The emerging paradigm of calcium homeostasis as a new therapeutic target for protozoan parasites.

Calcium channels (CCs), a group of ubiquitously expressed membrane proteins, are involved in many pathophysiological processes of protozoan parasites. Our understanding of CCs in cell signaling, organelle function, cellular homeostasis, and cell cycle control has led to improved insights into their structure and functions. In this article, we discuss CCs characteristics of five major protozoan parasites Plasmodium, Leishmania, Toxoplasma, Trypanosoma, and Cryptosporidium. We provide a comprehensive review of current antiparasitic drugs and the potential of using CCs as new therapeutic targets. Interestingly, previous studies have demonstrated that human CC modulators can kill or sensitize parasites to antiparasitic drugs. Still, none of the parasite CCs, pumps, or transporters has been validated as drug targets. Information for this review draws from extensive data mining of genome sequences, chemical library screenings, and drug design studies. Parasitic resistance to currently approved therapeutics is a serious and emerging threat to both disease control and management efforts. In this article, we suggest that the disruption of calcium homeostasis may be an effective approach to develop new anti-parasite drug candidates and reduce parasite resistance.

Female gender increases risk of stroke and readmission after carotid endarterectomy and carotid artery stenting.

OBJECTIVE: Carotid endarterectomy (CEA) has historically demonstrated a higher rate of perioperative adverse events for female patients. However, recent evidence suggests similar outcomes for CEA between genders. In contrast, fewer studies have examined gender in carotid artery stenting (CAS). Using contemporary data from the American College of Surgeons National Surgical Quality Improvement Program database, we aim to determine if gender impacts differences in postoperative complications in patients who undergo CEA or CAS. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was queried from 2005 to 2017 using Current Procedural Terminology and International Classification of Diseases codes for retrospective review. Patients with carotid intervention (CEA or CAS) were stratified into asymptomatic vs symptomatic cohorts to determine the effect of gender on 30-day postoperative outcomes. Symptomatic patients were defined as those with perioperative transient cerebral ischemic attack or stenosis of carotid artery with cerebral infarction. Descriptive statistics were calculated. Risk-adjusted odds of 30-day postoperative outcomes were calculated using multivariate regression analysis with fixed effects for age, race, and comorbidities. RESULTS: There were 106,568 patients with CEA or CAS (104,412 CEA and 2156 CAS). The average age was 70.9 years, and female patients accounted for 39.9% of the population. For asymptomatic patients that underwent CEA or CAS, female gender was associated with significantly higher rates of cerebrovascular accident (CVA)/stroke (13%; P = .005), readmission (10%; P = .004), bleeding complication (32%; P = .001), and urinary tract infection (54%; P = .001), as well as less infection (26%; P = .001). In the symptomatic cohort, female gender was associated with significantly higher rates of CVA/stroke (32%; P = .034), bleeding complication (203%; P = .001), and urinary tract infection (70%; P = .011), whereas female gender was associated with a lower rate of pneumonia (39%; P = .039). Subset analysis found that, compared with male patients, female patients <75 years old have an increased rate of CVA/stroke (21%; P = .001) and readmission (15%; P < .001), whereas female patients ≥75 years old did not. In asymptomatic and symptomatic patients that underwent CEA, female gender was associated with significantly higher rates of CVA/stroke (13%; P = .006 and 31%; P = .044, respectively), but this finding was not present in patients undergoing CAS. CONCLUSIONS: In patients undergoing carotid intervention, female gender was associated with significantly increased rates of postoperative CVA/stroke in the asymptomatic and symptomatic cohorts as well as readmission in the asymptomatic cohort. Female gender was associated with higher rates of CVA/stroke following CEA, but not CAS. We recommend that randomized control trials ensure adequate representation of female patients to better understand gender-based disparities in carotid intervention.

Repurposing Lansoprazole and Posaconazole to treat leishmaniasis: Integration of in vitro testing, pharmacological corroboration, and mechanisms of action.

Leishmaniasis remains a serious public health problem in many tropical regions of the world. Among neglected tropical diseases, the mortality rate of leishmaniasis is second only to malaria. All currently approved therapeutics have toxic side effects and face rapidly increasing resistance. To identify existing drugs with antileishmanial activity and predict the mechanism of action, we designed a drug-discovery pipeline utilizing both in-silico and in-vitro methods. First, we screened compounds from the Selleckchem Bio-Active Compound Library containing ~1622 FDA-approved drugs and narrowed these down to 96 candidates based on data mining for possible anti-parasitic properties. Next, we completed preliminary in-vitro testing of compounds against Leishmania amastigotes and selected the most promising active compounds, Lansoprazole and Posaconazole. We identified possible Leishmania drug targets of Lansoprazole and Posaconazole using several available servers. Our in-silico screen identified likely Lansoprazole targets as the closely related calcium-transporting ATPases (LdBPK_352080.1, LdBPK_040010.1, and LdBPK_170660.1), and the Posaconazole target as lanosterol 14-alpha-demethylase (LdBPK_111100.1). Further validation showed LdBPK_352080.1 to be the most plausible target based on induced-fit docking followed by long (100ns) MD simulations to confirm the stability of the docked complexes. We present a likely ion channel-based mechanism of action of Lansoprazole against Leishmania calcium-transporting ATPases, which are essential for parasite metabolism and infectivity. The LdBPK_111100.1 interaction with Posaconazole is very similar to the known fungal orthologue. Herein, we present two novel anti-leishmanial agents, Posaconazole and Lansoprazole, already approved by the FDA for different indications and propose plausible mechanisms of action for their antileishmanial activity.

Oseltamivir analogs with potent anti-influenza virus activity.

Influenza A and B viruses cause seasonal worldwide influenza epidemics each winter, and are a major public health concern and cause of morbidity and mortality. A substantial reduction in influenza-related deaths can be attributed to both vaccination and administration of oseltamivir (OS), which is approved for oral administration and inhibits viral neuraminidase (NA), a transmembrane protein. OS carboxylate (OSC), the active form of OS, is formed by the action of endogenous esterase, which targets NA and is shown to significantly reduce influenza-related deaths. However, the development of resistance in various viral variants, including H3N2 and H5N1, has raised concern about the effectiveness of OS. This comprehensive review covers a range of OS analogs shown to be effective against influenza virus, comparing different types of substituent group that contribute to the activity and bioavailability of these compounds.