Objectives: Left ventricular remodeling is a frequent complication of hypertension with no therapeutic treatment available for the subsequent onset of myocardial fibrosis. Pirfenidone is an antifibrotic small-molecular-size drug with anti-inflammatory properties that is used as a treatment for fibrotic diseases, but its effects on hypertension-induced myocardial fibrosis are unknown. Therefore, we tested whether pirfenidone could ameliorate hypertension-induced left ventricular remodeling and whether hypertension-induced NLRP3 (Nod-like receptor pyrin domain containing 3), a critical protein in NLRP3 inflammasome formation, is involved in the therapeutic mechanism. Methods: A TAC-induced mouse model of hypertension and left ventricular hypertrophy was treated with pirfenidone, and survival, collagen deposition by histopathologic examination, heart function by echocardiography, concentrations of fibrosis-related inflammatory cytokines TGF-β₁, IL-1β in heart homogenate and in vitro cell cultures by ELISA, levels of ROS and inflammatory cells by flow cytometry, and levels of NLRP3 by Western blotting and immunohistochemistry were measured. Results: Pirfenidone increased the survival rate and attenuated myocardial fibrosis and inflammatory mediators in the TAC-induced hypertension-complicated left ventricular remodeling mouse model. The inhibition of NLRP3 expression by pirfenidone attenuated the expression of IL-1β and IL-1β-induced inflammatory and profibrotic responses. Conclusions: Pirfenidone may be useful in the treatment of hypertension-induced myocardial fibrosis by inhibiting NLRP3-induced inflammation and fibrosis.

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Gonadotropin-releasing hormone (GnRH) has been found to be expressed in ovaries of various species and to modulate cell differentiation in ovarian cells. GnRH agonists (GnRHa) are widely used in the stimulation protocols of assisted reproduction. In the present study, the direct effects of a GnRHa on the incidence of apoptosis and sterodogenesis in porcine in human granulosa cells were investigated. Cells were obtained from 6-month-old swine and in vitro fertilization patients, and cultured in minimum essential medium (MEM) supplemented with 5% fetal bovine serum for 24 h. The GnRHa (burserelin acetate) was added to the MEM at various concentrations (0, 5, 50, 500 pg/ml, and 5 ng/ml). The nuclei of granulosa cells were examined by fluorescence microscopy after Hoechst 33258 staining, and the incidence of apoptotic cells was tabulated. The GnRHa directly increased the incidence of apoptosis in both types of granulosa cells. The concentration of GnRHa in clinical use is much higher than the concentration which produced apoptosis in granulosa cells here. The clinical dosage of GnRHa should be reconsidered with regard to its apoptosis-inducing effect.

Although it is well known that the uterine cervix contains mucin-producing glandular epithelium, only a few studies have described the changes in mucin that accompany malignant transformation. In this study the authors evaluated the characteristics of mucin expression in the normal endocervical epithelium and mucinous and endometrioid adenocarcinomas of the uterine cervix. The normal endocervical epithelium was characterized by predominant sulfomucin and MUC1 expression in all sites and MUC5AC expression in the surface epithelium, while MUC2 was not detected at all and pyloric gland type mucin (using antibody HIK1083) was detected in less than 1% of cases. Cervical adenocarcinomas, especially mucinous adenocarcinomas, showed marked variability in mucin expression that included mucins of pyloric gland and intestinal type.

Decreased n-3 fatty acid levels have been reported in patients with depression, schizophrenia or Alzheimer's disease. Recently, eicosapentaenoic acid (EPA) has been used to treat several psychiatric and neurodegenerative diseases due to its anti-inflammatory and neuroprotective effects. A total of six out of seven clinical trials have shown that EPA significantly improved depressive symptoms when compared with the placebo-treated populations. Several investigations have also reported that EPA could effectively treat schizophrenia. A case report and a clinical trial have shown that EPA was beneficial for the management of most symptoms of Huntington's disease, while a more extensive clinical investigation has demonstrated that EPA could only improve motor functions. Further clinical studies are required to fully explore the effects of EPA on other neurodegenerative diseases. The limitations of previous studies and further research directions have also been discussed.

Background Spinal cord injury (SCI) is a debilitating medical condition that can result in the irreversible loss of sensorimotor function. Current therapies fail to provide an effective recovery being crucial to develop more effective approaches. Mesenchymal stem cell (MSC) exosomes have been shown to be able to facilitate axonal growth and act as mediators to regulate neurogenesis and neuroprotection, holding great therapeutic potential in SCI conditions. This study aimed to assess the potential of human placental MSC (hpMSC)-derived exosomes on the functional recovery and reactivation of endogenous neurogenesis in an experimental animal model of SCI and to explore the possible mechanisms involved. Methods The hpMSC-derived exosomes were extracted and transplanted in an experimental animal model of SCI with complete transection of the thoracic segment. Functional recovery, the expression of neural stem/progenitor cell markers and the occurrence of neurogenesis, was assessed 60 days after the treatment. In vitro, neural stem cells (NSCs) were incubated with the isolated exosomes for 24 h, and the phosphorylation levels of mitogen-activated protein kinase kinase (MEK), extracellular signal-regulated kinases (ERK), and cAMP response element binding (CREB) proteins were assessed by western blot. Results Exosomes were successfully isolated and purified from hpMSCs. Intravenous injections of these purified exosomes significantly improved the locomotor activity and bladder dysfunction of SCI animals. Further study of the exosomes’ therapeutic action revealed that hpMSC-derived exosomes promoted the activation of proliferating endogenous neural stem/progenitor cells as denoted by the significant increase of spinal SOX2+GFAP+, PAX6+Nestin+, and SOX1+KI67+ cells. Moreover, animals treated with exosomes exhibited a significative higher neurogenesis, as indicated by the higher percentage of DCX+MAP 2+ neurons. In vitro, hpMSC-derived exosomes promoted the proliferation of NSCs and the increase of the phosphorylated levels of MEK, ERK, and CREB. Conclusions This study provides evidence that the use of hpMSC-derived exosomes may constitute a promising therapeutic strategy for the treatment of SCI.

