ABSTRACT
Congenital bilateral absence of the vas deferens (CBAVD) is observed in 1%-2% of males presenting with infertility and is clearly associated with cystic fibrosis transmembrane conductance regulator (CFTR) mutations. CFTR is one of the most well-known genes related to male fertility. The frequency of CFTR mutations or impaired CFTR expression is increased in men with nonobstructive azoospermia (NOA). CFTR mutations are highly polymorphic and have established ethnic specificity. Compared with F508Del in Caucasians, the p.G970D mutation is reported to be the most frequent CFTR mutation in Chinese patients with cystic fibrosis. However, whether p.G970D participates in male infertility remains unknown. Herein, a loss-of-function CFTR p.G970D missense mutation was identified in a patient with CBAVD and NOA. Subsequent retrospective analysis of 122 Chinese patients with CBAVD showed that the mutation is a common pathogenic mutation (4.1%, 5/122), excluding polymorphic sites. Furthermore, we generated model cell lines derived from mouse testes harboring the homozygous Cftr p.G965D mutation equivalent to the CFTR variant in patients. The Cftr p.G965D mutation may be lethal in spermatogonial stem cells and spermatogonia and affect the proliferation of spermatocytes and Sertoli cells. In spermatocyte GC-2(spd)ts (GC2) Cftr p.G965D cells, RNA splicing variants were detected and CFTR expression decreased, which may contribute to the phenotypes associated with impaired spermatogenesis. Thus, this study indicated that the CFTR p.G970D missense mutation might be a pathogenic mutation for CBAVD in Chinese males and associated with impaired spermatogenesis by affecting the proliferation of germ cells.
Subject(s)
Humans , Animals , Mice , Male , Mutation, Missense , Retrospective Studies , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Infertility, Male/genetics , Mutation , Vas Deferens/abnormalities , Spermatogenesis/geneticsABSTRACT
Cerebral malaria (CM) is the deadliest complication of Plasmodium falciparum infection and even with effective anti-malarial treatment the mortality of children can be as high as 18%; up to one-third of CM survivors are left with neurological and cognitive deficits. The pathophysiology of CM is not completely understood, but mechanical obstruction and immunopathology are its mainstream theories. Adjuvant therapy aims to improve clinical outcomes and/or reduce mortality, as well as preventing long-term neurocognitive deficits. Improving survival and reducing neurological damage to survivors are new goals for new antimalarials and adjuvant therapies. Herein, we discussed what is known about the disease mechanism of CM and systematically summarize the progress of adjuvant therapy research in protecting the vascular endothelium, reducing adhesion formation, regulating immune balance, interfering with malarial metabolism, protecting nerves, improving nitric oxide bioavailability, improving energy metabolism and alleviating inflammation, with the aim of exploiting this understanding to reduce the neurological damage to children with CM. This work also highlights some preclinical studies which may be candidate strategies in future clinical trials.
ABSTRACT
Objective: To investigate the protective effect of phenolic compounds 4-hydroxybenzylideneacetone and (HBAc)3,4-dihydroxybenzylideneacetone (DHBAc) of Osmundae Rhizoma on the systemic inflammatory response syndrome (SIRS) in mice by establishing the mice model of SIRS.Method: BALB/c mice were randomly divided into the normal group,the SIRS model group and the different doses of HBAC and DHBAc group (25,50,100 μg·kg-3).Lipopolysaccharides (LPS) was injected intraperitoneally after 7 days of prophylactic administration.After 5 hours of modeling,the anus temperature,respiratory rate,the number of white blood cell (WBC) and platelets (PLT),WBC classification,glycolipid metabolism,inflammatory factor and signal transducing phosphorylated protein of lung were measured.Result: Intraperitoneal injection with LPS (6 mg·kg-1) in mice can significantly reduce the respiratory rate (PPPPPβ(PPPPPPPPPβ(PConclusion: The SIRS model can be established through intraperitoneal injection of LPS.HBAc and DHBAc have protective effects on endotoxin-induced SIRS in mice,and may exert anti-inflammatory effects through IκB and c-JUN pathways.
