on total cancer incidence in the mice bred without estrogen receptors. The data imply that genistein requires the presence of both estrogen receptors (ERa and ERβ) to enact its protective action.

The researchers conclude in their upcoming article in Endocrinology* that their study offers unique insight into the effects of estrogen receptor signaling on the development of prostate cancer. They add that although many questions remain, their data suggest that targeting both ERa and ERβ would be useful in preventing and treating prostate cancer.

High-Dose Estrogen Treatment for Tall Girls Linked to Infertility

Taking high doses of estrogen can stunt undesired tall height in girls, but it may also have a lasting impact on their later fertility.

For decades, adolescent girls have requested treatment to reduce their fi- nal height. In the 1960s daily doses of ethinyl estradiol (EE) as high as 500 mg were prescribed, but in later decades were reduced to 100 mg or 200 mg. Although previous research has linked the treatment to later infertility, a new study examines whether or not a higher estrogen dose is associated with increased infertility.

A team of Dutch researchers led by A. E.J. Hendriks, M.D., from Erasmus Medical Center-Sophia in Rotterdam, the Netherlands, studied 125 women ages 20–42 years who were treated with high doses of EE beginning at age 12 for 23–24 months. Fifty-two participants had been treated with 100 mg/day and 43 were treated with 200 mg/day. At the start of treatment, the girls were about 177 cm (69.7 inches) tall and were predicted to have final heights of 188–189 cm (74 inches).

Compared with untreated women, women taking the high doses of estrogen took longer to conceive their first pregnancy. Of the untreated women, 80 percent got pregnant within one year compared to 69 percent of those treated with 100 mg EE and 59 percent of the women treated with 200 mg. Estrogen treatments of both 100 and 200 mg also reduced the women’s fecundity compared with untreated women, and the incidence of women seeking fertility treatment increased significantly with increased estrogen dose.

In an upcoming article in The Journal of Clinical Endocrinology & Metabolism,* the researchers write that their results demonstrate for the first time the dose-dependent association between estrogen treatment and infertility.

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