Cerebral ischemia and neuroregeneration

Cerebral ischemia is one of the leading causes of morbidity and mortality worldwide. Although stroke （a form of cerebral ischemia）-related costs are expected to reach 240.67 billion dollars by 2030, options for treatment against cerebral ischemia/stroke are limited. All therapies except anti-thrombolytics （i.e., tissue plasminogen activator） and hypothermia have failed to reduce neuronal injury, neurological deficits, and mortality rates following cerebral ischemia, which suggests that development of novel therapies again st stroke/cerebral ischemia are urgently needed. Here, we discuss the possible mechanism（s） underlying cerebral ischemia-induced brain injury, as well as current and future novel therapies （i.e., growth factors, nicotinamide adenine dinucleotide, melatonin, resveratrol, protein kinase C isozymes, pifithrin, hypothermia, fatty acids, sympathoplegic drugs, and stem cells） as it relates to cerebral ischemia.

The Knee Joint Tissues Differ Significantly in TGFβ1 Expression and Its Sensitivity

The knee joint is the largest and most complex joint in the human body. In this study, we investigated TGFβ1 expression in the outer meniscus, inner meniscus and articular cartilage of rabbit and human knee tissue (outer and inner menisci) in order to determine the potential role of this factor in normal meniscal function. We also examined the potential of TGF-β1 stimulation to promote tissue regeneration in the two different regions of rabbit knee meniscus tissue. Immunohistochemical investigations of TGF-β1 were performed on rabbit and human knee tissue. The rabbit outer, inner and articular cartilage cells were culture and stimulated with TGF-β1 followed by cell proliferation assay and extracellular matrix analysis. Regulatory studies were performed using TGF-β1 inhibitors SB-431542 and PD98059. Gene expression was analyzed by quantitative polymerase chain reaction. We found marked regional variation in the expression of TGF-β1 in rabbit and human knee. TGF-β1 expressions are relatively greater in the outer meniscus than inner meniscus. Furthermore, we found that exogenous TGF-β1 stimulation increased cell proliferation and aggrecan synthesis more so in the outer than in the inner meniscus. Articular cartilage tissue shows moderate levels of cell proliferation and ECM synthesis when compared with outer and inner meniscus. These findings suggest that growth factors used to enhance the repair and regeneration of meniscal tissue should be tailored to enhance region-specific variation in cell proliferation and extracellular matrix synthesis.

Gut sterilization in experimental colitis leukocyte mediated colon injury, and effects on angiogenesis/lymphangiogenesis

Inappropriate responses to normal commensal bacteria trigger immune activation in both inflammatory bowel disease and experimental colitis. How gut flora contribute to the pathogenesis of inflammatory bowel disease is unclear, but may involve entrapment of leukocytes and remodeling of the vascular system. Here we evaluated how the progression and tissue remodeling in experimental colitis differ in a germ- free model of mouse colitis. Four treatment groups were used: control, antibiotic-treated (ABX), dextran sulfate colitis (DSS) and DSS pre- and co-treated with antibiotics (DSS + ABX). In days 0 - 3 of the study, germ-free mice received antibiotics (vancomycin, neomycin, and metronidazole). During the next 11 days, antibiotics were continued and DSS (3%) added to “colitis” groups. Disease activity, weight, stool form and blood were monitored daily. Mice were sacrificed and tissue samples harvested. Histopathological scores in controls (0.00) and in ABX (1.0+/–0.81) were significantly (p –0). Extents of injury, inflammation and crypt damage were all improved in DSS + ABX. The Disease Activity Index score (day 11) was significantly worse in the DSS group compared to the DSS + ABX group. Stool blood and form scores were also significantly improved among these groups. Importantly, myeloper- oxidase was significantly reduced in DSS + ABX, indicating that neutrophil infiltration was blocked. Colitis was associated with an increase in blood and lymphatic vessels;both of these events were also significantly reduced by gut sterilization. Our experiment shows that clinical and histopathological severity of colitis was significantly worse in the DSS colitis group compared to the DSS + ABX group, supporting the hypothesis that development of IBD is likely to be less severe with appropriate antibiotic treatment. In particular, gut sterilization effectively reduces leuko- cyte-dependent (PMN) injury to improve outcomes and may be an important target for therapy.