ABSTRACT
Malaria is still the most severe strain of the human malaria parasites, and malaria disease is life-threatening which can result in severe anemia and cerebral malaria, especially in children in tropical Africa. Previous studies have shown that artemisinin and its derivatives could selectively kill erythrocytic stage of malaria and have a greater impact on the ring period. In recent years, there have been new findings of its mechanism continually. However, the concentration of artemisinin and its derivatives used in these studies can reach 50 to 80 times the half-inhibitory concentration in vitro. In this study, the international standard strain 3D7 of Plasmodium falciparum was used to culture in vitro. After half-inhibitory concentration of dihydroartemisinin was treated, the morphological changes of P. falciparum intraerythrocytic stage were observed, and then the 3D7 life cycle and effects of different developmental stages after dosing was explored. The 3D7 strain of P. falciparum was continuously synchronised more than 3 times. And dihydroartemisinin (DHA) at half maximal inhibitory concentration (10 nmol·L⁻¹) was administered for 6 hours after the last synchronization, and 3 life cycles were continuously observed (132 h). The results showed that compared with the parasites untreated by DHA, there was a noticeable delay in the life cycle of at least 36 h, indicating that the growth of 3D7 was significantly inhibited by DHA (<0.001), and the rate of ring formation was significantly reduced (<0.05). The trophozoites were abnormal in shape, such as shrink in size, and the number of merozoites in schizonts was significantly decreased (<0.05). These results suggested that non-killing concentrations of DHA (meaning parasites can be inhibited but not killed) can significantly inhibit the growth of P. falciparum, which may not only affect the ring stage, but also have an impact on other stages of the P. falciparum.
ABSTRACT
Cerebral malaria (CM) is the leading cause of death in children under 5 years in Africa, severe neurological sequelae may occur in surviving children. Although artesunate has made breakthrough progress in the clinical treatment of CM, the clinical problems of high mortality and high morbidity have not yet been completely resolved. In this study, an experimental cerebral malaria (ECM) model was established by infecting C57BL/6 mice with Pb ANKA (Plasmodium berghei ANKA) to compare parasitemia level, survival rates, and rapid murine coma behavior scale scores, cerebral microvascular obstruction, haemozoin deposition in the liver, body temperature and weight to investigate the anti-cerebral malaria effect of the artesunate compound combination. The results showed that the artesunate compound combination could improve the survival rate of Pb ANKA-infected mice, reduce the level of parasitemia, effectively improve the symptoms of ECM neurological injury, reduce cerebrovascular obstruction and haemozoin deposition in the liver, and also significantly improve body temperature, weight and other basic indicators. The results showed that the artesunate compound combination improved the pathological changes and neurological damage caused by CM. It is expected to provide a theoretical basis for human cerebral malaria patients in clinical adjuvant therapy.
ABSTRACT
Cerebral malaria (CM), a severe neurological syndrome caused by Plasmodium falciparum infection, is a serious life-threatening disease with a high mortality. Survivors' persistent brain injury is manifested as long-term neurocognitive disorders. The main neuropathological feature of CM is the sequestration of parasited red blood cells (pRBCs) in cerebral microvessels. Other neuropathological features of CM include petechial hemorrhage in the brain parenchyma, annular hemorrhage, extensive brain endothelial cell activation, and focal endothelial cell injury and necrosis. However, its pathogenesis is still not clear. Currently, some studies have suggested that the pathogenesis of cerebral malaria mainly include pRBC adhesion, inflammatory reaction cascade, vascular leakage damage and brain hypoxia. Studies have shown that the biomarkers currently used as diagnostic and prognostic markers for CM include C-X-C motif chemokine ligand 10 (CXCL10), CXC chemokine ligand 4 (CXCL4), angiopoietin (Ang). In this paper, we systematically summarize the basic and clinical research for cerebral malaria in recent years and the latest literatures for drug studies, and focused on the advance of studies on cerebral malaria and its immunologic mechanism in the recent three years in the aspects of cytokines, immune cells, regulatory factors and biomarkers, so as to provide references for relevant studies.
