Toxoplasma gondii causes a prevalent human infection for which only the acute stage has an FDA-approved therapy. To find inhibitors of both the acute stage parasites and the persistent cyst stage that causes a chronic infection, we repurposed a compound library containing known inhibitors of parasitic hexokinase, the first step in the glycolysis pathway, along with a larger collection of new structural derivatives. The focused screen of 22 compounds showed a 77% hit rate (>50% multistage inhibition) and revealed a series of aminobenzamide-linked picolinic acids with submicromolar potency against both T. gondii parasite forms. Picolinic acid 23, designed from an antiparasitic benzamidobenzoic acid class with challenging ADME properties, showed 60-fold-enhanced solubility, a moderate LogD7.4, and a 30% improvement in microsomal stability. Furthermore, isotopically labeled glucose tracing revealed that picolinic acid 23 does not function by hexokinase inhibition. Thus, we report a new probe scaffold to interrogate dual-stage inhibition of T. gondii. 相似文献
The World Health Organization has reported an annual global suicide rate of 14.5 per 100,000 people. On the other hand, it is estimated that approximately one‐third of the global population are infected with Toxoplasma gondii (T. gondii) parasite. It is widely assumed that microbial pathogens, such as T. gondii, are probably associated with affective and behavioural modulation. The present article aimed to assess the proposed role of toxoplasmosis in raising the risk of suicidal ideation (SI) and suicide attempts (SA) using the available epidemiological data. Seven major electronic databases and the Internet search engine Google were searched for all the studies published between the 1st of January 1950 and 31st of October 2019. The heterogeneity and the risk of bias within and across studies were assessed. Following data extraction, pooled odds ratios (ORs) with 95% confidence interval (CI) across studies were calculated using the random‐effects models. A total number of 9,696 articles were screened and 27 studies were regarded as eligible in our systematic review (SI with five papers and 22 papers on SA). A significant association was detected between antibodies against T. gondii with TA (ORs = 1.57; 95% confidence interval [CI] 1.23–2.00, p = .000). Exploration of the association between T. gondii and SA yielded a positive effect of seropositivity for IgG antibodies but not IgM. Despite the limited number of studies, a statistical association was detected between suicidal behaviours and infection with latent T. gondii. 相似文献
The molecular characterization of local isolates of Toxoplasma
gondii is considered significant so as to assess the homologous
variations between the different loci of various strains of parasites.
Design and setting:
The present communication deals with the molecular cloning and sequence analysis
of the 1158 bp entire open reading frame (ORF) of surface antigen 3 (SAG3) of two
Indian T. gondii isolates (Chennai and Izatnagar) being
maintained as cryostock at the IVRI.
Method:
The surface antigen 3 (SAG3) of two local Indian isolates were cloned and
sequenced before being compared with the available published sequences.
Results:
The sequence comparison analysis revealed 99.9% homology with the standard
published RH strain sequence of T. gondii. The strains were also
compared with other established published sequences and found to be most related
to the P-Br strain and CEP strain (both 99.3%), and least with PRU strain (98.4%).
However, the two Indian isolates had 100% homology between them.
Conclusion:
Finally, it was concluded that the Indian isolates were closer to the RH strain
than to the P-Br strain (Brazilian strain), the CEP strain and the PRU strains
(USA), with respect to nucleotide homology. The two Indian isolates used in the
present study are known to vary between themselves, as far as homologies related
to other genes are concerned, but they were found to be 100% homologous as far as
SAG3 locus is concerned. This could be attributed to the fact that this SAG3 might
be a conserved locus and thereby, further detailed studies are thereby warranted
to exploit the use of this particular molecule in diagnostics and
immunoprophylactics. The findings are important from the point of view of
molecular phylogeny. 相似文献
Bipolar disorder (BD) is frequently associated with immune dysfunctions. Studying the genetic diversity of the immuno-modulatory human leukocyte antigen (HLA)-G locus in a French BD cohort, we previously reported an association between a functionally relevant 14 bp Ins/Del polymorphism and BD risk. The present study investigated the genetic and expression diversities of HLA-G in a geographically distinct South Indian population-group BD patients, as well as the influence of exposure to the neurotropic Toxoplasma gondii pathogen. Three functionally relevant HLA-G polymorphisms, i.e. HLA-G 14 bp Ins/Del (rs66554220), +3142G>C (rs1063320) and +3187A>G (rs9380142) were genotyped by polymerase chain reaction (PCR) and real-time PCR. Sub-samples of BD patients and healthy controls (HC) were investigated for plasma levels of soluble HLA-G (sHLA-G) isoforms, as well as circulating stigma of T. gondii infection.
Findings indicate: (i) the frequency of the HLA-G 14 bp Del/Del genotype was higher in BD cases, as compared to HC; (ii) the HLA-G + 3142 C allele and CC genotype were more prevalent in BD patients than in HC; (iii) sHLA-G levels were significantly higher in BD cases, especially in females and in the early onset sub-group; and (iv) the InsGA haplotype was more prevalent in HC.
Our findings further support the genetic contribution of HLA-G to BD risk, as well as indicate relevant expression profiles. Such data may also indicate a potential developmental role in BD etiology, given that HLA-G is an important immune regulator from the intrauterine period and across development. 相似文献
The seroprevalence of Toxoplasma gondii infection in buffaloes, sheep and goats in Yunnan Province, southwestern China was conducted between May 2012 and December 2013.
Methods:
A total of 973 (427 buffaloes, 154 sheep and 392 goats) serum samples were collected from seven administrative regions of Yunnan Province, and examined for T. gondii antibodies by indirect hemagglutination (IHA) test. Some risk factors related to species, age, gender and geographical origin were determined using a multinomial logistic regression.
Results:
The overall seroprevalence of T. gondii in ruminant species was estimated at 11.9%. The final logistic regression model demonstrated that host species and geographical origin were the main risk factors associated with T. gondii infection (P<0.05).
Conclusion:
Taken together, the results of the present study revealed a high exposure to T. gondii in ruminant species in Yunnan Province, which has an important implication for public health. 相似文献