Leishmaniasis affects more than 12 million humans globally and a further 1 billion people are at risk in leishmaniasis endemic areas. The lack of a vaccine for leishmaniasis coupled with the limitations of existing anti-leishmanial therapies prompted this study. Cheminformatic techniques are widely used in screening large libraries of compounds, studying protein-ligand interactions, analysing pharmacokinetic properties, and designing new drug molecules with great speed, accuracy, and precision. This study was undertaken to evaluate the anti-leishmanial potential of some organoselenium compounds by quantitative structure-activity relationship (QSAR) modeling, molecular docking, pharmacokinetic analysis, and molecular dynamic (MD) simulation. The built QSAR model was validated (R²_train = 0.8646, R²_test = 0.8864, Q² = 0.5773) and the predicted inhibitory activity (pIC₅₀) values of the newly designed compounds were higher than that of the template (Compound 6). The new analogues (6a, 6b, and 6c) showed good binding interactions with the target protein (Pyridoxal kinase, PdxK) while also presenting excellent drug-likeness and pharmacokinetic profiles. The results of density functional theory, MD simulation, and molecular mechanics generalized Born surface area (MM/GBSA) analyses suggest the favourability and stability of protein-ligand interactions of the new analogues with PdxK, comparing favourably well with the reference drug (Pentamidine). Conclusively, the newly designed compounds could be synthesized and tested experimentally as potential anti-leishmanial drug molecules.Communicated by Ramaswamy H. Sarma.

T cells in the tumor microenvironment (TME) have diverse roles in anti-tumor immunity, including orchestration of immune responses and anti-tumor cytotoxic attack. However, different T cell subsets may have opposing roles in tumor progression, especially in inflammation-related cancers such as colorectal cancer (CRC). In this study, we phenotypically characterized CD3⁺CD4^- (CD8⁺) T cells in colorectal tumor tissues (TT), normal colon tissues (NT) and in circulation of CRC patients. We investigated the expression levels of key immune checkpoints (ICs) and Treg-related markers in CD8⁺ T cells. Importantly, we investigated associations between different tumor-infiltrating CD8⁺ T cell subpopulations and disease-free survival (DFS) in CRC patients. We found that FoxP3 expression and ICs including PD-1, CTLA-4, TIM-3, and LAG-3 were significantly increased in tumor-infiltrating CD8⁺ T cells compared with NT and peripheral blood. In the TME, we found that TIM-3 expression was significantly increased in patients with early stages and absent lymphovascular invasion (LVI) compared to patients with advanced stages and LVI. Importantly, we report that high levels of certain circulating CD8⁺ T cell subsets (TIM-3-expressing, FoxP3⁻Helios⁻TIM-3⁺ and FoxP3⁻Helios⁺TIM-3⁺ cells) in CRC patients were associated with better DFS. Moreover, in the TME, we report that elevated levels of CD25⁺ and TIM-3⁺ T cells, and FoxP3⁺Helios⁻TIM-3⁺ Tregs were associated with better DFS.

Over twelve million individuals worldwide suffer from leishmaniasis, and an additional billion people are at risk in places where the disease is prevalent. This work was motivated by the lack of vaccination against leishmaniasis and the shortcomings of current anti-leishmanial treatments. Large compound libraries can be screened using computational methods, which can also be used to analyze pharmacokinetic features, explore protein–ligand interactions, and quickly, accurately, and precisely create novel pharmacological entities. Virtual docking screening was performed to assess the multi-protein targeting capability of certain diselenides using four Leishmania protein targets—2XOX, 3SPX, 5ZWY, and 6K91. Following the Lipinski filter's screening of a subset of analogues, density functional theory (DFT), molecular dynamics (MD) simulation analysis, and ADMET profiles were used to profile the lead compounds. The overall average binding affinity of ligands to target proteins is as follows: 3SPX (− 184.998 kcal/mol) > 6K91 (− 180.114 kcal/mol) > 2XOX (− 176.581 kcal/mol) > 5ZWY (− 157.198 kcal/mol). The focus is on ligands that target all investigated proteins with binding scores greater than the average binding scores for the proteins as a whole for which seven compounds were identified that also showed higher MolDock scores than both reference drugs (Miltefosine and Pentamidine). Further screening showed four compounds (4, 7, 25, and 26) passed Lipinski’s test, making them orally bioavailable with excellent ADMET properties that compared well to both reference medications. The DFT analysis and MD simulation results indicate these compounds' favorability, stability, and reactivity in binding to the studied targets, 3SPX and 6K91 with 25_3SPX and 4_6K91 showing the highest binding free energy (MM-GBSA) of − 88.35 kcal/mol and − 90.29 kcal/mol respectively. Conclusively, the chosen diselenides could be developed as prospective anti-leishmanial pharmacological compounds or as useful scaffolds for creating more potent anti-leishmanial drugs.

