Biology subjects

Xuan, X.

Publications and source records attributed to Xuan, X..

3 recordsLinked to original sources

bioRxiv2024

Efficacy and mechanism of actions of cipargamin as an antibabesial drug candidate

Babesiosis is a disease brought on by intraerythrocytic parasites of the genus Babesia. Current chemotherapies are accompanied by side effects and parasite relapse. Therefore, it is crucial to develop highly effective drugs against Babesia. Cipargamin (CIP) has shown inhibition against apicomplexan parasites, mainly Plasmodium and Toxoplasma. This study evaluated the growth-inhibiting properties of CIP against Babesia spp. and investigated the mechanism of CIP on B. gibsoni. The half inhibitory concentration (IC50) values of CIP against the in vitro growth of B. bovis and B. gibsoni were 20.2 {+/-} 1.4 nM and 69.4 {+/-} 2.2 nM, respectively. CIP significantly inhibited the growth of B. microti and B. rodhaini in vivo. Resistance was conferred by L921V and L921I mutations in BgATP4, which reduced the sensitivity to CIP by 6.1- and 12.8-fold. The inhibitory potency of CIP against BgATP4-associated ATPase activity was moderately reduced in mutant strains, with a 1.3-fold and 2.4-fold decrease in BgATP4L921V and BgATP4L921I, respectively, compared to that of BgATP4WT. An in silico investigation revealed reductions in affinity for CIP binding to BgATP4L921V and BgATP4L921I compared to BgATP4WT. Resistant strains showed no significant cross-resistance to atovaquone (ATO) or tafenoquine succinate (TQ), with less than a onefold change in IC50 values. Combining CIP with TQ effectively eliminated B. microti infection in SCID mice with no relapse, and parasite DNA was not detected by qPCR within 90 days post-infection. Our findings reveal the efficacy of CIP as an anti-babesial agent, its limitations as a monotherapy due to resistance development, and the potential of combination therapy with TQ to overcome said resistance and achieve complete parasite clearance.

microbiology↗

bioRxiv2019

The relative transmissibility of shigellosis among male and female individuals in Hubei Province, China: a modelling study

ObjectiveShigellosis has been a heavy burden in China. However, its relative transmissibility in male and female individuals remains unclear.\n\nMethodA sex-based Susceptible-Exposed-Infectious/Asymptomatic-Recovered (SEIAR) model was applied to explore the dataset of reported shigellosis cases built by Hubei Province from 2005 to 2017. Two indicators, secondary attack rate (SAR) and relative ratio of SAR between males and females, were developed to assess the relative transmissibility in males and females.\n\nResultsThe number of cases and reported incidences in males and females demonstrated a significant decreasing trend (Male trend:{chi} 2 = 11.268, P = 0.001, Female trend:{chi} 2 = 11.144, P = 0.001). SEIAR model had a great fitting effect with the data of shigellosis (P < 0.001). Our simulation revealed that, when parameter {beta}fm = 0, the greatest decrease in cases were obtained for different genders. The median value for SARmm was 2.3225 x 10-8 (Range: 1.7574 x 10-8 - 3.8565 x 10-8), SARmf was 2.5729 x 10-8 (Range: 1.3772 x 10-8 - 3.2773 x 10-8), SARfm was 2.7630 x 10-8 (Range: 1.8387 x 10-8 - 4.2638 x 10-8) and SARff was 2.1061 x 10-8 (Range: 1.0201 x 10-8 - 3.2140 x 10-8). The median value of relative ratio calculated by SAR in mm versus (vs) mf was 0.93 (Range: 0.75 - 1.47), mm vs fm was 0.90 (Range: 0.41 - 1.81), mm vs ff was 1.07 (Range: 0.55 - 2.93), mf vs fm was 0.99 (Range: 0.32 - 1.25), mf vs ff was 1.17 (Range: 0.43 - 3.21) and ff vs fm was 0.75 (Range: 0.35 - 1.06).\n\nConclusionTransmissibility of shigellosis is different among male and female individuals. Shigellosis seems to be more transmissible in males than in females.\n\nAuthor summaryShigellosis, also known as bacillary dysentery, is an infectious disease caused by the genus Shigella spp. Developing countries have high disease burden of shigellosis. However, its relative transmissibility in male and female individuals remains unclear. In this study, we employed a mathematical model to explore the dataset of reported shigellosis cases built by Hubei Province, China from 2005 to 2017. Two indicators, secondary attack rate (SAR) and relative ratio of SAR between males and females, were developed to assess the relative transmissibility in males and females. We found that shigellosis has medium transmissibility among male and female individuals. The disease seems to be more transmissible in males than in females.

epidemiology↗

bioRxiv2019

Inhibition of RNA Polymerase I Transcription Activates Targeted DNA Damage Response and Enhances the Efficacy of PARP Inhibitors in High-Grade Serous Ovarian Cancer

High-grade serous ovarian cancer (HGSOC) accounts for the majority of ovarian cancer and has a dismal prognosis. PARP inhibitors (PARPi) have revolutionized disease management of patients with homologous recombination (HR) DNA repair-deficient HGSOC. However, acquired resistance to PARPi by complex mechanisms including HR restoration and stabilisation of replication forks is a major challenge in the clinic. Here, we demonstrate CX-5461, an inhibitor of RNA polymerase I transcription of ribosomal RNA genes (rDNA), induces replication stress at rDNA leading to activation of DNA damage response and DNA damage involving MRE11-dependent degradation of replication forks. CX-5461 cooperates with PARPi in exacerbating DNA damage and enhances synthetic lethal interactions of PARPi with HR deficiency in HGSOC-patient-derived xenograft (PDX) in vivo. We demonstrate CX-5461 has a different sensitivity spectrum to PARPi and destabilises replication forks irrespective of HR pathway status, overcoming two well-known mechanisms of resistance to PARPi. Importantly, CX-5461 exhibits single agent efficacy in PARPi-resistant HGSOC-PDX. Further, we identify CX-5461-sensitivity gene expression signatures in primary and relapsed HGSOC. Therefore, CX-5461 is a promising therapy alone and in combination therapy with PARPi in HR-deficient HGSOC. CX-5461 is also an exciting treatment option for patients with relapsed HGSOC tumors that have poor clinical outcome.

cancer biology↗