对中国以人巨细胞病毒感染小鼠模型进行相关研究的质疑和剖析

人巨细胞病毒（HCMV）也称疱疹病毒5型,属疱疹病毒β亚科,为线状双链DNA病毒。HCMV感染是人类最常见的感染性疾病,几乎任何年龄的个体均可患病。在发达国家和发展中国家人群的感染率为40%～100%。中国是HCMV感染的高发区,上海人群CMVIgG阳性率1～3岁组为60.37%,〉20岁组为97.03%[1]。

Role of the endothelium in inflammatory bowel diseases

Inflammatory bowel diseases(IBD) are a complex group of diseases involving alterations in mucosal immunity and gastrointestinal physiology during both initiation and progressive phases of the disease.At the core of these alterations are endothelial cells,whose continual adjustments in structure and function coordinate vascular supply,immune cell emigration,and regulation of the tissue environment.Expansion of the endothelium in IBD(angiogenesis),mediated by inflammatory growth factors,cytokines and chemokines,is a hallmark of active gut disease and is closely related to disease severity.The endothelium in newly formed or inflamed vessels differs from that in normal vessels in the production of and response to inflammatory cytokines,growth factors,and adhesion molecules,altering coagulant capacity,barrier function and blood cell recruitment in injury.This review examines the roles of the endothelium in the initiation and propagation of IBD pathology and distinctive features of the intestinal endothelium contributing to these conditions.

Selective serotonin re-uptake inhibitor sertraline inhibits bone healing in a calvarial defect model

Bone wound healing is a highly dynamic and precisely controlled process through which damaged bone undergoes repair and complete regeneration. External factors can alter this process, leading to delayed or failed bone wound healing. The findings of recent studies suggest that the use of selective serotonin reuptake inhibitors(SSRIs) can reduce bone mass, precipitate osteoporotic fractures and increase the rate of dental implant failure. With 10% of Americans prescribed antidepressants, the potential of SSRIs to impair bone healing may adversely affect millions of patients’ ability to heal after sustaining trauma. Here, we investigate the effect of the SSRI sertraline on bone healing through pre-treatment with(10 mg·kg-1sertraline in drinking water, n = 26) or without(control, n = 30) SSRI followed by the creation of a 5-mm calvarial defect. Animals were randomized into three surgical groups:(a) empty/sham,(b) implanted with a DermaMatrix scaffold soak-loaded with sterile PBS or(c) DermaMatrix soak-loaded with542.5 ng BMP2. SSRI exposure continued until sacrifice in the exposed groups at 4 weeks after surgery. Sertraline exposure resulted in decreased bone healing with significant decreases in trabecular thickness, trabecular number and osteoclast dysfunction while significantly increasing mature collagen fiber formation. These findings indicate that sertraline exposure can impair bone wound healing through disruption of bone repair and regeneration while promoting or defaulting to scar formation within the defect site.

Loss of microRNAs in thymus perturbs invariant NKT cell development and function

microRNAs(miRNAs)are small noncoding RNAs that mediate RNA interference to suppress protein expression at the translational level.Accumulated evidence indicates that miRNAs play critical roles in various biological processes and disease development,including autoimmune diseases.Invariant natural killer T(iNKT)cells are an unusual CD1d-restricted subset of thymus-derived T cells that are potent regulators of diverse immune responses.Our previous studies with the mouse model of bone marrow-specific Dicer deletion suggest the involvement of Dicer-dependent miRNAs in the development and function of iNKT cells.In the present study,to further dissect the functional levels of Dicer-dependent miRNAs in regulating iNKT cell development,we generated a mouse model with the Dicer deletion in the thymus.Our data indicate that lack of miRNAs following the deletion of Dicer in the thymus severely interrupted the development and maturation of iNKT cells in the thymus and significantly decreased the number of iNKT cells in the peripheral immune organs.miRNA-deficient peripheral iNKT cells display profound defects in activation and cytokine production upon a-galactosylceramide(a-GalCer)stimulation.Our results demonstrate a critical role of the miRNA-dependent pathway in the thymus in the regulation of iNKT cell development and function.

MicroRNAs are key regulators controlling iNKT and regulatory T-cell development and function

MicroRNAs(miRNAs)are an abundant class of evolutionarily conserved,small,non-coding RNAs that post-transcriptionally regulate expression of their target genes.Emerging evidence indicates that miRNAs are important regulators that control the development,differentiation and function of different immune cells.Both CD4^(+)CD25^(+)Foxp3^(+) regulatory T(Treg)cells and invariant natural killer T(iNKT)cells are critical for immune homeostasis and play a pivotal role in the maintenance of self-tolerance and immunity.Here,we review the important roles of miRNAs in the development and function of iNKT and Treg cells.

