Pivotal role of cell hyperactivation in the pathogenesis of different diseases and its mechanism / 中华危重病急救医学

Inflammasomes are key inflammatory signaling platforms that detect several stimulus derived from microbial substances and sterile environmental insults, eliciting pyroptosis and the release of cytokines. Recent studies have found that inflammasomes could also elicit cell hyperactivation which is defined as living cells that release interleukin-1 (IL-1). Hyperactive cells promote long-term IL-1 release and then activate adaptive immune response, which has a pivotal role in the infection ofSalmonella andStaphylococcus aureus, as well as in non-lethal inflammatory sepsis. So it is of great significance to explore the pathogenesis of cell hyperactivation in several inflammatory diseases. Here, we summarized the possible pathogenesis of cell hyperactivation in different inflammatory diseases, such as infection, sepsis and acute respiratory distress syndrome (ARDS), providing a theoretical basis for clinical treatment of these diseases.

CatSper in sperm hyperactivation and male infertility: Advances in studies / 中华男科学杂志

The CatSper channel is known as one of the most important Ca²⁺ channels on the cell membrane of mammalian sperm and plays a key role in the motility, hyperactivation and fertilization function of sperm. The CatSper protein, expressed exclusively in the principal piece of the sperm tail, is composed of CatSper1-4 and 5 auxiliary unitsβ,γ,δ and ε, and has an essential part in the functional and structural domains of Ca²⁺as well as in the spatiotemporal regulation of the P-Tyr protein, sperm hyperactivation, efficient sperm migration in the oviduct, egg penetration, and normal fertility. Recent studies show that functional deficiency of CatSper seriously affects sperm function,and the loss of any one of its 9 subunits may lead to male reproductive dysfunction. This paper outlines recent advances in the studies of the CatSperprotein, focusing on its expression, location, structure, and regulation,as well as itsinfluence on sperm hyperactivation and male reproduction.

Paclitaxel inhibits the hyper-activation of spleen cells by lipopolysaccharide and induces cell death

Paclitaxel was isolated from the bark of the Pacific yew, Taxus brevifolia, and used as an anticancer agent. Paclitaxel prevents cancer cell division by inhibiting spindle fiber function, inducing cell death. A recent study demonstrated that paclitaxel binds to myeloid differentiation protein-2 of Toll-like receptor 4 and prevents the signal transduction of lipopolysaccharide (LPS). Paclitaxel converts immune cells hypo-responsive to LPS. In this study, we investigated whether paclitaxel can inhibit the phenotype and function of immune cells. To accomplish this, we used spleen cells, a major type of immune cell, LPS, a representative inflammatory agent and a mitogen for B lymphocytes. LPS profoundly increased the activation and cytokine production of spleen cells. However, paclitaxel significantly inhibited LPS-induced hyper-activation of spleen cells. Furthermore, we found that paclitaxel induced cell death of LPS-treated spleen cells. These results suggest that paclitaxel can inhibit the hyper-immune response of LPS in spleen cells via a variety of mechanisms. These findings suggest that paclitaxel can be used as a modulating agent for diseases induced by hyper-activation of B lymphocytes. Taken together, these results demonstrate that paclitaxel inhibits the function of spleen cells activated by LPS, and further induces cell death.

Participación de las células Th17 en la patogenia de la infección por el virus de la inmunodeficiencia humana de tipo 1 / Th17 cells involvement in the pathogenesis of the human immunodeficiency virus type 1

La infección por el VIH-1 se caracteriza por la eliminación de linfocitos T CD4+, particularmente en la mucosa gastrointestinal, que favorece la traslocación microbiana y la hiperactivación inmunitaria, principal mecanismo patogénico en esta infección. Las células Th17 son una subpoblación proinflamatoria de linfocitos CD4+, que producen IL-17, IL-21 e IL-22, y son importantes en la respuesta antimicrobiana, principalmente en el sistema gastrointestinal, donde promueven la restauración de la mucosa. Aunque su eliminación se ha asociado con progresión de la infección por el VIH-1 y por el virus de la inmunodeficiencia de los simios, y han sido descritas como deletérea en autoinmunidad. Su papel en la patogenia de la infección por el VIH-1 no está claramente establecido. Considerando su capacidad funcional, las células Th17 podrían tener un impacto dual, dependiendo de la fase de la infección en que se encuentre el individuo. Actualmente, hay más información que sugiere que estas células tienen un papel benéfico al promover la recuperación de la mucosa intestinal y disminuir la traslocación microbiana, así como la hiperactivación inmunitaria. Sin embargo, su papel patogénico, particularmente promoviendo la replicación viral mediante la producción de citocinas proinflamatorias, no debe descartarse. En esta revisión, se presentan los datos científicos disponibles del efecto de las células Th17 en la patogenia de la infección por el VIH-1.

HIV-1 infection is characterized by a gradual decrease of the immunological competence and a massive depletion of CD4+ T cells, particularly in gut-associated lymphoid tissue, which leads to microbial translocation, contributing to immune hyperactivation, the main pathogenic mechanism during HIV-1 infection. Th17 cells are a proinflammatory CD4+ T cell subset, which produce IL-17, IL-21 and IL-22 and play a pivotal role in host defense, mainly in the gastrointestinal tissue, where they promote antimicrobial responses and gut mucosa restoration. Although Th17 depletion is a hallmark of the progression of the simian and human immunodeficiency viral infections and they have been involved in the pathogenic process in some autoimmune diseases, the role of these cells during HIV-1 infection is not completely understood. Considering their functional potential, Th17 cells could have a dual role, depending on the stage of HIV infection a patient has reached. Currently, most evidence suggests that Th17 cells have a beneficial role by promoting gut mucosa recovery, preventing microbial translocation and decreasing immune hyperactivation. However, the pathogenic role of these cells, particularly, increasing viral replication through the production of inflammatory cytokines should not be ruled out. In this review, scientific evidence regarding the role of Th17 on the pathogenesis of HIV infection is discussed.

