Bioavailability of Inhaled Or Ingested PFOA Adsorbed To House Dust

Indoor environments may impact human health due to chemical pollutants in the indoor air and house dust. This study aimed at comparing the bioavailability and distribution of PFOA following both an inhalation and an oral exposure to PFOA coated house dust in rats. In addition, extractable organofluorine (EOF) was measured in different tissue samples to assess any potential influence of other organofluorine compounds in the experimental house dust. Blood samples were collected at sequential time points after exposure and at the time of termination; lung, liver and kidney were collected for quantification of PFOA and EOF. The concentration of PFOA in plasma increased rapidly in both exposure groups attaining a Cmax at 3 h post exposure. The Cmax following inhalation was four times higher compared to oral exposures. At 48 h post exposure, the levels of PFOA in plasma, liver and kidney were twice as high from inhalation exposures. This shows that PFOA is readily bioavailable and has a rapid systemic distribution following an inhalation- or oral exposure to house dust coated with PFOA. The proportion of PFOA to EOF corresponded to approximately 54-68% and >80% in plasma and tissues, respectively. The mass balance between EOF and target PFOA indicate that there might be other unknown PFAS precursor and/or fluorinated compounds that co-existed in the house dust sample that might have accumulated in rats.

Designing distribution of adjuvants: Synthesis of lipidated nucleic acid adjuvant compounds

<p>Peptide vaccines can generate antigen-specific immune responses against tumours. However, peptides on their own are not usually immunogenic and require an adjuvant to ensure antigen-presenting cells are appropriately activated. Adjuvant localisation is essential for its activity; targeting an immunomodulatory compound to the lymph nodes appropriately positions it among a high density of immune cells, where immune responses are coordinated. Furthermore, systemic distribution of a potent immune modulator can lead to severe systemic toxicities. Lymph node targeting reduces systemic exposure with simultaneous reduction of side effects. Where a compound distributes in viva is determined by its pharmacokinetic properties and its route of administration. Once the route has been defined, a drug's pharmacokinetic properties can be modified by structural changes. To this end, we modified existing adjuvants to distribute into the lymphatics preferentially. One method was to increase the hydrophilicity and size of agalactosylceramide to favour lymphatic uptake. The second was to exploit albumin hitchhiking to access the lymph nodes. Here, a-galactosylceramide was chemically linked via an enzyme-labile linker to CpG ODN 1826, a TLR-9 agonist. The properties of each adjuvant mutually alter those of the other: to the CpG, a-galactosylceramide acts as an albumin binding domain; to the a-galactosylceramide, the CpG serves as a large hydrophilic group creating an amphiphile. In vivo, this should activate a strong, multilineage T cell response through the synergy of the two adjuvants. Furthermore, this should reduce the toxicity and side effects of the adjuvant by limiting its systemic distribution. This adjuvant may find further use in vaccines for diseases requiring a Thl response for effective clearance.</p>

Designing distribution of adjuvants: Synthesis of lipidated nucleic acid adjuvant compounds

<p>Peptide vaccines can generate antigen-specific immune responses against tumours. However, peptides on their own are not usually immunogenic and require an adjuvant to ensure antigen-presenting cells are appropriately activated. Adjuvant localisation is essential for its activity; targeting an immunomodulatory compound to the lymph nodes appropriately positions it among a high density of immune cells, where immune responses are coordinated. Furthermore, systemic distribution of a potent immune modulator can lead to severe systemic toxicities. Lymph node targeting reduces systemic exposure with simultaneous reduction of side effects. Where a compound distributes in viva is determined by its pharmacokinetic properties and its route of administration. Once the route has been defined, a drug's pharmacokinetic properties can be modified by structural changes. To this end, we modified existing adjuvants to distribute into the lymphatics preferentially. One method was to increase the hydrophilicity and size of agalactosylceramide to favour lymphatic uptake. The second was to exploit albumin hitchhiking to access the lymph nodes. Here, a-galactosylceramide was chemically linked via an enzyme-labile linker to CpG ODN 1826, a TLR-9 agonist. The properties of each adjuvant mutually alter those of the other: to the CpG, a-galactosylceramide acts as an albumin binding domain; to the a-galactosylceramide, the CpG serves as a large hydrophilic group creating an amphiphile. In vivo, this should activate a strong, multilineage T cell response through the synergy of the two adjuvants. Furthermore, this should reduce the toxicity and side effects of the adjuvant by limiting its systemic distribution. This adjuvant may find further use in vaccines for diseases requiring a Thl response for effective clearance.</p>