ABSTRACT
This study was designed to investigate the activity of Shenlian tablet in stabilization of the atherosclerosis (As) plaque in apoE-/- mice and explore the mechanisms. Rat peritoneal mast cells were randomly allocated and treated with Shenlian tablet (100, 50, 25, 12.5 mg ·L-1) or cromoglicate sodium (200 μg·L-1) for 2 h before exposure to substance P. Histamine, tryptase, IL-1β and NF-κB were measured in the cell culture supernatant by ELISA assay. The plaque formation was induced by common carotid artery cannula method combined with high-fat diet in apoE-/- mice, and the plaque instability was induced by substance P through local mast cell degranulation. Mice were divided into eight groups that included the model 1 (M1, sham-operated group), M2 (carotid artery cannula combined with high-fat diet), M3 (M2 combined with substance P 0.5 μg/mouse), Shenlian extract (95, 190 and 380 mg·kg-1·d-1), atorvastatin (2.6 mg·kg-1·d-1) and normal control group. Total cholesterol (TC), high-density lipoprotein (HDL-C), high-sensitivity C-reactive protein (hs CRP), matrix metalloproteinases 9 (MMP-9) and histamine were measured by ELISA. Thickness, plaque area, mast cell degranulation were observed by hematoxylin and eosin staining, toluidine blue staining. CD117 antigen expression were observed by confocal microscopy. Intracellular phosphorylation was detected using the Bio-Plex 6-plex phosphoprotein assay kit. The results show that the mast cell membrane was stabilized by Shenlian tablet. Histamine, tryptase, interleukin l-β and NF-κB exhibited a significantly reduction in the Shenlian tablet-treated group (PP-/- mice model group. The proliferation, degranulation and inflammation of mast cell were significantly inhibited by Shenlian tablet. On the other hand, the same treatment decreased hs-CRP, MMP-9 and histamine in serum. IκB, p38 MAPK phosphorylation, intraplaque hemorrhage and collagen degradation were reduced in the presence of Shenlian tablet, which increased the stability of the As plaque. The results show that the vulnerable plaque model induced by mast cell activation in adventitia was established. Shenlian tablet exhibited a protective effect in this model. Shenlian tablet may increase the plaque stability via inhibition of mast cell-mediated inflammatory response.
ABSTRACT
<p><b>OBJECTIVE</b>To explore the neutralization capacities of different types of human serum to measles virus epidemic strains and vaccine strain.</p><p><b>METHODS</b>Neutralization antibody (NT) to Shanghai 191 and measles virus isolates in 2005 were tested using acute and convalescent serum samples from diagnosed measles patients, children serum samples collected before and after vaccination and serum samples of migrant residents, from 3 different regions. Additionally, animal immune serum referring to vaccine strain and 3 epidemic strains were prepared and used to undergo crossing neutralization test with corresponding strains mentioned-above. Antigenic ratios were calculated.</p><p><b>RESULTS</b>GMT value of NT of after-immune serum to vaccine strains was 50.82,1.86 times higher than that to MVi/ZJ/05/7 (GMT was 27.35), whereas GMT value of convalescent serum to MVi/ZJ/05/7 (GMT was 386.95) was obviously higher than that to vaccine strain (GMT was 1:151.83),and GMT value of migrant residents' serum in 3 regions to MVi/ZJ/05/7 were 2.22-4.17 times lower than that to vaccine strain. Meanwhile,the antigenic ratios between MVi/ZJ/ 99/1, MVi/ZJ/04/1, MVi/ZJ/05/7 and vaccine strain were found to be 4.28,5.24 and 5.66 respectively. Additionally,low NT titers to vaccine strain were found in patients' acute sera and GMT value was over 1:4.</p><p><b>CONCLUSION</b>There were obvious differences on neutralization antibody of different types of serum to measles vaccine strain and epidemic strains which indicating the antigenic diversity of epidemic strains had influenced the protective effectiveness of vaccine antibody to epidemic strains. It was of significance to carry on research projects on the antigenic diversity and effectiveness of measles vaccine.</p>