Artemisone effective against murine cerebral malaria

<p>Abstract</p> <p>Background</p> <p>Artemisinins are the newest class of drug approved for malaria treatment. Due to their unique mechanism of action, rapid effect on Plasmodium, and high efficacy in vivo, artemisinins have become essential components of malaria treatment. Administration of artemisinin derivatives in combination with other anti-plasmodials has become the first-line treatment for uncomplicated falciparum malaria. However, their efficiency in cases of cerebral malaria (CM) remains to be determined.</p> <p>Methods</p> <p>The efficacy of several artemisinin derivatives for treatment of experimental CM was evaluated in ICR or C57BL/6 mice infected by <it>Plasmodium berghei </it>ANKA. Both mouse strains serve as murine models for CM.</p> <p>Results</p> <p>Artemisone was the most efficient drug tested, and could prevent death even when administered at relatively late stages of cerebral pathogenesis. No parasite resistance to artemisone was detected in recrudescence. Co-administration of artemisone together with chloroquine was more effective than monotherapy with either drug, and led to complete cure. Artemiside was even more effective than artemisone, but this substance has yet to be submitted to preclinical toxicological evaluation.</p> <p>Conclusions</p> <p>Altogether, the results support the use of artemisone for combined therapy of CM.</p

Association between duration of gonadotrophin-releasing hormone agonist use and cardiovascular risks: A population-based competing-risk analysis

Background Although androgen deprivation therapy has known cardiovascular risks, it is unclear if its duration is related to cardiovascular risks. This study thus aimed to investigate the associations between gonadotrophin-releasing hormone (GnRH) agonist use duration and cardiovascular risks. Methods This retrospective cohort study included adult patients with prostate cancer receiving GnRH agonists in Hong Kong during 1999–2021. Patients who switched to GnRH antagonists, underwent bilateral orchidectomy, had <6 months of GnRH agonist, prior myocardial infarction (MI), or prior stroke was excluded. All patients were followed up until September 2021 for a composite endpoint of MI and stroke. Multivariable competing-risk regression using the Fine-Gray subdistribution model was used, with mortality from any cause as the competing event. Results In total, 4038 patients were analyzed (median age 74.9 years old, interquartile range (IQR) 68.7–80.8 years old). Over a median follow-up of 4.1 years (IQR 2.1–7.5 years), longer GnRH agonists use was associated with higher risk of the endpoint (sub-hazard ratio per year 1.04 [1.01–1.06], p = 0.001), with those using GnRH agonists for ≥2 years having an estimated 23% increase in the sub-hazard of the endpoint (sub-hazard ratio 1.23 [1.04–1.46], p = 0.017). Conclusion Longer GnRH agonist use may be associated with greater cardiovascular risks

Evaluation of hazardous airborne carbonyls in five urban roadside dwellings: A comprehensive indoor air assessment in Sri Lanka

Indoor hazardous airborne carbonyls were quantified in five natural-ventilated roadside dwellings in Colombo, Sri Lanka. The total concentrations of all targeted carbonyls ranged from 13.6 to 18.6 mu g/m(3). Formaldehyde (C1) was the most abundant carbonyl, followed by acetaldehyde (C2) and acetone (C3K). The concentrations of C1 and C2 ranged from 3.3 to 8.5 mu g/m(3) and 2.3 to 4.4 mu g/m(3), respectively, which accounted for 23 to 42% and 18 to 26% respectively, to the total quantified carbonyls. The highest carbonyls levels were obtained in the dwelling located in an urban district with a mixture of industrial, commercial and residential areas. Much lower concentrations of carbonyls were measured in a light local traffic value was counted. Moderate correlations between individual combustion markers from vehicular emissions suggest the strong impacts from traffics to the indoor airs. The concentrations of C1 and C2 were compared with international indoor guidelines established by different authorities. A health assessment was conducted by estimation of inhalation cancer risk, implementing the inhalation unit risk values provided by Integrated Risk Information System (IRIS), associated with C1 and C2, which were 6.2 x 10(-5) and 7.7 x 10(-6), respectively. Even though the risks did not reach the action level (1 x 10(-4)), their health impact should not be overlooked. This kick-off indoor monitoring study provides valuable scientific data to the environmental science community since only limit data is available in Sri Lanka

Uncoupling Protein-4 (UCP4) Increases ATP Supply by Interacting with Mitochondrial Complex II in Neuroblastoma Cells

