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International Journal of Molecular... Mar 2024Cardiomyocyte survival is a critical contributing process of host adaptive responses to cardiovascular diseases (CVD). Cells of the cardiovascular endothelium have...
Cardiomyocyte survival is a critical contributing process of host adaptive responses to cardiovascular diseases (CVD). Cells of the cardiovascular endothelium have recently been reported to promote cardiomyocyte survival through exosome-loading cargos. Sphingosylphosphorylcholine (SPC), an intermediate metabolite of sphingolipids, mediates protection against myocardial infarction (MI). Nevertheless, the mechanism of SPC delivery by vascular endothelial cell (VEC)-derived exosomes (VEC-Exos) remains uncharacterized at the time of this writing. The present study utilized a mice model of ischemia/reperfusion (I/R) to demonstrate that the administration of exosomes via tail vein injection significantly diminished the severity of I/R-induced cardiac damage and prevented apoptosis of cardiomyocytes. Moreover, SPC was here identified as the primary mediator of the observed protective effects of VEC-Exos. In addition, within this investigation, in vitro experiments using cardiomyocytes showed that SPC counteracted myocardial I/R injury by activating the Parkin and nuclear receptor subfamily group A member 2/optineurin (NR4A2/OPTN) pathways, in turn resulting in increased levels of mitophagy within I/R-affected myocardium. The present study highlights the potential therapeutic effects of SPC-rich exosomes secreted by VECs on alleviating I/R-induced apoptosis in cardiomyocytes, thereby providing strong experimental evidence to support the application of SPC as a potential therapeutic target in the prevention and treatment of myocardial infarction.
Topics: Mice; Animals; Myocardial Reperfusion Injury; Mitophagy; Myocytes, Cardiac; Myocardial Infarction; Endothelial Cells; Exosomes; Apoptosis; Phosphorylcholine; Sphingosine
PubMed: 38542280
DOI: 10.3390/ijms25063305 -
Microbiology Spectrum Jun 2024Post-kala-azar dermal leishmaniasis (PKDL) patients are a key source of parasites, hindering the goal of eliminating visceral leishmaniasis (VL). Monitoring treatment...
UNLABELLED
Post-kala-azar dermal leishmaniasis (PKDL) patients are a key source of parasites, hindering the goal of eliminating visceral leishmaniasis (VL). Monitoring treatment response and parasite susceptibility is essential due to increasing drug resistance. We assessed the drug susceptibility of PKDL isolates ( = 18) from pre-miltefosine (MIL) era (1997-2004) with isolates ( = 16) from the post-miltefosine era (2010-2019) and post-miltefosine treatment relapse isolates ( = 5) towards miltefosine and amphotericin B (AmB) at promastigote stage and towards sodium antimony gluconate (SAG) at amastigote stage. PKDL isolates were examined for mutation in gene-encoding AQP1 transporter, C26882T mutation on chromosome 24, and miltefosine-transporter (MT). PKDL isolates from the post-miltefosine era were significantly more susceptible to SAG than SAG-resistant isolates from the pre-miltefosine era ( = 0.0002). There was no significant difference in the susceptibility of parasites to miltefosine between pre- and post-miltefosine era isolates. The susceptibility of PKDL isolates towards AmB remained unchanged between the pre- and post-miltefosine era. However, the post-miltefosine era isolates had a higher IC value towards AmB compared with PKDL relapse isolates. We did not find any association between AQP1 gene sequence variation and susceptibility to SAG, or between miltefosine susceptibility and single nucleotide polymorphisms (SNPs in the MT gene. This study demonstrates that recent isolates of have resumed susceptibility to antimonials . The study also offers significant insights into the intrinsic drug susceptibility of parasites over the past two decades, covering the period before the introduction of miltefosine and after its extensive use.
IMPORTANCE
Post-kala-azar dermal leishmaniasis (PKDL) patients, a key source of parasites, hinder eliminating visceral-leishmaniasis. Assessment of the susceptibility of PKDL isolates to antimony, miltefosine (MIL), and amphotericin-B indicated that recent isolates remain susceptible to antimony, enabling its use with other drugs for treating PKDL.
Topics: Humans; Leishmania donovani; Phosphorylcholine; Leishmaniasis, Visceral; Antiprotozoal Agents; Antimony; Leishmaniasis, Cutaneous; Drug Resistance; Amphotericin B; Parasitic Sensitivity Tests; Antimony Sodium Gluconate; Mutation
PubMed: 38712926
DOI: 10.1128/spectrum.04026-23 -
PLoS Neglected Tropical Diseases Apr 2024Currently available treatment options are mostly effective in achieving long-term cure in visceral leishmaniasis (VL) patients. However, there have been reports of...
BACKGROUND
Currently available treatment options are mostly effective in achieving long-term cure in visceral leishmaniasis (VL) patients. However, there have been reports of recurrence of this illness in both immunosuppressed and immunocompetent patients.
CASE PRESENTATION
We report the first case of recurrent VL relapse in a 19-year-old immunocompetent female with functional hypopituitarism (hypogonadotropic hypogonadism with central hypothyroidism) from Bangladesh, who has been treated three times previously with optimal dosage and duration- liposomal amphotericin B (LAmB) alone and in combination with miltefosine. We treated the patient successfully with a modified treatment regimen of 10 mg/kg body weight LAmB for two consecutive days along with oral miltefosine for seven days as loading dose. For secondary prophylaxis, the patient received 3 mg/kg body weight LAmB along with oral miltefosine for seven days monthly for five doses followed by hormonal replacement. The patient remained relapse free after 12 months of her treatment completion.
CONCLUSION
In the absence of protective vaccines against Leishmania species and standard treatment regimen, this modified treatment regimen could help the management of recurrent relapse cases.
Topics: Female; Humans; Young Adult; Amphotericin B; Antiprotozoal Agents; Bangladesh; Hypopituitarism; Leishmaniasis, Visceral; Phosphorylcholine; Recurrence; Treatment Outcome; Adult
PubMed: 38669211
DOI: 10.1371/journal.pntd.0012134