CD8⁺ T cells play basic roles in the immune system in a tumor microenvironment (TME) to fight cancer. Several reports have suggested signs of the involvement of tumor protein p53 (TP53) in a complex immune system network. Moreover, our previous research indicated that TP53 orchestrates the polarization and infiltration of macrophages into the TME. In the present study, the clinical function of TP53 status (wild/mutant) in CD8⁺ T cell infiltration was assessed using more than 10,000 The Cancer Genome Atlas (TCGA) samples from 30 cancer types through Tumor Immune Estimation (TIMER). Our investigation revealed that CD8⁺ T cell infiltration was higher in head and neck squamous cell carcinoma (HNSC) and uterine corpus endometrial carcinoma (UCEC) patients with wild-type TP53 than in those with mutant TP53. Wild-type TP53 conferred a good prognosis for HNSC and UCEC (P<0.05). In contrast, CD8⁺ T cell infiltration in lung adenocarcinoma (LUAD) patients with wild-type TP53 was much lower than in those with mutant TP53. Notably, clinical outcomes for LUAD with wild-type TP53 were poor (P<0.05). This study was the first to provide insights into the novel association of TP53 with CD8⁺ T cells infiltration in the TME in patients with HNSC, LUAD, and UCEC. Therefore, TP53 status acts as a prognostic marker, and this can be used as a basis to further study the effect of targeting TP53 in these patients. Furthermore, our study found that TP53 status was a reliable predictive factor and therapeutic target in patients with HNSC and UCEC.

Enterobius vermicularis is a threadlike parasite also known as “pinworms”. It is the most common helminth infection, affecting the gastrointestinal tracts of children worldwide, although it seldom causes any fatalities. Enterobius vermicularis infections are usually asymptomatic and may only cause anal pruritis, with occasional reported cases of ectopic migration into the appendix or the female genital tract by adult pinworms. Here, we report a case of a 15-year-old girl who presented to the emergency department with high-grade fever, vomiting, and vague abdominal pain for three days. She was diagnosed with acute abdominal pain and underwent emergency ileocecectomy, but died the following day. Pathological examination of ileocecal junction showed intraluminal and intramural Enterobius vermicularis, which were attributed as the cause of her death in the absence of any other pathologies. Death due to Enterobius vermicularis is rare; this case calls for clinicians to be vigilant in exploring Enterobius vermicularis infections in patients with undiagnosed acute abdominal pain, since it could be a potential cause of death.

In the present study was to determine the anti-inflammatory activity of the aqueous extract of the bark and root of Myrica esculenta and their active phytoconstituents through in vitro and in silico studies. The bioactive phytoconstituent of Myrica esculenta was determined by GC-MS spectroscopy techniques. After that, total phenolic and flavonoid content of both bark and root extract was determined. Furthermore, in vitro anti-inflammatory activity was determined in both extracts. The molecular docking analysis determined the binding affinity of bioactive compounds against inflammatory proteins such as COX-1, COX-2, IL-10, and TNF-α. The present study revealed that bark extract of Myrica esculenta has the highest total phenolic and flavonoid content compared with root extract (553.44 ± 18.38 mg GAE/g equivalent and 336.02 ± 8.04 mg quercetin/g equivalent, respectively). Similarly, the bark extract showed good inhibitory activity with 5-LOX and HYA assay (IC₅₀ 11.26 ± 3.93 and 21.61 ± 8.27 µg/mL, respectively), but 15-Lox inhibitory assay root extract showed the highest inhibitory activity, IC₅₀ 16.95 ± 5.92 µg/mL. The docking result showed that myricetin, arjunolic acid, and myricanone have the highest binding affinity with all inflammatory proteins in respective order: myricetin > arjunolic acid > celecoxib > myricanone > myricitrin > 3-epi-ursonic acid. The MD simulation of COX-1 and myricetin showed the highest stability and low deviation at 310 K through RMSD values (1.07–2.3 Å) as compared with COX-1 and myricitrin (0.193–1.885 Å) and TNF-α and myricanone (1.377 to 3.457 Å), respectively, when analyzed at 100 ns time frame. The extracts and their active constituents showed good anti-inflammatory activity. Further study is essential to define their mechanism of action.