A main challenge in the development of new agents for the treatment of Pseudomonas aeruginosa infections is the identification of chemotypes that efficiently penetrate the cell envelope and are not susceptible to established resistance mechanisms. Siderophore-conjugated monocarbams are attractive because of their ability to hijack the bacteria's iron uptake machinery for transport into the periplasm and their inherent stability to metallo-β-lactamases. Through development of the SAR we identified a number of modifications to the scaffold that afforded active anti-P. aeruginosa agents with good physicochemical properties. Through crystallographic efforts we gained a better understanding into how these compounds bind to the target penicillin binding protein PBP3 and factors to consider for future design. KEYWORDS: Pseudomonas aeruginosa, β-lactam, penicillin binding protein, siderophore, monocarbam, structure-guided design O ne of the largest challenges in the discovery of new Gram-negative antibacterial agents is the identification of chemotypes that can penetrate the cell envelope. 1 The pathogens, such as Pseudomonas aeruginosa (P. aeruginosa), have evolved complex cell architectures including an outer membrane composed of charged lipopolysaccharides, a thin peptidogylcan layer, and an inner membrane made up of phospholipids. 2 Identifying molecules with the necessary features to enable permeation has been a challenge.β-Lactams are one chemotype that have been successful in the treatment of P. aeruginosa. 3 Since the discovery of penicillin, β-lactams have been used in the clinic and are still widely prescribed. One of the most effective classes of β-lactams for the treatment of P. aeruginosa infections are the carbapenems (e.g., meropenem, 1, Figure 1). 4 Their effectiveness stems from their ability to acylate their penicillin-binding protein (PBP) targets, aided by high permeability into P. aeruginosa through the outer membrane porins. 5 However, they are currently being challenged in the clinic by the increasing emergence of broadspectrum serine β-lactamases and metallo-β-lactamases which hydrolyze most β-lactams and render them ineffective. 6 There is one class of β-lactams that is stable to the metallo-β-lactamases: the monocyclic β-lactams represented by aztreonam (2). Aztreonam however has limited effectiveness against P. aeruginosa presumably due to its poor permeation of the outer membrane, β-lactamase susceptibility, and high propensity for efflux (P. aeruginosa MIC 90 ≥ 1024 μg/mL, n = 20 panel). 3,7 To address the poor activity of 2, we focused on improving permeation by introducing siderophore mimics to promote uptake. 8−10 Siderophores are small Fe-chelating molecules synthesized and secreted by bacteria to scavenge iron from the host. 9,11 The iron-complexed siderophores are then brought into the cell via the iron uptake machinery, enabling the bacteria to access the much needed nutrient. It has been shown that introduction of iron-chelating groups to a monocyclic β-lactam scaffold ca...

Classic hypotheses of Alzheimer’s disease (AD) include cholinergic neuron death, acetylcholine (ACh) deficiency, metal ion dynamic equilibrium disorder, and deposition of amyloid and tau. Increased evidence suggests neuroinflammation and oxidative stress may cause AD. However, none of these factors induces AD independently, but they are all associated with the formation of Aβ and tau proteins. Current clinical treatments based on ACh deficiency can only temporarily relieve symptoms, accompanied with many side-effects. Hence, searching for natural neuroprotective agents, which can significantly improve the major symptoms and reverse disease progress, have received great attention. Currently, several bioactive marine products have shown neuroprotective activities, immunomodulatory and anti-inflammatory effects with low toxicity and mild side effects in laboratory studies. Recently, chitosan (CTS), chitooligosaccharide (COS) and their derivatives from exoskeletons of crustaceans and cell walls of fungi have shown neuroprotective and antioxidative effects, matrix metalloproteinase inhibition, anti-HIV and anti-inflammatory properties. With regards to the hypotheses of AD, the neuroprotective effect of CTS, COS, and their derivatives on AD-like changes in several models have been reported. CTS and COS exert beneficial effects on cognitive impairments via inhibiting oxidative stress and neuroinflammation. They are also a new type of non-toxic β-secretase and AChE inhibitor. As neuroprotective agents, they could reduce the cell membrane damage caused by copper ions and decrease the content of reactive oxygen species. This review will focus on their anti-neuroinflammation, antioxidants and their inhibition of β-amyloid, acetylcholinesterase and copper ions adsorption. Finally, the limitations and future work will be discussed.