Mitochondrial uncoupling protein-4 (UCP4) protects against Complex I deficiency as induced by 1-methyl-4-phenylpyridinium (MPP+), but how UCP4 affects mitochondrial function is unclear. Here we investigated how UCP4 affects mitochondrial bioenergetics in SH-SY5Y cells. Cells stably overexpressing UCP4 exhibited higher oxygen consumption (10.1%, p<0.01), with 20% greater proton leak than vector controls (p<0.01). Increased ATP supply was observed in UCP4-overexpressing cells compared to controls (p<0.05). Although state 4 and state 3 respiration rates of UCP4-overexpressing and control cells were similar, Complex II activity in UCP4-overexpressing cells was 30% higher (p<0.05), associated with protein binding between UCP4 and Complex II, but not that of either Complex I or IV. Mitochondrial ADP consumption by succinate-induced respiration was 26% higher in UCP4-overexpressing cells, with 20% higher ADP:O ratio (p<0.05). ADP/ATP exchange rate was not altered by UCP4 overexpression, as shown by unchanged mitochondrial ADP uptake activity. UCP4 overexpression retained normal mitochondrial morphology in situ, with similar mitochondrial membrane potential compared to controls. Our findings elucidate how UCP4 overexpression increases ATP synthesis by specifically interacting with Complex II. This highlights a unique role of UCP4 as a potential regulatory target to modulate mitochondrial Complex II and ATP output in preserving existing neurons against energy crisis

Association between duration of gonadotrophin‐releasing hormone agonist use and cardiovascular risks: A population‐based competing‐risk analysis

Background Although androgen deprivation therapy has known cardiovascular risks, it is unclear if its duration is related to cardiovascular risks. This study thus aimed to investigate the associations between gonadotrophin-releasing hormone (GnRH) agonist use duration and cardiovascular risks. Methods This retrospective cohort study included adult patients with prostate cancer receiving GnRH agonists in Hong Kong during 1999–2021. Patients who switched to GnRH antagonists, underwent bilateral orchidectomy, had <6 months of GnRH agonist, prior myocardial infarction (MI), or prior stroke was excluded. All patients were followed up until September 2021 for a composite endpoint of MI and stroke. Multivariable competing-risk regression using the Fine-Gray subdistribution model was used, with mortality from any cause as the competing event. Results In total, 4038 patients were analyzed (median age 74.9 years old, interquartile range (IQR) 68.7–80.8 years old). Over a median follow-up of 4.1 years (IQR 2.1–7.5 years), longer GnRH agonists use was associated with higher risk of the endpoint (sub-hazard ratio per year 1.04 [1.01–1.06], p = 0.001), with those using GnRH agonists for ≥2 years having an estimated 23% increase in the sub-hazard of the endpoint (sub-hazard ratio 1.23 [1.04–1.46], p = 0.017). Conclusion Longer GnRH agonist use may be associated with greater cardiovascular risks

A Comparison Between Chinese Children Infected with Coronavirus Disease-2019 and with Severe Acute Respiratory Syndrome 2003

OBJECTIVES: To compare the clinical and laboratory features of severe acute respiratory syndrome 2003 (SARS) and coronavirus disease 2019 (COVID-19) in two Chinese pediatric cohorts, given that the causative pathogens and are biologically similar. , STUDY DESIGN: This is a cross-sectional study reviewing paediatric patients with SARS (n = 43) and COVID-19 (n=244) who were admitted to the Princess Margaret Hospital in Hong Kong and Wuhan Children's Hospital in Wuhan, respectively. Demographics, hospital length of stay, clinical and laboratory features were compared RESULTS: Overall, 97.7% of patients with SARS and 85.2% of patients with COVID-19 had epidemiological associations with known cases. Significantly more patients with SARS developed fever, chills, myalgia, malaise, coryza, sore throat, sputum production, nausea, headache, and dizziness than patients COVID-19. No SARS patients were asymptomatic at the time of admission. 29.1% and 20.9% COVID-19 patients were asymptomatic on admission and throughout their hospital stay, respectively. More SARS patients required oxygen supplementation than COVID-19 patients (18.6 vs. 4.7%, P = 004). Only 1.6% COVID-19 and 2.3% SARS patients required mechanical ventilation. Leukopenia (37.2% vs. 18.6%, p=0.008), lymphopenia (95.4% versus 32.6%, p<0.01), and thrombocytopenia (41.9% vs 3.8%, p<0.001) were significantly more common in SARS than COVID-19 patients. The duration between positive and negative nasopharyngeal aspirate and the length in hospital stay were similar in COVID-19 patients regardless of whether they were asymptomatic or symptomatic, suggesting a similar duration of viral shedding. CONCLUSIONS: Children with COVID-19 were less symptomatic and had more favorable hematological findings than children with SARS