Detection of Systemic Canine Kobuvirus Infection in Peripheral Tissues and the Central Nervous System of a Fox Infected with Canine Distemper Virus

Canine kobuvirus (CaKV) is a globally distributed pathogen of dogs and is predominantly associated with infection of the gastrointestinal tract. However, an etiological link to enteric disease has not been established since CaKV has been identified in both asymptomatic dogs and animals with diarrheic symptoms. In this study, an extraintestinal CaKV infection was detected by next-generation sequencing in a fox (Vulpes vulpes) in Germany concomitant with a canine distemper virus (canine morbillivirus; CDV) co-infection. Phylogenetic analysis of the complete coding region sequence showed that this strain was most closely related to a CaKV strain detected in a dog in the United Kingdom in 2008. The tissue and cellular tropism of CaKV was characterized by the detection of viral antigens and RNA. CaKV RNA was detected by in situ hybridization in different tissues, including epithelial cells of the stomach and ependymal cells in the brain. The use of a new RT-qPCR assay for CaKV confirmed the systemic distribution of CaKV with viral RNA also detected in the lymph nodes, bladder, trachea, and brain. The detection of a CDV infection in this fox suggests that immunosuppression should be further investigated as a contributing factor to the enhanced extraintestinal spread of CaKV.

Albumin Substitution in Decompensated Liver Cirrhosis: Don’t Forget Zinc

Decompensated liver cirrhosis has a dismal prognosis, with patients surviving on average for 2–4 years after the first diagnosis of ascites. Albumin is an important tool in the therapy of cirrhotic ascites. By virtue of its oncotic properties, it reduces the risk of cardiovascular dysfunction after paracentesis. Treatment with albumin also counteracts the development of hepatorenal syndrome and spontaneous bacterial peritonitis. More recently, the positive impact of long-term albumin supplementation in liver disease, based on its pleiotropic non-oncotic activities, has been recognized. These include transport of endo- and exogenous substances, anti-inflammatory, antioxidant and immunomodulatory activities, and stabilizing effects on the endothelium. Besides the growing recognition that effective albumin therapy requires adjustment of the plasma level to normal physiological values, the search for substances with adjuvant activities is becoming increasingly important. More than 75% of patients with decompensated liver cirrhosis do not only present with hypoalbuminemia but also with zinc deficiency. There is a close relationship between albumin and the essential trace element zinc. First and foremost, albumin is the main carrier of zinc in plasma, and is hence critical for systemic distribution of zinc. In this review, we discuss important functions of albumin in the context of metabolic, immunological, oxidative, transport, and distribution processes, alongside crucial functions and effects of zinc and their mutual dependencies. In particular, we focus on the major role of chronic inflammatory processes in pathogenesis and progression of liver cirrhosis and how albumin therapy and zinc supplementation may affect these processes.

Recent advances in selective photothermal therapy of tumor

Photothermal therapy (PTT), which converts light energy to heat energy, has become a new research hotspot in cancer treatment. Although researchers have investigated various ways to improve the efficiency of tumor heat ablation to treat cancer, PTT may cause severe damage to normal tissue due to the systemic distribution of photothermal agents (PTAs) in the body and inaccurate laser exposure during treatment. To further improve the survival rate of cancer patients and reduce possible side effects on other parts of the body, it is still necessary to explore PTAs with high selectivity and precise treatment. In this review, we summarized strategies to improve the treatment selectivity of PTT, such as increasing the accumulation of PTAs at tumor sites and endowing PTAs with a self-regulating photothermal conversion function. The views and challenges of selective PTT were discussed, especially the prospects and challenges of their clinical applications.

