Induction of liver-resident memory T cells and protection at liver-stage malaria by mRNA-containing lipid nanoparticles.

Recent studies have suggested that CD8+ liver-resident memory T (TRM) cells are crucial in the protection against liver-stage malaria. We used liver-directed mRNA-containing lipid nanoparticles (mRNA-LNPs) to induce liver TRM cells in a murine model. Single-dose intravenous injections of ovalbumin mRNA-LNPs effectively induced antigen-specific cytotoxic T lymphocytes in a dose-dependent manner in the liver on day 7. TRM cells (CD8+ CD44hi CD62Llo CD69+ KLRG1-) were induced 5 weeks after immunization. To examine the protective efficacy, mice were intramuscularly immunized with two doses of circumsporozoite protein mRNA-LNPs at 3-week intervals and challenged with sporozoites of Plasmodium berghei ANKA. Sterile immunity was observed in some of the mice, and the other mice showed a delay in blood-stage development when compared with the control mice. mRNA-LNPs therefore induce memory CD8+ T cells that can protect against sporozoites during liver-stage malaria and may provide a basis for vaccines against the disease.

Challenges Based on Antiplasmodial and Antiviral Activities of 7-Chloro-4-aminoquinoline Derivatives.

We report the structural functionalization of the terminal amino group of N1 -(7-chloroquinolin-4-yl) butane-1,4-diamine, leading to a series of 7-chloro-4-aminoquinoline derivatives, and their evaluation as potent anti-malarial and anti-viral agents. Some compounds exhibited promising anti-malarial effects against the Plasmodium falciparum 3D7 (chloroquine-sensitive) and Dd2 (chloroquine-resistant) strains. In addition, these compounds were assayed in vitro against influenza A virus (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Compound 5 h, bearing an N-mesityl thiourea group, displayed pronounced anti-infectious effects against malaria, IAV, and SARS-CoV-2. These results provide new insights into drug discovery for the prevention or treatment of malaria and virus co-infection.

Efficacy and Safety of Metformin Versus the Other Oral Antidiabetic Drugs in Japanese Type 2 Diabetes Patients: A Network Meta-analysis.

INTRODUCTION: Although metformin is recommended as a first-line treatment for patients with type 2 diabetes (T2D) in Western countries, no specific treatment is recommended in Japan, and various agents are used. Metformin has long been used at low doses in Japan, and information regarding its effect at the maximum maintenance dose is lacking. Here, we compared the efficacy and safety of metformin at 1500 mg/day with those of the other oral anti-diabetic drugs (OADs) approved in Japan. METHODS: Randomized controlled trials comparing a change in hemoglobin A1c (HbA1c) from baseline at 12 weeks or later (ΔHbA1c) among OADs (including placebo) as a first-line treatment in adult patients with T2D were selected by systematic review with comprehensive searching of CENTRAL, MEDLINE, Ichushi Web, and EMBASE and manual searching of clinical trial registries. The ΔHbA1c and incidence of hypoglycemia were compared among OAD treatments using Bayesian network meta-analysis (NMA). The relative risk (RR) of the incidence of hypoglycemia was determined relative to that of placebo. RESULTS: Forty-six randomized controlled trials were identified in the systematic review, and 37 studies, comprising 38 different types of treatments, including placebos, were selected for the NMA of ΔHbA1c. Compared with metformin 1500 mg/day, 20 OAD treatments were significantly less effective in reducing HbA1c from baseline (differences from metformin 1500 mg/day: 0.40-0.96%). Two treatments (glimepiride 2 mg/day and pioglitazone 45 mg/day) showed greater mean reductions in HbA1c from baseline than metformin 1500 mg/day (- 0.38% and - 0.03%), although these differences were not significant. Regarding the incidence of hypoglycemia, only pioglitazone 30 mg/day among 31 treatments showed a lower RR (< - 0.01), whereas 23 treatments showed a significantly higher RR (1.02-66.71) than metformin 1500 mg/day. CONCLUSION: The NMA suggested a preferable efficacy and safety profile of metformin 1500 mg/day compared with the other OADs approved in Japan.

Phenylpropanoid-conjugated iridoid glucosides from leaves of Morinda morindoides.

Three phenylpropanoid-conjugated iridoid glucosides, acetylgaertneric acid (1), acetyldehydrogaertneroside (2), and dehydrogaertneric acid (10), together with nine known related iridoid glucosides (3-9, 11, and 12), two coumaroyl alkaloids, one benzenoid, and three flavonoid glucosides were isolated from leaves of Morinda morindoides (Rubiaceae). Structures of these isolated compounds were determined using spectroscopic analysis. Compounds 1-18 and previously isolated compounds (19-29) were evaluated for anti-trypanosomal activity against Trypanosoma cruzi Tulahuen strain (trypomastigote and amastigote) together with cytotoxicity against host cells, new-born mouse heart cells. Among them, molucidin (21) and prismatomerin (22) exhibited good anti-trypanosomal activity (IC50 of 4.67 and 5.70 µM, respectively), together with cytotoxicity (CC50 of 2.76 and 3.22 µM, respectively). Compounds 1-18 did not show anti-malarial activity against a chloroquine/mefloquine-sensitive strain of Plasmodium falciparum.

Phenylpropanoid conjugated iridoids with anti-malarial activity from the leaves of Morinda morindoides.

Two phenylpropanoid-conjugated iridoids, deglucosyl gaertneroside (1) and morindoidin (2), were isolated from the leaves of Morinda morindoides (Rubiaceae) by activity-guided fractionation using an anti-malarial activity assay. The known related iridoids molucidin (3) and prismatomerin (4), two lignans, abscisic acid, two megastigmanes, and two flavonol glycosides were also identified. The structures of isolated compounds were elucidated using spectroscopic analysis. The isolated compounds were evaluated for anti-malarial activity against the chloroquine/mefloquine-sensitive strains of Plasmodium falciparum together with cytotoxicity against adult mouse brain cells. Potent anti-malarial activity of 3 and 4 (IC50 of 0.96 and 0.80 µM, CC50 of 1.02 and 0.88 µM, and SI of 1.06 and 1.10, respectively) was shown, while new iridoids 1 and 2 and pinoresinol (5) displayed moderate activity (IC50 of 40.9, 20.6, and 24.2 µM) without cytotoxicity (CC50 > 50 µM). These results indicate that 1-5 may be promising lead compounds for anti-malarial drugs. In addition, our results imply the necessity of the quality control of the extract of M. morindoides leaves based on the contents of 1-5 in terms of the safety and efficacy.