Does MgSO_(4) protect the preterm brain?Dissecting its role in the pathophysiology of hypoxic ischemic encephalopathy

Mitigating preterm encephalopathy continues to be one of the greatest challenges in perinatal medicine.Preterm encephalopathy is associated with high mortality,serious morbidity,and significant socio-economic impacts on the individuals,their families,and public health sectors and welfare systems that last a lifetime.The cost of disability associated with preterm brain injury continues to rise.Prevention of this injury,and disability,would significantly reduce this socioeconomic burden.

Glia and hemichannels: key mediators of perinatal encephalopathy

Perinatal encephalopathy remains a major cause of disability, such as cerebral palsy. Therapeutic hypo- thermia is now well established to partially reduce risk of disability in late preterm/term infants. However, new and complementary therapeutic targets are needed to further improve outcomes. There is increasing evidence that glia play a key role in neural damage after hypoxia-ischemia and infection/inflammation. In this review, we discuss the role of astrocytic gap junction （connexin） hemichannels in the spread of neural injury after hypoxia-ischemia and/or infection/inflammation. Potential mechanisms of hemichannel medi- ated injury likely involve impaired intraceUular calcium handling, loss of blood-brain barrier integrity and release of adenosine triphosphate （ATP） resulting in over-activation of purinergic receptors. We propose the hypothesis that inflammation-induced opening of connexin hemichannels is a key regulating event that initiates a vicious cycle of excessive ATP release, which in turn propagates activation of purinergic receptors on microglia and astrocytes. This suggests that developing new neuroprotective strategies for preterm infants will benefit from a detailed understanding of glial and connexin hemichannel responses.

Interleukin-1:an important target for perinatal neuroprotection?

Perinatal inflammation is a significant risk factor for lifelong neurodevelopmental impairments such as cerebral palsy.Extensive clinical and preclinical evidence links the severity and pattern of perinatal inflammation to impaired maturation of white and grey matters and reduced brain growth.Multiple pathways are involved in the pathogenesis of perinatal inflammation.However,studies of human and experimental perinatal encephalopathy have demonstrated a strong causative link between perinatal encephalopathy and excessive production of the pro-inflammatory effector cytokine interleukin-1.In this review,we summarize clinical and preclinical evidence that underpins interleukin-1 as a critical factor in initiating and perpatuating systemic and central nervous system inflammation and subsequent perinatal brain injury.We also highlight the important role of endogenous interleukin-1 receptor antagonist in mitigating interleukin-1-driven neuroinflammation and tissue damage,and summarize outcomes from clinical and mechanistic animal studies that establish the commercially available interleukin-1 receptor antagonist,anakinra,as a safe and effective therapeutic intervention.We reflect on the evidence supporting clinical translation of interleukin-1 receptor antagonist for infants at the greatest risk of perinatal inflammation and impaired neurodevelopment,and suggest a path to advance interleukin-1 receptor antagonist along the translational path for perinatal neuroprotection.

Thirteen years to get from b to a:one of the neglected isoforms of IL-37 enters the stage

Interleukin(IL)-37 is one of the few anti-inflammatory members of the predominantly pro-inflammatory IL-1 cytokine family.IL-37 possesses alarmin-like properties[1]and exerts its activities via intracellular[2]as well as cell surface receptor-dependent mechanisms,and the latter involves IL-1R8 and IL-18Rα[3].Because of its powerful and broad-spectrum“peacemaking”[4]functions,considerable efforts have been invested in developing IL-37-based anti-inflammatory therapeutics[5,6].

Endometrial mesenchymal stem cells as a cell based therapy for pelvic organ prolapse

Pelvic organ prolapse(POP) occurs when the pelvic organs(bladder, bowel or uterus) herniate into the vagina, causing incontinence, voiding, bowel and sexual dysfunction, negatively impacting upon a woman's quality of life. POP affects 25% of all women and results from childbirth injury. For 19% of all women, surgical reconstructive surgery is required for treatment, often augmented with surgical mesh. The surgical treatment fails in up to 30% of cases or results in adverse effects, such as pain and mesh erosion into the bladder, bowel or vagina. Due to these complications the Food and Drug Administration cautioned against the use of vaginal mesh and several major brands have been recently been withdrawn from market. In this review we will discuss new cell-based approaches being developed for the treatment of POP. Several cell types have been investigated in animal models, including a new source of mesenchymal stem/stromal cells(MSC) derived from human endometrium. The unique characteristics of endometrial MSC, methods for their isolation and purification and steps towards their development for good manufacturing practice production will be described. Animal models that could be used to examine the potential for this approach will also be discussed as will a rodent model showing promise in developing an endometrial MSC-based therapy for POP. The development of a preclinical large animal model for assessing tissue engineering constructs for treating POP will also be mentioned.

Amnion epithelial cells——a novel therapy for ischemic stroke?