Drug targeting to sites of oxidative stress using the Baeyer-Villiger reaction

The antioxidant nuclear factor erythroid 2-related factor 2 (Nrf2) is a desirable therapeutic target for a broad range of pathologies, including chronic diseases of the lung and liver, and autoimmune, neurodegenerative, and cardiovascular disorders. However, current Nrf2 activators are limited by unwanted effects due to non-specificity, and systemic distribution and action. Here we report that a 1,2-dicarbonyl moiety masks the electrophilic reactivity of the Nrf2 activator monomethyl fumarate (MMF), otherwise responsible for its non-specific effects. The 1,2-dicarbonyl compound is highly susceptible to Baeyer-Villiger oxidation, with generation of MMF specifically on exposure to pathological levels of hydrogen peroxide or peroxynitrite. Oral treatment with the MMF generating 1,2-dicarbonyl compound reversed chronic neuropathic and osteoarthritis pain in mice, and selectively activated Nrf2 at sites of oxidative stress. This 1,2-dicarbonyl platform may be used to treat additional disorders of oxidative stress, and to selectively target other therapeutics to sites of redox imbalance.

Identification of Biomarkers for Systemic Distribution of Nanovesicles From Lactobacillus johnsonii N6.2

The ability of bacterial extracellular vesicles (EV) to transport biological molecules has increased the research to determine their potential as therapeutic agents. In this study, Lactobacillus johnsonii N6.2-derived nanovesicles (NV) were characterized to identify components that may serve as biomarkers in host-microbe interactions. Comparative proteomic and lipidomic analyses of L. johnsonii N6.2 NV and cell membrane (CM) were performed. The lipidomic profiles indicated that both fractions contained similar lipids, however, significant differences were observed in several classes. LC-MS/MS proteomic analysis indicated that NV contained several unique and differentially expressed proteins when compared to the CM. Analysis of Gene Ontology (GO) terms, based on cellular component, showed significant enrichment of proteins in the cytoplasm/intracellular space category for the NV fraction. Based on these results, the proteins T285_RS00825 (named Sdp), Eno3 and LexA were selected for studies of localization and as potential biomarkers for host-microbe interactions. Immunogold staining, followed by scanning and transmission electron microscopy (SEM and TEM, respectively), revealed that Sdp was preferentially localized along the cell wall/membrane, and on NV-like structures surrounding the bacteria. These results were confirmed using immunofluorescence staining in Caco-2 cells incubated with NV. Consequently, we evaluated the potential for NV surface-exposed proteins to generate an immune response in the host. Plasma from individuals administered L. johnsonii N6.2 showed that IgA and IgG antibodies were generated against NV and Sdp domains in vivo. Altogether, these results show that L. johnsonii N6.2 NV have the potential to mediate host interactions through immune modulation.

A cohort autopsy study defines COVID-19 systemic pathogenesis

Severe COVID-19 disease caused by SARS-CoV-2 is frequently accompanied by dysfunction of the lungs and extrapulmonary organs. However, the organotropism of SARS-CoV-2 and the port of virus entry for systemic dissemination remain largely unknown. We profiled 26 COVID-19 autopsy cases from four cohorts in Wuhan, China, and determined the systemic distribution of SARS-CoV-2. SARS-CoV-2 was detected in the lungs and multiple extrapulmonary organs of critically ill COVID-19 patients up to 67 days after symptom onset. Based on organotropism and pathological features of the patients, COVID-19 was divided into viral intrapulmonary and systemic subtypes. In patients with systemic viral distribution, SARS-CoV-2 was detected in monocytes, macrophages, and vascular endothelia at blood–air barrier, blood–testis barrier, and filtration barrier. Critically ill patients with long disease duration showed decreased pulmonary cell proliferation, reduced viral RNA, and marked fibrosis in the lungs. Permanent SARS-CoV-2 presence and tissue injuries in the lungs and extrapulmonary organs suggest direct viral invasion as a mechanism of pathogenicity in critically ill patients. SARS-CoV-2 may hijack monocytes, macrophages, and vascular endothelia at physiological barriers as the ports of entry for systemic dissemination. Our study thus delineates systemic pathological features of SARS-CoV-2 infection, which sheds light on the development of novel COVID-19 treatment.