Application of Exosomes-Derived Mesenchymal Stem Cells in Treatment of Fungal Diseases: From Basic to Clinical Sciences

Fungal diseases such as candidiasis are some of the deadliest diseases among immunocompromised patients. These fungi naturally exist on human skin and throughout the digestive system. When the microbiota balance becomes upset, these fungi become pathogenic and potentially lethal. At the pathogenesis of fungal diseases, host immune system response is diverse. At the early stages of fungal pathogenesis such as Candida albicans, it was shown that these fungi use the immune cells of the host body and cause malfunction the early induction of proinflammatory cytokines of the host body leading to a reduction in their numbers. However, at some stages of fungal diseases, the immune response is severe. Despite many treatments already being available, it seems that one of the best treatments could be an immune-stimulatory agent. Some of the subsets of MSCs and exosome-derived cells, as a cell-to-cell communicator agent, have many roles in the human body, including anti-inflammatory and immune-modulatory effects. However, the TLR4-primed and IL-17+ subsets of MSCs have been shown to have immune-stimulatory effects. These subsets of the MSCs produce pro-inflammatory cytokines and reduce immunosuppressive cytokines and chemokines. Thus, they could trigger inflammation and stop fungal pathogenesis. As some biological activities and molecules inherit elements of their exosomes from their maternal cells, the exosome-derived TLR4-primed and IL-17+ subsets of MSCs could be a good candidate for fighting against fungal diseases. The applications of exosomes in human diseases are well-known and expanding. It is time to investigate the exosomes application in fungal diseases. In this review, the probable role of exosomes in treating fungal diseases is explored.

Aging, Melatonin, and the Pro- and Anti-Inflammatory Networks

Aging and various age-related diseases are associated with reductions in melatonin secretion, proinflammatory changes in the immune system, a deteriorating circadian system, and reductions in sirtuin-1 (SIRT1) activity. In non-tumor cells, several effects of melatonin are abolished by inhibiting SIRT1, indicating mediation by SIRT1. Melatonin is, in addition to its circadian and antioxidant roles, an immune stimulatory agent. However, it can act as either a pro- or anti-inflammatory regulator in a context-dependent way. Melatonin can stimulate the release of proinflammatory cytokines and other mediators, but also, under different conditions, it can suppress inflammation-promoting processes such as NO release, activation of cyclooxygenase-2, inflammasome NLRP3, gasdermin D, toll-like receptor-4 and mTOR signaling, and cytokine release by SASP (senescence-associated secretory phenotype), and amyloid-β toxicity. It also activates processes in an anti-inflammatory network, in which SIRT1 activation, upregulation of Nrf2 and downregulation of NF-κB, and release of the anti-inflammatory cytokines IL-4 and IL-10 are involved. A perhaps crucial action may be the promotion of macrophage or microglia polarization in favor of the anti-inflammatory phenotype M2. In addition, many factors of the pro- and anti-inflammatory networks are subject to regulation by microRNAs that either target mRNAs of the respective factors or upregulate them by targeting mRNAs of their inhibitor proteins.

Usefulness of Growth Hormone (GH) Stimulation Tests and IGF-1 Concentration Measurement in GH Deficiency Diagnosis

The diagnosis of growth hormone (GH) deficiency (GHD) is still problematic for the clinician. There is no gold standard for estimating GH secretion. The aim of this study was to compare the diagnostic usefulness of spontaneous GH secretion test, pharmacological tests with insulin, clonidine, L-dopa, and glucagon, and IGF-1 measurement in GHD. We studied 180 prepubertal, short children. Predictive values were calculated for different GH cutoff levels for each diagnostic test. ROC curves were used to estimate the diagnostic usefulness of the tests. The results show that sleep is the strongest stimulatory agent for GH secretion. The estimation of GH secretion after onset of sleep can be used as a screening test in GHD diagnosis. The insulin test has the highest discrimination. A combination of insulin test with another provocative test allows high discrimination and accuracy for standard cut-off GH level. Measurement of IGF -I is characterized by low predictive values. IGF-1 level below the mean according to age indicates high probability of GHD. Auxological parameters should be the most important factor in diagnosing GHD.

Involvement of brain-derived neurotrophic factor in the regulation of hypothalamic somatostatin in vivo

Brain-derived neurotrophic factor (BDNF) has been extensively studied in the central nervous system as a survival and differentiation factor and in plasticity processes. In vitro, BDNF has been shown to stimulate cellular differentiation and neurohormones synthesis and release. We demonstrated that BDNF is a potent and specific stimulatory agent of somatostatin (SRIH) synthesis in primary cultures of hypothalamic neurons. However, less information is available about its function on SRIH neurons in vivo. In the present study, we examined the effect of in vivo intracerebroventricular BDNF administration in adult non-anesthetized male rats. Two distinct experimental approaches were used: acute intracerebroventricular injection and long-term (14 days) continuous infusion (Alzet micro-pumps). We demonstrate that single intracerebroventricular BDNF injections (5 μg/rat) induce an early (60 and 180 min) decrease in the SRIH mRNA signal in the hypothalamic periventricular nucleus (PeVN) accompanied by a decrease of the hypothalamic SRIH content. 48 h after the acute injection, SRIH mRNA levels and peptide content strongly and significantly increased. After continuous intracerebroventricular BDNF administration (12 μg/day for 14 days), a significant increase in the SRIH hypothalamic content was observed. Nevertheless, the increase in peptide content was not correlated with a similar increase in the PeVN messenger level. These findings show the involvement of BDNF in the in vivo regulation of somatostatinergic neurons in adult rats, which clearly differs according to the BDNF administration mode.

Macroscopic and Microscopic Authentication of Chinese and North American Species of Ephedra

Ephedra sinica Stapf or Ma Huang has been used in traditional Chinese medicine for over 5000 years as a bronchodilating and stimulatory agent. In the West, it is popularly used in dietary supplements for weight loss and to enhance athletic performance. Adverse events have been reported following consumption of dietary supplements containing ephedrine alkaloids. There are about 50 known species of Ephedra. The ratio of ephedrine to other alkaloids varies from species to species; all North American species lack alkaloids. The method commonly used in the dietary supplement industry for botanical authentication is to analyze the product for the presence of chemical markers known to be present in the specific herb. However, this method does not ensure that the product contains authentic herb, especially if it has been spiked with chemical marker compounds. In the trade and raw drug market, Ephedra is available in the form of stem cuttings or powders, without any vouchers, thus making identification of the species difficult. Using light microscopy, we can detect the presence of Ephedra herb, even in powder form, and identify within certain limits its geographical origin. Identification of Chinese and North American species of Ephedra has been made easier by developing a key using leaf and internode length as key identification characters.