Mitochondria as a target for neuroprotection: role of methylene blue and photobiomodulation

Mitochondrial dysfunction plays a central role in the formation of neuroinflammation and oxidative stress,which are important factors contributing to the development of brain disease.Ample evidence suggests mitochondria are a promising target for neuroprotection.Recently,methods targeting mitochondria have been considered as potential approaches for treatment of brain disease through the inhibition of inflammation and oxidative injury.This review will discuss two widely studied approaches for the improvement of brain mitochondrial respiration,methylene blue(MB)and photobiomodulation(PBM).MB is a widely studied drug with potential beneficial effects in animal models of brain disease,as well as limited human studies.Similarly,PBM is a non-invasive treatment that promotes energy production and reduces both oxidative stress and inflammation,and has garnered increasing attention in recent years.MB and PBM have similar beneficial effects on mitochondrial function,oxidative damage,inflammation,and subsequent behavioral symptoms.However,the mechanisms underlying the energy enhancing,antioxidant,and anti-inflammatory effects of MB and PBM differ.This review will focus on mitochondrial dysfunction in several different brain diseases and the pathological improvements following MB and PBM treatment.

Potential underlying genetic associations between keratoconus and diabetes mellitus

Background:Keratoconus(KC)is the most common ectatic corneal disease,characterized by significantly localized thinning of the corneal stroma.Genetic,environmental,hormonal,and metabolic factors contribute to the pathogenesis of KC.Additionally,multiple comorbidities,such as diabetes mellitus,may affect the risk of KC.Main Text:Patients with diabetes mellitus(DM)have been reported to have lower risk of developing KC by way of increased endogenous collagen crosslinking in response to chronic hyperglycemia.However,this remains a debated topic as other studies have suggested either a positive association or no association between DM and KC.To gain further insight into the underlying genetic components of these two diseases,we reviewed candidate genes associated with KC and central corneal thickness in the literature.We then explored how these genes may be regulated similarly or differentially under hyperglycemic conditions and the role they play in the systemic complications associated with DM.Conclusions:Our comprehensive review of potential genetic factors underlying KC and DM provides a direction for future studies to further determine the genetic etiology of KC and how it is influenced by systemic diseases such as diabetes.

Microglial SIRPα Deletion Facilitates Synapse Loss in Preclinical Models of Neurodegeneration

Microglia,the principal immune cells in the brain,play a vital role in the development and homeostasis of the central nervous system[1,2].During early brain development,microglia-mediated synapse pruning contributes to eliminating excess synapses that are unnecessary in adulthood[3].Excessive microglia-mediated pruning in the adult brain is implicated in neurodegeneration-associated behav・ioral deficits[4,5].

MicroRNAs in treatment-induced neuroendocrine differentiation in prostate cancer

Prostate cancer is a condition commonly associated with men worldwide.Androgen deprivation therapy remains one of the targeted therapies.However,after some years,there is biochemical recurrence and metastatic progression into castration-resistant prostate cancer(CRPC).CRPC cases are treated with second-line androgen deprivation therapy,after which,these CRPCs transdifferentiate to form neuroendocrine prostate cancer(NEPC),a highly aggressive variant of CRPC.NEPC arises via a reversible transdifferentiation process,known as neuroendocrine differentiation(NED),which is associated with altered expression of lineage markers such as decreased expression of androgen receptor and increased expression of neuroendocrine lineage markers including enolase 2,chromogranin A and synaptophysin.The etiological factors and molecular basis for NED are poorly understood,contributing to a lack of adequate molecular biomarkers for its diagnosis and therapy.Therefore,there is a need to fully understand the underlying molecular basis for this cancer.Recent studies have shown that microRNAs(miRNAs)play a key epigenetic role in driving therapy-induced NED in prostate cancer.In this review,we briefly describe the role of miRNAs in prostate cancer and CRPCs,discuss some key players in NEPCs and elaborate on miRNA dysregulation as a key epigenetic process that accompanies therapy-induced NED in metastatic CRPC.This understanding will contribute to better clinical management of the disease.