Stroke is a leading cause of death and disability and new therapies are desperately needed. Given the complex nature of ischemic brain injury, it has been postulated that cell-based therapies may be useful. However, cell resources, invasive extraction procedures, immunological rejection, tumorigenesis and ethical challenges make it unlikely that many stem cell types could serve as a practical source for therapy. By contrast, these issues do not pertain to human amnion epithelial cells（h AECs）, which are placenta-derived stem cells. We recently assessed the effects of systemically delivered hAECs on stroke outcome using four animal models of stroke. We demonstrated that when injected intravenously after ischemia onset, hAECs migrate preferentially to the spleen and injured brain to limit apoptosis and inflammation, and attenuate early brain infiltration of immune cells, progression of infarction and systemic immunosuppression and to ultimately ameliorate functional deficits. When administration of hAECs is delayed by 1-3 days poststroke, long-term functional recovery can still be enhanced in young and aged mice of either sex. Moreover, our proof-of-principle findings suggest that h AECs are effective at limiting post-stroke infarct development in non-human primates. Overall, the results suggest that hAECs could be a viable clinical stroke therapy.

The landscape of aging

Aging is characterized by a progressive deterioration of physiological integrity,leading to impaired functional ability and ultimately increased susceptibility to death.It is a major risk factor for chronic human diseases,including cardiovascular disease,diabetes,neurological degeneration,and cancer.Therefore,the growing emphasis on “healthy aging” raises a series of important questions in life and social sciences.In recent years,there has been unprecedented progress in aging research,particularly the discovery that the rate of aging is at least partly controlled by evolutionarily conserved genetic pathways and biological processes.In an attempt to bring full-fledged understanding to both the aging process and age-associated diseases,we review the descriptive,conceptual,and interventive aspects of the landscape of aging composed of a number of layers at the cellular,tissue,organ,organ system,and organismal levels.

Claudin-11 and occludin are major contributors to Sertoli cell tight junction function, in vitro

The Sertoli cell tight junction （T J） is the key component of the blood-testis barrier, where it sequesters developing germ cells undergoing spermatogenesis within the seminiferous tubules. Hormonally regulated claudin-11 is a critical transmembrane protein involved in barrier function and its murine knockout results in infertility. We aimed to assess quantitatively the significance of the contribution of claudin-11 to TJ function, in vitro, using siRNA-mediated gene silencing. We also conducted an analysis of the contribution of occludin, another intrinsic transmembrane protein of the TJ. Silencing of claudin-11 and/or occludin was conducted using siRNA in an immature rat Sertoli cell culture model. Transepithelial electrical resistance was used to assess quantitatively TJ function throughout the culture. Two days after siRNA treatment, cells were fixed for immunocytochemical localization of junction proteins or lyzed for RT-PCR assessment of mRNA expression. Silencing of claudin-11, occludin, or both resulted in significant decreases in TJ function of 55% （P 〈 0.01）, 51% （P 〈 0.01）, and 62% （P 〈 0.01）, respectively. Data were concomitant with significant decreases in mRNA expression and marked reductions in the localization of targeted proteins to the Sertoli cell TJ. We provide quantitative evidence that claudin-11 contributes significantly （P 〈 0.01） to Sertoli cell TJ function in vitro. Interestingly, occludin, which is hormonally regulated but not implicated in infertility until late adulthood, is also a significant （P 〈 0.01） contributor to barrier function. Our data are consistent with in vivo studies that clearly demonstrate a role for these proteins in maintaining normal TJ barrier structure and function.

Putting things in place for fertilization： discovering roles for importin proteins in cell fate and spermatogenesis

Importin proteins were originally characterized for their central role in protein transport through the nuclear pores, the only intracellular entry to the nucleus. This vital function must be tightly regulated to control access by transcription factors and other nuclear proteins to genomic DNA, to achieve appropriate modulation of cellular behaviors affecting cell fate. Importin-mediated nucleocytoplasmic transport relies on their specific recognition of cargoes, with each importin binding to distinct and overlapping protein subsets. Knowledge of importin function has expanded substantially in regard to three key developmental systems： embryonic stem cells, muscle cells and the germ line. In the decade since the potential for regulated nucleocytoplasmic transport to contribute to spermatogenesis was proposed, we and others have shown that the importins that ferry transcription factors into the nucleus perform additional roles, which control cell fate. This review presents key findings from studies of mammalian spermatogenesis that reveal potential new pathways by which male fertility and infertility arise. These studies of germline genesis illuminate new ways in which importin proteins govern cellular differentiation, includ ng v a d rect ng proteins to d st nct ntrace ular compartments and by determining cellular stress responses.

Ets-2 deletion in myeloid cells attenuates IL-1α-mediated inflammatory disease caused by a Ptpn6 point mutation

The SHP-1 protein encoded by the Ptpn6 gene has been extensively studied in hematopoietic cells in the context of inflammation.A point mutation in this gene(Ptpn6spin)causes spontaneous inflammation in mice,which has a striking similarity to neutrophilic dermatoses in humans.Recent findings highlighted the role of signaling adapters and kinases in promoting inflammation in Ptpn6spin mice;however,the underlying transcriptional regulation is poorly understood.Here,we report that SYK is important for driving neutrophil infiltration and initiating wound healing responses in Ptpn6spin mice.Moreover,we found that deletion of the transcription factor Ets2 in myeloid cells ameliorates cutaneous inflammatory disease in Ptpn6spin mice through transcriptional regulation of its target inflammatory genes.Furthermore,Ets-2 drives IL-1α-mediated inflammatory signaling in neutrophils of Ptpn6spin mice.Overall,in addition to its well-known role in driving inflammation in cancer,Ets-2 plays a major role in regulating IL-1α-driven Ptpn6spin-mediated neutrophilic dermatoses.