Embryonic Lethality in Mice Lacking the Nuclear Factor of Activated T Cells 5 Protein Due to Impaired Cardiac Development and Function

Nuclear factor of activated T cells 5 protein (NFAT5) is thought to be important for cellular adaptation to osmotic stress by regulating the transcription of genes responsible for the synthesis or transport of organic osmolytes. It is also thought to play a role in immune function, myogenesis and cancer invasion. To better understand the function of NFAT5, we developed NFAT5 gene knockout mice. Homozygous NFAT5 null (NFAT5−/−) mouse embryos failed to develop normally and died after 14.5 days of embryonic development (E14.5). The embryos showed peripheral edema, and abnormal heart development as indicated by thinner ventricular wall and reduced cell density at the compact and trabecular areas of myocardium. This is associated with reduced level of proliferating cell nuclear antigen and increased caspase-3 in these tissues. Cardiomyocytes from E14.5 NFAT5−/− embryos showed a significant reduction of beating rate and abnormal Ca2+ signaling profile as a consequence of reduced sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) and ryanodine receptor (RyR) expressions. Expression of NFAT5 target genes, such as HSP 70 and SMIT were reduced in NFAT5−/− cardiomyocytes. Our findings demonstrated an essential role of NFAT5 in cardiac development and Ca2+ signaling. Cardiac failure is most likely responsible for the peripheral edema and death of NFAT5−/− embryos at E14.5 days

Smc5/6 coordinates formation and resolution of joint molecules with chromosome morphology to ensure meiotic divisions

During meiosis, Structural Maintenance of Chromosome (SMC) complexes underpin two fundamental features of meiosis: homologous recombination and chromosome segregation. While meiotic functions of the cohesin and condensin complexes have been delineated, the role of the third SMC complex, Smc5/6, remains enigmatic. Here we identify specific, essential meiotic functions for the Smc5/6 complex in homologous recombination and the regulation of cohesin. We show that Smc5/6 is enriched at centromeres and cohesin-association sites where it regulates sister-chromatid cohesion and the timely removal of cohesin from chromosomal arms, respectively. Smc5/6 also localizes to recombination hotspots, where it promotes normal formation and resolution of a subset of joint-molecule intermediates. In this regard, Smc5/6 functions independently of the major crossover pathway defined by the MutLγ complex. Furthermore, we show that Smc5/6 is required for stable chromosomal localization of the XPF-family endonuclease, Mus81-Mms4Eme1. Our data suggest that the Smc5/6 complex is required for specific recombination and chromosomal processes throughout meiosis and that in its absence, attempts at cell division with unresolved joint molecules and residual cohesin lead to severe recombination-induced meiotic catastroph

Mitochondrial Uncoupling Protein-2 (UCP2) Mediates Leptin Protection Against MPP+ Toxicity in Neuronal Cells

Mitochondrial dysfunction is involved in the pathogenesis of neurodegenerative diseases, including Parkinson’s disease (PD). Uncoupling proteins (UCPs) delink ATP production from biofuel oxidation in mitochondria to reduce oxidative stress. UCP2 is expressed in brain, and has neuroprotective effects under various toxic insults. We observed induction of UCP2 expression by leptin in neuronal cultures, and hypothesize that leptin may preserve neuronal survival via UCP2. We showed that leptin preserved cell survival in neuronal SH-SY5Y cells against MPP+ toxicity (widely used in experimental Parkinsonian models) by maintaining ATP levels and mitochondrial membrane potential (MMP); these effects were accompanied by increased UCP2 expression. Leptin had no effect in modulating reactive oxygen species levels. Stable knockdown of UCP2 expression reduced ATP levels, and abolished leptin protection against MPP+-induced mitochondrial depolarization, ATP deficiency, and cell death, indicating that UCP2 is critical in mediating these neuroprotective effects of leptin against MPP+ toxicity. Interestingly, UCP2 knockdown increased UCP4 expression, but not of UCP5. Our findings show that leptin preserves cell survival by maintaining MMP and ATP levels mediated through UCP2 in MPP+-induced toxicity