Sex differences in the biomechanical and biochemical responses of caudal rat intervertebral discs to injury.

Background: Intervertebral disc degeneration (IDD) is a major cause of low back pain (LBP) worldwide. Sexual dimorphism, or sex-based differences, appear to exist in the severity of LBP. However, it is unknown if there are sex-based differences in the inflammatory, biomechanical, biochemical, and histological responses of intervertebral discs (IVDs). Methods: Caudal (Coccygeal/Co) bone-disc-bone motion segments were isolated from multiple spinal levels (Co8 to Co14) of male and female Sprague-Dawley rats. Changes in motion segment biomechanics and extracellular matrix (ECM) biochemistry (glycosaminoglycan [GAG], collagen [COL], water, and DNA content) were evaluated at baseline and in response to chemical insult (lipopolysaccharide [LPS]) or puncture injury ex vivo. We also investigated the contributions of Toll-like receptor (TLR4) signaling on responses to LPS or puncture injury ex vivo, using a small molecule TLR4 inhibitor, TAK-242. Results: Findings indicate that IVD motion segments from female donors had greater nitric oxide (NO) release in LPS groups compared to male donors. HMGB1 release was increased in punctured discs, but not LPS injured discs, with no sex effect. Although both male and female discs exhibited reductions in dynamic moduli in response to LPS and puncture injuries, dynamic moduli from female donors were higher than male donors across all groups. In uninjured (baseline) samples, a significant sex effect was observed in nucleus pulposus (NP) DNA and water content. Female annulus fibrosus (AF) also had higher DNA, GAG, and COL content (normalized by dry weight), but lower water content than male AF. Additional injury- and sex-dependent effects were observed in AF GAG/DNA and COL/DNA content. Finally, TAK-242 improved the dynamic modulus of female but not male punctured discs. Conclusions: Our findings demonstrate that there are differences in rat IVD motion segments based on sex, and that the response to injury in inflammatory, biomechanical, biochemical, and histological outcomes also exhibit sex differences. TLR4 inhibition protected against loss of mechanical integrity of puncture-injured IVD motion segments, with differences responses based on donor sex.

Impact of Metabolic Hormones Secreted in Human Breast Milk on Nutritional Programming in Childhood Obesity.

Obesity is the most common metabolic disease whose prevalence is increasing worldwide. This condition is considered a serious public health problem due to associated comorbidities such as diabetes mellitus and hypertension. Perinatal morbidity related to obesity does not end with birth; this continues affecting the mother/infant binomial and could negatively impact on metabolism during early infant nutrition. Nutrition in early stages of growth may be essential in the development of obesity in adulthood, supporting the concept of "nutritional programming". For this reason, breastfeeding may play an important role in this programming. Breast milk is the most recommended feeding for the newborn due to the provided benefits such as protection against obesity and diabetes. Health benefits are based on milk components such as bioactive molecules, specifically hormones involved in the regulation of food intake. Identification of these molecules has increased in recent years but its action has not been fully clarified. Hormones such as leptin, insulin, ghrelin, adiponectin, resistin, obestatin and insulin-like growth factor-1 copeptin, apelin, and nesfatin, among others, have been identified in the milk of normal-weight women and may influence the energy balance because they can activate orexigenic or anorexigenic pathways depending on energy requirements and body stores. It is important to emphasize that, although the number of biomolecules identified in milk involved in regulating food intake has increased considerably, there is a lack of studies aimed at elucidating the effect these hormones may have on metabolism and development of the newborn. Therefore, we present a state-of-the-art review regarding bioactive compounds such as hormones secreted in breast milk and their possible impact on nutritional programming in the infant, analyzing their functions in appetite regulation.

The tyrphostin B42 inhibits cell proliferation and HER-2 autophosphorylation in cervical carcinoma cell lines.

The HER family receptors have an important role controlling cell growth and differentiation. Although the activity of the HER-2 receptor is strictly controlled in normal cells, its overexpression plays a pivotal role in transformation and tumorigenesis. Constitutive phosphorylation of HER-2 protein has been implicated in conferring uncontrolled growth to mammary cancer cells, and to a lesser extent, with adenocarcinoma of uterus, cervix, fallopian tube, and endometrium. This study addresses the role of HER-2 in cervical carcinoma. Firstly, we demonstrate the presence of HER-2 protein expression by flow cytometry in two new cervical carcinoma cell lines CALO and INBL. Secondly, we use the specific tyrosine kinase inhibitors, Tyrphostins to examine HER-2 regulation by the crystal violet assay. Thirdly, we use western blot analysis to assess the state of HER-2 phosphorylation. The most efficient agent, Tyrphostin B42, known as an inhibitor of epithelial growth factor receptor, arrested cervical carcinoma cell lines growth in vitro at micromolar concentrations within 72 h of application. Tyrphostin B42 inhibited the HER2 signal-regulated kinase pathway, as observed by the reduction in the phosphorylated forms of HER2. The loss of phosphorylated forms of HER2 at early time points after Tyrphostin B42 application was associated with suppression of cell growth. Thus, the inhibition of the proliferation of our cervical carcinoma cell lines by Tyrphostin B42 is associated with inhibition of HER2 protein kinase signal.