Cyclic nucleotide phosphodiesterase inhibition increases tyrosine phosphorylation and hyper motility in normal and pathological human spermatozoa

Our objective was to determine the effect of phosphodiesterase (PDE) inhibition on: 1) tyrosine phosphorylation of human spermatozoa at the tail level; and 2) sperm motion parameters and hyperactivated motility. The study was conducted with normozoospermic and asthenozoospermic samples incubated under in vitro capacitating conditions. The main outcome measures were computer-assisted sperm motion analysis and fluorescent immunodetection of phosphotyrosine-containing proteins. Pentoxifylline (PTX) was used as PDE inhibitor because of its wide use in the clinic. PTX-treatment significantly increased sperm velocity, hyperactivated motility and tyrosine-phosphorylation, both in normo and asthenozoospermic samples. Tyrosine-phosphorylation of tail proteins was highly conspicuous in both types of samples, showing no differential pattern after PTX-treatment. Normozoospermic samples treated with pentoxifylline showed an increase in the number of spermatozoa displaying hyperactivated movement and tyrosine-phosphorylation at the tail level. Preliminary data on asthenozoospermic samples exhibiting altered motion characteristics and defective phosphorylation of sperm-tail proteins showed that both defects can be concomitantly overcome by pentoxifylline treatment. Tyrosine-phosphorylation of sperm-tail proteins is underlying the enhancement of hyperactivated motility resulting from PDE inhibition by pentoxifylline.

The Effects of Sperm Motility Stimulants on the Hyperactivation, Acrosomal Reaction of Sperm and their in vitro Fertilization / 대한산부인과학회잡지

OBJECTIVES: To evaluate the effects of sperm motility stimulants on the hyperactivation (HA), acrosomal reaction (AR) and sperm penetration assay (SPA) in fresh and frozen-thawed spermatozoa from fertile men. METHODS: We treated the semen samples obtained from 20 normospermic men (fresh semens from 10 and cryopreserved ones from 10) with pentoxiphylline (PF) and 2-deoxyadenosine (2-DXA) to evaluate the change of the patterns of motility using the computerized motility analyzer. The semen samples treated with motility stimulants were incubated in the medium with calcium ionophore A23187 for the examination of the proportion of acrosome lost spermatozoa. Finally we performed SPA in both groups for the evaluation of fertilizing capacity after stimulant treatments. RESULTS: In both fresh and cryopreserved semen samples, the addition of PF and 2-DXA significantly altered the patterns of motility (ALH, VCL, HA) known to have association with sperm quality without increasing the number of sperms with progressive motility and velocity. A23187 induced AR was also augmented by the treatment with PF and 2-DZA. Although the treatment with PF did not increase the mean rates of egg penetration significantly, in selected cases in the cryopreserved semen group, the improvement of the motility pattern was impressive. CONCLUSION: PF and 2-DXA can improve the quality of sperm function in both fresh and frozen-thawed semen from normal fertile men and may increase the sperm penetration rate of zona-free hamster eggs in selected samples of the frozen-thawed semen. The results suggest that PF and 2-DXA pretreatment can be used in the clinical practice for intrauterine insemination (IUI) program with frozen-thawed sperms as well as with samples from men with abnormal semen parameters. In addition, it may be a cost- effective therapy to try IUI combined with such a pretreatment for the couples planned to enter into the ART program.

Effects of Reactive Oxygen Species on Hyperactivation of Human Sperms / 대한비뇨기과학회지

capacitation of human sperm is essential for fertilization and is characterized visually by hyperactivated motility. There is a controversy whether reactive oxygen radicals cause infertility or stimulate sperm-zona interaction. We investigated the exact role of reactive oxygen radicals on hyperactivation (HA) of human sperm which could be a part of the capacitation process. Hyperactivation of human sperm was compared to the Ham's F-10 controls by the addition of superoxide anion and hydrogen peroxide generating enzymes on the percale treated sperms. The motility parameters of human sperms were estimated by computer assisted semen analysis system. The addition of xanthine + xanthine oxidase + catalase (generating system of superoxide anion and removal of hydrogen peroxide) on the sperms induced levels of HA (10.5% at 2 hour, 11.3% at 5 hour) which were about 2 times higher than those of controls (HA: 5.4% at 2 hour, 5.6% at 5 hour). The addition of glucose + glucose oxidase (generation of hydrogen peroxide) decreased the levels of HA (0.0% at 2 and 5 hour) significantly. Superoxide dismutase, the scavenger of superoxide anion inhibited HA significantly, whereas catalase, the scavenger of hydrogen peroxide promoted HA significantly These results suggest that the reactive oxygen radicals may be involved in hyperactivation of human sperms by the way that superoxide anion promotes and hydrogen peroxide inhibits hyperactivation of the fertile human sperms. It may be very important in the process of fertilization that promotion or inhibition of hyperactivation occurs at the proper time and location of female genital organ.