Previous studies have demonstrated that hesperidin, a flavanone glycoside from citrus fruits, produces antidepressant-like effects in both mice and rats. However, whether these effects are mediated by pro-inflammatory cytokines remains unknown. In the present study, we attempted to investigate the effects of hesperidin on the depressive-like behavior; the serum corticosterone concentrations; and the interleukin (IL)-1β, IL-6, and tumor necrosis factor alpha (TNF-α) levels in lipopolysaccharide (LPS)-induced depression-like mice. In particular, we evaluated the miRNA-132 expression after LPS and hesperidin treatment. We found that LPS injection not only decreased the sucrose preference and increased the serum corticosterone levels but also elevated IL-1β, IL-6, and TNF-α in the prefrontal cortex. More importantly, LPS down-regulated the expression of miRNA-132. Pre-treatment with hesperidin (25, 50, 100 mg/kg) for 7 days prevented these abnormalities induced by LPS injection. In contrast, this effect of hesperidin was abolished by a miRNA-132 antagomir. Taken together, these results suggest that the antidepressant-like mechanisms of hesperidin are at least partially related to decreased pro-inflammatory cytokine levels via the miRNA-132 pathway in the brain.

Dynamic or hybrid configurations for extracorporeal membrane oxygenation (ECMO) are needed when patient physiology or clinical conditions change. Dynamic configurations included configurations converting from veno-arterial (V-A) ECMO or veno-venous (V-V) ECMO to other forms. Hybrid configurations included venous-arteriovenous (V-AV) and venovenous-arterial (VV-A) ECMO. This study retrospectively analyzed a total of 3,814 ECMO cases (3,102 adult cases) reported to the Chinese Society of Extracorporeal Life Support from January 1, 2017 to December 31, 2019. Eight-three adult patients had dynamic or hybrid ECMO configurations, whose primary diagnoses included cardiogenic shock (33.7%), cardiac arrest (6.0%), acute respiratory failure (39.8%), septic shock (9.6%), multiple trauma (3.6%), pulmonary hypertension (3.6%), and others (3.6%). Configuration changes occurred in 37 patients with the initial configuration of VA (20 to VV, 13 to V-AV, and 4 to VV-A) and 27 with the initial configuration of VV (7 to VA, and 20 to V-AV). A total of 46 (55.4%) patients received hybrid configurations of V-AV and 10 (12.0%) received VV-A. Patients with the initial configuration of VV who converted to other configurations had higher in-hospital mortality (74.1%) than other initial configurations (VA 45.9%, V-AV 76.9%, VV-A 66.7%, P = 0.021). We concluded that dynamic or hybrid ECMO configurations were used in various underlying diseases, in which V-AV was most commonly used. Patients receiving VV ECMO for respiratory support initially, who then converted to other configurations for both respiratory and circulatory support, had significantly worst outcomes among the groups studied. The initial configuration should be selected carefully after thorough assessment of patient condition.

Pyrimidine metabolism was studied in the obligate intracellular bacterium Chlamydia psittaci AA Mp in the wild type and a variety of mutant host cell lines with well-defined mutations affecting pyrimidine metabolism.C. psittaci AA Mp cannot synthesize pyrimidines de novo, as assessed by its inability to incorporate aspartic acid into nucleic acid pyrimidines. In addition, the parasite cannot take UTP, CTP, or dCTP from the host cell, nor can it salvage exogenously supplied uridine, cytidine, or deoxycytidine. The (7,20). The species C. trachomatis and C pneumoniae are primarily human pathogens (6, 26).In contrast, C. psittaci has been isolated from humans and a very large number of avian and mammalian species, in which it produces a variety of diseases (26,28). Despite the clinical and economic importance of chlamydiae, many aspects of their basic biology have not been studied and the metabolic relationships that exist between the parasites and their hosts remain largely unknown (20). This is, in part, due to the fact that axenic growth of chlamydiae has not been realized. In addition, host-free chlamydiae display limited metabolic activity (12,20).Our laboratory is particularly interested in nucleotide metabolism in chlamydiae. To study nucleotide metabolism in C. trachomatis, we have employed an in situ approach with well-defined mutant host cell lines and several different radiolabelled nucleic acid precursors (4,5,18,24,29,30). The results generated indicate that C. trachomatis (i) cannot de novo synthesize purines or pyrimidines, (ii) lacks the ability to salvage preformed purine or pyrimidine nucleobases and (deoxy)nucleosides, (iii) can obtain all four ribonucleotides directly from the host cell, (iv) encodes a ribonucleotide reductase and thymidylate synthase for synthesizing deoxyribonucleotides from host-derived ribonucle-* Corresponding author. t Present address:

Chlamydiae have evolved a biphasic life cycle to facilitate their survival in two discontinuous habitats. The unique growth cycle is represented by two alternating forms of the organism, the elementary body and the reticulate body. Chlamydiae have an absolute nutritional dependency on the host cell to provide ribonucleoside triphosphates and other essential intermediates of metabolism. This report describes the pleiotropic effects of the purine antimetabolite 6-thioguanine on chlamydial replication. In order to display cytotoxicity, 6-thioguanine must first be converted to the nucleotide level by the host cell enzyme hypoxanthine-guanine phosphoribosyltransferase. Our results show that 6-thioguanine is an effective inhibitor of chlamydial growth with either wild-type or hypoxanthine-guanine phosphoribosyltransferase-deficient cell lines as the host. Interestingly, the mechanism of 6-thioguanine-induced inhibition of chlamydial growth is different depending on which cell line is used. With wild-type cells as the host, the cytotoxic effects of 6-thioguanine on chlamydial growth are relatively fast and irreversible. Under these circumstances, cytotoxicity likely results from the combined effect of starving chlamydiae for purine ribonucleotides and incorporation of host-derived 6-thioguanine-containing nucleotides into chlamydial nucleic acids. With hypoxanthine-guanine phosphoribosyltransferase-deficient cells as the host, 6-thioguanine must be present at the start of the chlamydial infection cycle to be effective and the growth inhibition is reversible upon removal of the antimetabolite. These findings suggest that in hypoxanthineguanine phosphoribosyltransferase-deficient cells, the free base 6-thioguanine may inhibit the differentiation of elementary bodies to reticulate bodies. With hypoxanthine-guanine phosphoribosyltransferase-deficient cells as the host, 6-thioguanine was used as a selective agent in culture to isolate a Chlamydia trachomatis isolate resistant to the effects of the drug. This drug-resistant C. trachomatis isolate was completely resistant to 6-thioguanine in hypoxanthine-guanine phosphoribosyltransferase-deficient cells; however, it displayed wildtype sensitivity to 6-thioguanine when cultured in wild-type host cells.Chlamydiae are gram-negative procaryotes that live as obligate intracellular parasites in a wide range of host cells (25,28,29). Currently, the genus is divided into three species, Chlamydia trachomatis, C. psittaci, and C. pneumoniae (12,25). There are two chlamydial cell types, the elementary body (EB) and the reticulate body (RB), and the alternation of these two cell types constitutes the chlamydial developmental cycle (25,28,29 The chlamydiae display the unique characteristic of being energy parasites, i.e., they depend entirely on their host for supplies of high-energy metabolites such as nucleoside triphosphates (25,28,29 supported not only by the inability to detect enzymes necessary for energy generation but also by the finding that chlamydial RBs possess a membrane-loca...