The effect of black cohosh extract and risedronate coadministration on bone health in an ovariectomized rat model

Preparations of black cohosh extract are sold as dietary supplements marketed to relieve the vasomotor symptoms of menopause, and some studies suggest it may protect against postmenopausal bone loss. Postmenopausal women are also frequently prescribed bisphosphonates, such as risedronate, to prevent osteoporotic bone loss. However, the pharmacodynamic interactions between these compounds when taken together is not known. To investigate possible interactions, 6-month-old, female Sprague-Dawley rats underwent bilateral ovariectomy or sham surgery and were treated for 24 weeks with either vehicle, ethinyl estradiol, risedronate, black cohosh extract or coadministration of risedronate and black cohosh extract, at low or high doses. Bone mineral density (BMD) of the femur, tibia, and lumbar vertebrae was then measured by dual-energy X-ray absorptiometry (DEXA) at weeks 0, 8, 16, and 24. A high dose of risedronate significantly increased BMD of the femur and vertebrae, while black cohosh extract had no significant effect on BMD individually and minimal effects upon coadministration with risedronate. Under these experimental conditions, black cohosh extract alone had no effect on BMD, nor did it negatively impact the BMD-enhancing properties of risedronate

Zika virus protection by a single low dose nucleoside modified mRNA vaccination

Zika virus (ZIKV) has recently emerged as an explosive pandemic associated with severe neuropathology in newborns and adults1. There are no ZIKV-specific treatments or preventatives; thus, development of a safe and effective vaccine is a high priority. Messenger RNA (mRNA) has emerged as a versatile and highly effective platform to deliver vaccine antigens and therapeutic proteins2,3. Here, we demonstrate that a single low-dose intradermal immunization with lipid nanoparticle-encapsulated nucleoside-modified mRNA (mRNA-LNP) encoding the pre-membrane and envelope (prM-E) glycoproteins of a 2013 ZIKV outbreak strain elicited potent and durable neutralizing antibody responses in mice and non-human primates. Immunization with 30 μg of nucleoside-modified ZIKV mRNA-LNPs protected mice from ZIKV challenges at 2 weeks or 5 months post-vaccination, and a single dose of 50 μg was sufficient to protect non-human primates from a challenge at 5 weeks post-vaccination. These data demonstrate that nucleoside-modified mRNA-LNPs elicit rapid and durable protective immunity and thus represent a new and promising vaccine candidate for the global fight against ZIKV

Route of Arsenic Exposure Differentially Impacts the Expression of Genes Involved in Gut-Mucosa-Associated Immune Responses and Gastrointestinal Permeability

First-pass metabolism alters arsenic biotransformation and its immunomodulatory activities. This study aims to determine the mRNA expression of intestinal-immunity- and permeability-associated genes, levels of cytokine/chemokines and levels of immunoglobulin isotypes when CD-1 mice were exposed to a single dose of intravenous (IV) sodium arsenite (50 µg/kg body weight (BW)) and to compare these responses to exposure via oral gavage (OG) (50 µg/kg BW). Samples were collected at 1, 4, 24 and 48 h post IV exposure and 24 and 48 h post OG. Sodium arsenite IV exposure led to a transient modulation of mRNA expression and protein levels of immunity-related genes involved in inflammation/apoptotic pathways and production of cytokines/chemokines, whereas it also led to downregulated expression of genes encoding tight junction, focal adhesion, and gap junction proteins, which are responsible for maintaining cell permeability. Oral exposure perturbed fewer cell-permeability-related genes at 24 and 48 h post exposure. At 24 h post exposure, OG decreased IgA and IgG2b levels; however, IV exposure significantly increased IgG2b, IgG3 and IgA in ileal tissue. Earlier, we showed significant downregulation of mRNA expression of genes involved in the immune-related pathways during OG in the intestinal mucosa of the same animals. Cumulatively, these results provide evidence that the exposure route of a xenobiotic can differentially impact the intestinal responses due to the impact of first-pass metabolism

Quantitative proteomic analysis of the Anopheles gambiae (Diptera: Culicidae) midgut infected with o’nyong–nyong virus

Alphaviruses are arthropod-borne pathogens that infect a range of hosts. In humans and other mammals, alphavirus infection can cause severe disease. In mosquito hosts, however, there are generally few symptoms. Little is known about the cellular responses of mosquitoes that allow them to cope with infection. In this investigation, a six-plex tandem mass tagging proteomic approach was used to study protein accumulation changes in the midgut of Anopheles gambiae (Giles) (Diptera: Culicidae) mosquitoes infected with o'nyong-nyong virus (Togaviridae, Alphavirus). Five hundred thirty-six nonredundant proteins were identified. Twenty-two were found in significantly different quantities in infected midguts compared with controls. Of interest, analysis revealed molecular pathways possibly targeted by virus proteins, such as those involving TAF4 and DNA polymerase phi proteins. Also identified was an FK506-binding protein. FK506-binding protein orthologs have been described as conserved host resistance factors, which suppress dengue and West Nile virus infection in human HeLa cells. This investigation constitutes the first study of the midgut-specific proteome of An. gambiae in relation to alphavirus infection. Our findings offer insight into mosquito immunity, including factors that possibly contribute to the different pathological outcomes observed in vertebrate and insect hosts

