Apoptosis-like cell death in Leishmania donovani treated with KalsomeTM10, a new liposomal amphotericin B

The present study aimed to elucidate the cell death mechanism in Leishmania donovani upon treatment with KalsomeTM10, a new liposomal amphotericin B. Methodology/Principal findings We studied morphological alterations in promastigotes through phase contrast and scanning electron microscopy. Phosphatidylserine (PS) exposure, loss of mitochondrial membrane potential and disruption of mitochondrial integrity was determined by flow cytometry using annexinV-FITC, JC-1 and mitotraker, respectively. For analysing oxidative stress, generation of H2O2 (bioluminescence kit) and mitochondrial superoxide O2 − (mitosox) were measured. DNA fragmentation was evaluated using terminal deoxyribonucleotidyl transferase mediated dUTP nick-end labelling (TUNEL) and DNA laddering assay. We found that KalsomeTM10 is more effective then Ambisome against the promastigote as well as intracellular amastigote forms. The mechanistic study showed that KalsomeTM10 induced several morphological alterations in promastigotes typical of apoptosis. KalsomeTM10 treatment showed a dose- and time-dependent exposure of PS in promastigotes. Further,study on mitochondrial pathway revealed loss of mitochondrial membrane potential as well as disruption in mitochondrial integrity with depletion of intracellular pool of ATP. KalsomeTM10 treated promastigotes showed increased ROS production, diminished GSH levels and increased caspase-like activity. DNA fragmentation and cell cycle arrest was observed in KalsomeTM10 treated promastigotes. Apoptotic DNA fragmentation was also observed in KalsomeTM10 treated intracellular amastigotes. KalsomeTM10 induced generation of ROS and nitric oxide leads to the killing of the intracellular parasites. Moreover, endocytosis is indispensable for KalsomeTM10 mediated anti-leishmanial effect in host macrophag

MSDM Berbasis Kinerja : Membangun Organisasi Unggul

Buku MSDM Berbasis Kinerja: Membangun Organisasi Unggul adalah panduan komprehensif untuk memahami dan menerapkan manajemen sumber daya manusia yang berfokus pada kinerja sebagai kunci keberhasilan organisasi. Buku ini menggali strategi untuk mengintegrasikan tujuan individu dan organisasi, menciptakan sinergi yang menghasilkan produktivitas tinggi. Melalui pendekatan berbasis data, pembaca diajak untuk mengenal pentingnya pengukuran kinerja yang objektif, pemberian umpan balik yang konstruktif, serta pengelolaan talenta yang efektif. Selain itu, buku ini mengupas berbagai metode untuk membangun budaya kerja yang mendukung inovasi, kolaborasi, dan pencapaian target secara konsisten. Dengan contoh kasus nyata dan panduan praktis, buku ini membantu para manajer, pemimpin, dan praktisi MSDM memahami bagaimana menerapkan kebijakan dan sistem berbasis kinerja dalam konteks beragam industri. Pembahasan tentang teknologi, seperti analitik SDM dan alat digital, memperkaya wawasan pembaca dalam menghadapi tantangan era digital. MSDM Berbasis Kinerja adalah panduan strategis yang relevan untuk setiap organisasi yang ingin mengoptimalkan potensi sumber daya manusianya demi mencapai keunggulan kompetitif di pasar global

Synthesis, anti-inflammatory, analgesic, COX1/2-inhibitory activity, and molecular docking studies of hybrid pyrazole analogues

Md Jahangir Alam,1 Ozair Alam,1 Suroor Ahmad Khan,1 Mohd Javed Naim,1 Mohammad Islamuddin,2 Girdhar Singh Deora3 1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, 2Parasite Immunology Laboratory, Department of Biotechnology, Faculty of Science, Jamia Hamdard, New Delhi, 3Institute of Life Sciences, University of Hyderabad, Hyderabad, India Abstract: This article reports on the design, synthesis, and pharmacological activity of a new series of hybrid pyrazole analogues: 5a–5u. Among the series 5a–5u, the compounds 5u and 5s exhibited potent anti-inflammatory activity of 80.63% and 78.09% and inhibition of 80.87% and 76.56% compared with the standard drug ibuprofen, which showed 81.32% and 79.23% inhibition after 3 and 4 hours, respectively. On the basis of in vivo studies, 12 compounds were selected for assessment of their in vitro inhibitory action against COX1/2 and TNFα. The compounds 5u and 5s showed high COX2-inhibitory activity, with half-maximal inhibitory concentrations of 1.79 and 2.51 µM and selectivity index values of 72.73 and 65.75, respectively, comparable to celecoxib (selectivity index =78.06). These selected compounds were also tested for TNFα, cytotoxicity, and ulcerogenicity. Docking studies were also carried out to determine possible interactions of the potent compounds (5u and 5s), which also showed high docking scores of -12.907 and -12.24 compared to celecoxib, with a -9.924 docking score. These selective COX2 inhibitors were docked into the active site of COX2, and showed the same orientation and binding mode to that of celecoxib (selective COX2 inhibitor). Docking studies also showed that the SO2NH2 of 5u and 5s is inserted deep inside the selective pocket of the COX2-active site and formed a hydrogen-bond interaction with His90, Arg513, Phe518, Ser353, Gln192, and Ile517, which was further validated by superimposed docked pose with celecoxib. Keywords: anti-inflammatory activity, analgesic activity, selective COX2 inhibition, TNFα inhibition, molecular docking studies, pyrazole&nbsp