Activin proteins are members of the transforming growth factor-β family. Activin A is involved in several biological responses including wound repair, cell death, proliferation and differentiation of many cell types. Biologically active activins consist of homodimers or heterodimers of two beta (β) subunits that are linked together by a single covalent disulphide bond. The subunits in humans are βA, βB, βC and βE. As an example, a combination of two βA subunits will produce a unit of activin A. These proteins are found in most cells of body such as macrophage and activated circulating monocytes. Their role in inflammation can be categorised into two types, either pro- or anti-inflammatory agents, depending on the cell type and phase. Activin signals are kept in balance by antagonist follistatin (Fst), which is a glycoprotein expressed in tissues and encoded by the follistatin gene in humans.
Introduction:Acyclovir, a widely marketed antiviral drug is used for the treatment of Herpes Simplex infection. High doses of acyclovir are prescribed to patients to attain its maximum therapeutic effect due to its poor absorption and low oral bioavailability. The current therapeutics regiment of acyclovir are known to cause unwarranted adverse effects, thus prompted the need for a suitable drug carrier to improve the pharmacokinetic limitations. Develop-ment of solid lipid nanoparticles for oral delivery of acyclovir proposed in this study aimed to enhance acyclovir oral bioavailability. Methods: Comprehensive experiments and a series of optimization process were carried out to ensure reproducibility and assurance of product quality. The physicochemical characteristics of the solid lipid nanoparticles developed from plant-based solid lipid, Biogapress Vegetal 297 ATO with polysorbate 80 as an emul-sifying agent were also evaluated. Results: The spherical-shaped nanoparticles had an average size of 123 nm with good drug entrapment efficiency, up to 80%. The in vitro drug release study showed that solid lipid nanoparticles had prolonged acyclovir release in simulated intestinal fluid for 24 hours. The nanoparticles formulation was con-sidered stable during storage at refrigerated temperature for at least three months. In vivo oral bioavailability study showed that acyclovir-loaded solid lipid nanoparticles possessed superior oral bioavailability when compared with the commercial acyclovir suspension. Conclusion: In conclusion, this study exhibited the feasibility of solid lipid nanoparticles as an oral delivery vehicle for acyclovir and therefore represent a new promising therapeutic concept of nanoparticulate delivery system.
Candida bloodstream infections remain the most frequent life-threatening fungal disease, with Candida albicans accounting for 70% to 80% of the Candida isolates recovered from infected patients. In nature, Candida species are part of the normal commensal flora in mammalian hosts. However, they can transform into pathogens once the host immune system is weakened or breached. More recently, mortality attributed to Candida infections has continued to increase due to both inherent and acquired drug resistance in Candida, the inefficacy of the available antifungal drugs, tedious diagnostic procedures, and a rising number of immunocompromised patients. Adoption of animal models, viz. minihosts, mice, and zebrafish, has brought us closer to unraveling the pathogenesis and complexity of Candida infection in human hosts, leading towards the discovery of biomarkers and identification of potential therapeutic agents. In addition, the advancement of omics technologies offers a holistic view of the Candida-host interaction in a non-targeted and non-biased manner. Hence, in this review, we seek to summarize past and present milestone findings on C. albicans virulence, adoption of animal models in the study of C. albicans infection, and the application of omics technologies in the study of Candida-host interaction. A profound understanding of the interaction between host defense and pathogenesis is imperative for better design of novel immunotherapeutic strategies in future.
Different murine species differ in their susceptibility to systemic infection with Candida albicans, giving rise to varied host immune responses, and this is compounded by variations in virulence of the different yeast strains used. Hence, this study was aimed at elucidating the pathogenesis of a clinical C. albicans isolate (HVS6360) in a murine intravenous challenge model by examining the different parameters which included the counts of red blood cells and associated components as well as the organ-specific expression profiles of cytokines and chemokines. Kidneys and brains of infected mice have higher fungal recovery rates as compared to other organs and there were extensive yeast infiltration with moderate to severe inflammation seen in kidney and brain tissues. Red blood cells (RBCs) and haemoglobin (Hb) counts were reduced throughout the infection period. Pattern recognition receptors (PRRs), chemokines and cytokine transcription profiles were varied among the different organs (kidney, spleen and brain) over 72 h post infections. Transcription of most of the PRRs, cytokines and chemokines were suppressed at 72 h post infection in spleen while continuous expression of PRRs, cytokines and chemokines genes were seen in brain and kidney. Reduction in red blood cells and haemoglobin counts might be associated with the action of extracellular haemolysin enzyme and haeme oxygenase of C. albicans in conjunction with iron scavenging for the fungal growth. Renal cells responsible for erythropoietin production may be injured by the infection and hence the combined effect of haemolysis plus lack of erythropoietin-induced RBC replenishment leads to aggravated reduction in RBC numbers. The varied local host immune profiles among target organs during systemic C. albicans infection could be of importance for future work in designing targeted immunotherapy through immunomodulatory approaches.
Local cytokine production is a significant indicator for disease pathogenesis or progression. Previous studies on cytokine production during systemic Candida albicans (C. albicans) infection were solely on kidney or single cell type interaction with C. albicans. Therefore, the present study aimed to assess the early cytokine expression of various target organs (kidney, spleen and brain) over a 72-h time course during systemic C. albicans infection. The local cytokine profiles of the target organs during systemic C. albicans infection were measured by cytometric bead array and ELISA analysis. The results demonstrated that interleukin-6 (IL-6) and IL-2 were statistically significant (P<0.05) in the spleen at 24 and 72 h post-infection, whereas in the kidney, IL-6 and tumor necrosis factor-α (TNF-α) were statistically significant (P<0.05) at 24 and 72 h post-infection and CXCL-1 and transforming growth factor-β (TGF-β) were statistically significant (P<0.05) at 72 h post-infection. In the brain, IL-6 and TNF-α were statistically significant (P<0.05) at 24 and 72 h post-infection, whereas TGF-β was statistically significant (P<0.05) at 72 h post-infection. These findings demonstrate that host immune responses were varied among target organs during systemic C. albicans infection. This could be important for designing targeted immunotherapy against this pathogen through immunomodulatory approaches in future exploratory research.