Exposure to Arsenite in CD-1 Mice during Juvenile and Adult Stages: Effects on Intestinal Microbiota and Gut-Associated Immune Status

Intestinal microbiota composition and gut-associated immune response can contribute to the toxicity of arsenic. We investigated the potential toxicity of short-term arsenic exposure on gut microbiome composition, intestinal immune status, microbial arsenic resistance gene, and arsenic metabolic profiles in adult and developmental stages of CD-1 mice. The potential toxicity of arsenite [As(III)] was determined for two life stages: (i) adult animals at 24 or 48 h after single gavage (0.05 mg/kg body weight [b.w.] [low dose], 0.1 mg/kg b.w. [medium dose], and 0.2 mg/kg b.w. [high dose]) and repeated exposure at 1 mg/liter for 8 days and (ii) postnatal day 10 (PND10) and PND21 after single gavage (0.05 mg/kg b.w.). Dose- and time-dependent responses in bacterial recovery/microbial composition were observed in adults after a single gavage. Repeated exposure caused a transient decrease in the recovery of intestinal bacteria, a shift in the bacterial population with abundance of arsenic resistance genes, and evidence for host metabolism of arsenite into less-reactive trivalent methylated species. Arsenic exposure in adult animals induced high levels of CC chemokines and of proinflammatory and anti-inflammatory cytokine secretion in intestine. Arsenic exposure at PND21 resulted in the development of distinct bacterial populations. Results of this study highlight significant changes in the intestinal microbiome and gut-associated immune status during a single or repeated exposure to arsenic in juvenile and adult animals. The data warrant investigation of the long-term effects of oral arsenic exposure on the microbiome and of immune system development and responses.Transformation of organic arsenic to toxic inorganic arsenic (iAs) is likely carried out by intestinal bacteria, and iAs may alter the viability of certain microbial populations. This study addressed the impact of arsenic exposure on intestinal microbiota diversity and host gut-associated immune mediators during early development or adulthood using scenarios of acute or repeated doses. During acute arsenic exposure, animals developed defense functions characterized by higher abundances of bacteria that are involved in arsenic resistance or detoxification mechanisms. Arsenite had a negative effect on the abundance of bacterial species that are involved in the conversion of protein to butyrate, which is an alternative energy source in the intestine. The intestinal mucosal immune cytokine profile reflected a mechanism of protection from arsenic toxicity

Impaired everyday memory associated with encephalopathy of severe malaria: the role of seizures and hippocampal damage.

BACKGROUND: Seizures are common in children admitted with severe falciparum malaria and are associated with neuro-cognitive impairments. Prolonged febrile seizures are associated with hippocampal damage and impaired memory. It was hypothesized that severe malaria causes impaired everyday memory which may be associated with hippocampal damage. METHODS: An everyday memory battery was administered on 152 children with cerebral malaria (CM) (mean age, 7 y 4 months [SD 13 months]; 77 males) 156 children (mean age, 7 y 4 months [SD, 14 months]; 72 males) with malaria plus complex seizures (MS) and 179 children (mean age, 7 y 6 months [SD, 13 months]; 93 males) unexposed to either condition. RESULTS: CM was associated with poorer everyday memory [95% CI, -2.46 to -0.36, p = 0.004] but not MS [95% CI, -0.91 to 1.16, p = 1.00] compared to unexposed children. Children with exposure to CM performed more poorly in recall [95% CI, -0.79 to -0.04, p = 0.024] and recognition subtests [95% CI, -0.90 to -0.17, p = 0.001] but not in prospective memory tests compared to controls. The health factors that predicted impaired everyday memory outcome in children with exposure to CM was profound coma [95% CI, 0.02 to 0.88, p = 0.037] and multiple episodes of hypoglycaemia [95% CI, 0.05 to 0.78, p = 0.020], but not seizures. DISCUSSION: The findings show that exposure to CM was associated with a specific impairment of everyday memory. Seizures commonly observed in severe malaria may not have a causal relationship with poor outcome, but rather be associated with profound coma and repeated metabolic insults (multi-hypoglycaemia) that are strongly associated with impaired everyday memory